• Psychedelic Medicine

PHARMACOLOGY | +80 articles

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Dopamine release and duration of action: Predicting the addictive potential of phenethylamines

by Benjamin Malcolm | Spirit Pharmacist | 16 Jan 2021

Phenethylamine (PEA) is both a naturally occurring neurotransmitter and chemical backbone for several other types of medications and neurotransmitters. Legendary psychedelic chemist Alexander Shulgin synthesized dozens of novel psychedelic phenethylamines that he documents in his and his wife’s book PIHKAL (Phenethylamines I have Known and Loved). He is credited with re-synthesizing MDMA as well as inventing designer phenethylamines such as 2CB.​

Types of phenethylamines​

Phenethylamines are much broader than a class of psychedelics and are primarily known as ‘sympathomimetics’ because of their actions on the sympathetic (fight or flight) nervous system. Catecholamine neurotransmitters like norepinephrine and dopamine as well as the hormone epinephrine are the chemical mediators of sympathetic neurotransmission and drugs derived from phenethylamine traditionally used of therapeutic purposes mimic their actions.

Non-psychoactive phenethylamines include bronchodilator medications used for asthma such as albuterol while psychoactive phenethylamines include psychostimulants such as amphetamine, methamphetamine, and cathinones (‘bath salts’). Psychostimulants such as amphetamine act as ‘releasers’ of norepinephrine and dopamine, which stimulate the sympathetic nervous system. It is release of dopamine in the central nervous system that is thought to drive the habituating and addictive potentials of amphetamine. Thus, paying attention to dopamine releasing effect of phenethylamines is an important clue in understanding risk for habituation, re-enforcement, or addiction.

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The psychedelic phenethylamines tend to act as ‘releasers’ of serotonin and be able to bind 5HT2A receptors, although preserve some of the effects of traditional stimulants by acting on norepinephrine or dopamine. They are hybrids between traditional stimulants and psychedelics. The prototype psychedelic phenethylamine is 3,4-methylendioxymethamphetamine (MDMA). MDMA tends to be euphoric and preserve the ego structure. It carries some risks of habituation, dependence, or addiction linked to release of dopamine. MDMA tends to distort sensory perceptions or cause hallucinations much less than classical tryptamine psychedelics (e.g. psilocybin, LSD, DMT). For these reasons one may consider MDMA more of a serotonergic amphetamine than a true psychedelic.​

Comparative pharmacology of amphetamine, MDMA and 4-MMC: Dopamine & duration of action

The degree of effect on dopamine neurotransmission and duration of action appear to help guide understanding of habituation. When comparing phenethylamine psychedelics like MDMA with novel designer phenethylamines, substances with higher release of dopamine and shorter duration of action can tempt the user to frequently re-dose. For example, when comparing the actions of mephedrone (4-methylmethcathinone or 4-MMC) with MDMA it is noted that MDMA has considerably less dopamine release than mephedrone and that mephedrone has dopamine release similar to amphetamine. In addition, mephedrone also has a much shorter half-life than MDMA meaning that pleasurable effects wear off sooner. Frequent re-dosing creates a stacking of physical effects, the risks of behavioral reinforcement and addiction as well as adverse reactions such as cardiovascular events, seizures, or psychosis increases.

None of this is to raise alarm bells about the addictive potential of MDMA or demonize amphetamine and cathinones. On the contrary, if we know traditional stimulants can be therapeutic and know that serotonergic psychedelics can also be therapeutic, drugs that hybridize their effects deserve thorough exploration for therapeutic potentials. The point is that the mechanisms of phenethylamine psychedelics are rather broad and tends to differentially effect serotonin, norepinephrine, and dopamine neurotransmitter systems. Psychedelic actions and effects occur due to release of serotonin and modulation of ‘psychedelic’ 5HT2A receptors while propensity for re-dosing and habituation is linked to duration of action and effects on dopamine. Chemical fingerprinting of psychedelic phenethylamines across neurotransmitter systems and measurement of basic pharmacokinetic parameters may guide harm reduction efforts as drugs with high potential for habituation and re-dosing are identified among the sea of alphabet-amines (phenethylamine psychedelics) available in today’s clandestine marketplaces.

*From the article here :
 
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Finding the Psychedelic Sweet Spot

by Alaina M. Jaster, BS | Psychedelic Science Review | 1 Mar 2021

The relationship between efficacy and potency is a key concept in understanding psychedelic drug pharmacology.

Creating safe drug combinations and investigating the potential therapeutic effects of psychedelics requires an understanding of the relationship between potency and efficacy. This is also known as the “dose-effect relationship.” Sometimes more attention is paid to the effects of drugs than how much is required to give those effects. Also, it can be a delicate balance between potency and efficacy when it comes to formulating effective drugs with few side effects.​

What is drug efficacy?

Drug efficacy is defined as “the degree to which different agonists produce varying responses, even when occupying the same proportion of receptors.” It is commonly expressed in the literature as the “maximum effective dose” or Emax.

Efficacy isn’t just the activation of a receptor by the drug. When a drug binds the receptor or multiple receptors it can produce a complete response, no response, or even a partial response. So, once Emax of a given drug is achieved, giving an increasingly higher dose of the drug will not produce an increase in the magnitude of the effect. This can be thought of as the ceiling of the response.

For example, in the figure below, Drug A shows a higher Emax (effect) than Drug B when occupying the same amount of receptors.​

What is drug potency?

Drug potency is an expression of the activity of a drug, in terms of the concentration or amount needed to produce a defined effect, which is 50% of the maximum efficacy. Potency is therefore commonly expressed as the effective concentration (EC50) or effective dose (ED50).

The 50% maximum efficacy comes from the potency being half of the Emax mentioned above. If an Emax is 100 then the ED50 would be seen at 50; if an Emax is 30 then the ED50 would be 50% of that, or 15. A drug with a lower Emax can still be more potent than a drug with a higher Emax because it takes less of the compound to elicit the same effect.

For example, in the figure below, Drug A and B have equal efficacy but Drug A induces the effect at a lower dose., This means that Drug A is more potent.

The dose-response curve

Taken together, potency and efficacy represent the dose-effect of a compound, most often shown as a dose-response curve. This type of graph is usually created from data that is generated in functional and behavioral assays that test for efficacy and potency.

When analyzing dose-response curves, changes in potency can be inferred by a horizontal shift in the sigmoid curve. A rightward shift is representative of lower potency and a leftward shift is representative of higher potency. Changes in efficacy are inferred by a vertical shift. A downward shift shows lower efficacy and upward shifts indicate higher efficacy.

For example, LSD and psilocin both activate the serotonin 5-HT2A receptor and cause different effects. LSD only requires a very small dose for the user to feel the effects (EC50 = 0.261 µM). In comparison, psilocin is less potent because it takes a higher dose (EC50 = 0.721 µM) to bring on the desired effects. In recreational use, an average LSD dose is between 50-200 µg, whereas an average psilocybin (a prodrug of psilocin) dose is 2-10 grams.

In the graph below there are four compounds, each with a different EC50 and the same Emax. The compound at the far left is the most potent. This illustration is representative of the horizontal shifts in potency that are seen across a wide variety of psychedelic drugs.​

Importance of the dose-effect relationship in psychedelic drug formulations

Psychedelic compounds can have a variety of mix-matched potencies and efficacies. This variability underscores why finding that sweet spot is such a critical step in drug research and development. Other variables like absorption, distribution, metabolism, and drug excretion all play a part in the overall effects of drugs. Determining efficacy and potency helps scientists find doses that are effective but don’t cause unwanted side effects due to high potency. But, the dose-response relationship is just one piece of the puzzle that is essential for discovering potential therapeutic and effective doses of psychedelics.

 
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The psychedelic experience may not be required for psilocybin’s antidepressant-like benefits*

University of Maryland | Neuroscience News | 13 Apr 2021

A mouse study refutes the common belief that psilocybin’s ability to produce an anti-depressant effect is attributed to the psychedelic experience it creates. Blocking the psychedelic effect did not affect psilocybin’s anti-depressant effects.

University of Maryland School of Medicine (UMSOM) researchers have shown that psilocybin–the active chemical in “magic mushrooms”– still works its antidepressant-like actions, at least in mice, even when the psychedelic experience is blocked.

The new findings suggest that psychedelic drugs work in multiple ways in the brain and it may be possible to deliver the fast-acting antidepressant therapeutic benefit without requiring daylong guided therapy sessions.

A version of the drug without, or with less of, the psychedelic effects could loosen restrictions on who could receive the therapy, and lower costs, making the benefits of psilocybin more available to more people in need.

In all clinical trials performed to date, the person treated with psilocybin remains under the care of a guide, who keeps the person calm and reassures them during their daylong experience. This can include hallucinations, altered perception of time and space, and intense emotional and spiritual encounters.

Researchers in the field have long attributed psilocybin’s effectiveness to the intense psychedelic experience.

“We do not understand the mechanisms that underlie the antidepressant actions of psilocybin and the role that the profound psychedelic experience during these sessions plays in the therapeutic benefits,” says Scott Thompson, Ph.D., Professor and Chair, Department of Physiology at UMSOM and senior author of the study.
“The psychedelic experience is incredibly powerful and can be life-changing, but that could be too much for some people.”

Several barriers prevent the wide-spread use of psychedelic compounds. For example, there is fear that the psychedelic experience may promote psychosis in people who are predisposed to severe mental disorders, like bipolar disorder and schizophrenia, so the clinical therapy sessions performed to-date have been limited to a highly selected screened group without a family history of these disorders.

Dr. Thompson adds that there may also be an equity issue because not everyone can take several days off work to prepare and engage in the experience. The costs of staffing a facility with at least one trained guide per treated person per day and a private space may also be prohibitive to all but a few.

He says it is conceivable that a depression treatment derived from psilocybin could be developed without the psychedelic effects so people can take it safely at home without requiring a full day in a care facility.

For their study, led by UMSOM MD/PhD student Natalie Hesselgrave, the team used a mouse model of depression in which mice were stressed for several hours a day over 2-3 weeks. Because researchers cannot measure mouse moods, they measure their ability to work for rewards, such as choosing to drink sugar water over plain water.

People suffering from depression lose the feeling of pleasure for rewarding events. Similarly, stressed mice no longer preferred sugar water over plain water. However, 24 hours after a dose of psilocybin, the stressed mice regained their preference for the sugar water, demonstrating that the drug restored the mice’s pleasure response.

Psilocybin exerts its effects in people by binding to and turning on receptors for the chemical messenger serotonin. One of these receptors, the serotonin 2A receptor, is known to be responsible for the psychedelic response.

To see if the psychedelic effects of psilocybin were needed for the anti-depressive benefits, the researchers treated the stressed mice with psilocybin together with a drug, ketanserin, which binds to the serotonin 2A receptor and keeps it from being turned on. The researchers found that the stressed mice regained their preference for the sugar water in response to psilocybin, even without the activation of the psychedelic receptor.

“These findings show that activation of the receptor causing the psychedelic effect isn’t absolutely required for the antidepressant benefits, at least in mice,” says Dr. Thompson, “but the same experiment needs to be performed in depressed human subjects.” He says his team plans to investigate which of the 13 other serotonin receptors are the ones responsible for the antidepressant actions.

“This new study has interesting implications, and shows that more basic research is needed in animals to reveal the mechanisms for how these drugs work, so that treatments for these devastating disorders can be developed” says Albert Reece, MD, PhD, MBA, Executive Vice President for Medical Affairs, University of Maryland Baltimore, and the John and Akiko Bowers Distinguished Professor and Dean, University of Maryland School of Medicine.

Although not approved yet, Dr. Thompson and the University of Maryland Baltimore have filed a patent on using psilocybin with drugs that block serotonin 2A receptors to treat depression.

*From the article here :

 
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Study suggests beneficial effects of psilocybin are independent of 5-HT2A

Mice experienced antidepressant effects even with the receptor blocked.

by Barbara Bauer, MS | Psychedelic Science Review | 16 Apr 2021

The results of a study published today in the Proceedings of the National Academy of Sciences (PNAS) suggest that activation of the serotonin 5-HT2A receptor (5-HT2AR) may not be the main component in the mechanism of the antidepressant effects of psilocybin. More specifically, the authors propose that altered perceptions (i.e., a psychedelic experience) may not go hand in hand with psilocybin’s antidepressant effects.
How psilocybin exerts its therapeutic actions is not known, but it is widely presumed that these actions require altered consciousness, which is known to be dependent on serotonin 2A receptor (5-HT2AR) activation. This hypothesis has never been tested, however.

Psychedelic Science Review recently published an article summarizing a study by Dr. David Olson, suggesting that the therapeutic effects of psilocybin may occur separately from its subjective effects.

In the PNAS study, a research team led by Dr. Natalie Hesselgrave of the Department of Physiology at the University of Maryland School of Medicine pre-treated mice with the 5-HT2AR blocker (antagonist) compound ketanserin. Using electrophysiology and behavioral tests, including the head twitch response (HTR), the data showed that the mice experienced antidepressant effects from psilocybin even when their 5-HT2ARs were blocked by ketanserin.
Mice with little or no evidence of psilocybin-induced head twitches, indicative of a lack of 5-HT2AR activation, still exhibited a robust psilocybin-induced antianhedonic effect.

In addition, there was another important finding from the study.
We also showed that psilocybin strengthens connections between brain cells in regions important for processing rewards and emotions.

The authors cautioned that the study was conducted using mice, so the final word on whether these results would apply to humans remains to be determined. They also acknowledged the need for additional studies examining the effects over time. “We cannot exclude that 5-HT2AR activation is required for some antidepressant activity at postpsilocybin time points longer than the 24 to 48 h we examined here.”

In addition, Dr. Hesselgrave and her team point to a 2013 study indicating that the serotonin 5-HT1BR may contribute to the antidepressant effects of selective serotonin reuptake inhibitors (SSRIs). From this, they hypothesize that “It is possible that psilocin and novel ibogaine analogs, which both have a high affinity for 5-HT1BRs, exert their beneficial actions through activation of 5-HT1BRs.”

The authors concluded by suggesting how ketanserin could be used in conjunction with psilocybin.

“If 5-HT2AR activation is not necessary, then the combination of psilocybin and a 5-HT2AR antagonist safe for human use, such as ketanserin, offers a potential means to eliminate, attenuate, or shorten the duration of psilocybin-induced alterations of perception while retaining its therapeutic benefits.”

*From the article here :
 
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Psychedelic Science 101: What are Psychedelic Drugs?

A look at some fundamental ideas defining these intriguing compounds.

by Sabrina Eisenberg, MS | Psychedelic Science Review | 20 May 2021

LSD, DMT, psilocybin, ayahuasca, mescaline, and other psychedelic compounds have long drawn attention from the scientific and non-scientific community. Modern technology enables fascination by granting unlimited access to a ceaseless stream of information. Social media accounts publish psychedelic advocacy, anecdotes, and information (albeit, with varying degrees of verification). For some, the content inspires a curiosity about the foundation of psychedelics and how something that sounds so mysterious could be securely rooted in reality.

To give these substances a name that suited their impact, psychiatrist and researcher Humphry Osmond coined the term “psychedelic,” meaning “mind-manifesting,” indicative of their consciousness-changing abilities. Still, psychedelics had other names prior, and other names have been suggested since. The dilemma of landing on a name befitting their function is one consequence of psychedelic’s famous “ineffable” quality; however, the natural human inclination to explain the inexplicable persists.

The definition of any single phenomenon, including the psychedelic experience, varies according to perspective. In explaining what psychedelics are, the following description will encompass both the physiological mechanisms through which they act, as well as the ensuing subjective effects. To begin, the following will present a commentary on cell receptor proteins and then extend to a discussion of one particular family of proteins, the serotonin receptors.

Intercellular communication

Establishing a basic understanding of this communication pathway first entails discussing the most basic functional unit of any organism: the cell. Like employees of a large organization, cells engage in teamwork and communication to perform a variety of functions. Proteins take on versatile roles essential to the communication process. They transport substances into and out of the cell, facilitate cell-to-cell binding, catalyze enzymatic activity, and relay signals.

In signal transduction, when a series of stimuli produce a cellular response, proteins embedded in and on a cell’s surface act as receptors for information from other cells. Complementary-shaped chemical messengers target the distinct “binding sites” of these intricately built proteins, similar to a key and lock.

This is how one cell “receives” signals from other cells. The complementary binding induces a response, such as stimulating the protein to change shape, which then causes various intracellular interactions. The resulting interactions eventually manifest as a cellular response, either excitatory or inhibitory in nature, meaning it either promotes or prevents a response, respectively. The most varied family of cellular proteins, and the one most relevant to this article, is the G-Protein Coupled Receptor (GPCR).

Serotonin receptors

Serotonin is one of many hormones and neurotransmitters that act as signaling molecules. The serotonin receptor is a GPCR that is also known by its common name, 5-hydroxytryptamine or 5-HT. It exists in a range of concentrations throughout the body and causes an assortment of responses in every location; e.g., mood, memory, and appetite. Several subtypes of the 5-HT receptor exist, such as 5-HT2A, 5-HT1A, and 5-HT3. Several receptors have previously been written about on Psychedelic Science Review, but evidence distinguishes the 5-HT2A receptor as a principle to psychedelic pathways.

As mentioned previously, the structure of 5-HT receptors complements the specific structure of serotonin, guiding serotonin’s binding to the target cell, and ensuring the target cell only receives signals from compatible molecules. These safeguards allow for smooth and reliable intercellular communication; however, the expected signal molecule is not always the one inducing a change. The precise interdependence of signal and target has a loophole: when ingested, drugs and substances with similar structures to signaling molecules capitalize on the lock and key dynamic to produce their desired response.

The chemical structure of some psychedelic compounds mimics that of serotonin. They bind to serotonergic receptors, particularly the 5-HT2A receptor, and induce different effects than serotonin. One example is hallucinations but also includes other facets of the psychedelic experience and the resulting subjective effects.
Yet it does not suffice to describe revelatory insight as a mere electrical impulse or an emotion as the squirt of a hormone.

Subjective effects

Depending on the compound and dose, the range of potential hallucinations and acute effects of psychedelics spans the five senses and can transcend physical sensation to include significant cognitive distortions. The intensity and presentation are often unpredictable and vary significantly on a case-by-case basis.

Similarly, while research often propounds transformative or mystical experiences as the source of many long-term positive effects, they are not the be-all and end-all of the psychedelic experience.

For this reason, rather than listing every reaction to psychedelics imaginable, the following will briefly overview some of the effects that one is likely to encounter, sorted by their relation to the senses.

Visual
  • Changes in color, tone, clarity, brightness, and intensity​
  • Distortion of depth perception and morphing/warping of objects​
  • The appearance of diffractions, geometric patterns, and trails moving behind objects (tracers)​
  • External or internal hallucinations (within the mind or projected onto your surroundings)​
Auditory
  • Distortion of noises​
  • Hallucinations with or without a specifically located source (external or internal, respectively)​
Cognitive
  • Changes in the ability to analyze or process information logically​
  • Enhanced introspection and mindfulness​
  • Ego inflation/death​
  • Perception of the interdependence of opposites (life and death; self and other)​
  • Spirituality​
  • Empathy, sociability, euphoria, and humor​
  • Absorption with familiar or mundane objects​
  • Wakefulness​
  • Negative: delirium, sleepiness, mental fatigue, thought loops, dysphoria, panic, depersonalization​
Physical
  • Sensory stimulation​
  • Perception of bodily heaviness or lightness​
  • Negative: altered heart rate, blood pressure, diminished temperature regulation, back pain, dehydration, dry mouth, nausea​
The negative effects listed often occur under the influence of heavy doses of substances of unknown composition, especially to vulnerable populations (i.e. psilocybin can increase blood pressure and is not recommended for individuals with cardiovascular conditions).

Conclusion

In sum, psychedelics are compounds that cause a variety of sensory effects via interaction with the 5-HT2A and other receptors. Receptors are proteins on cell surfaces that, upon binding, change their shape to cause a cascade of intracellular interactions, leading to a cellular response. In the case of psychedelics, these responses appear as some of the subjective effects mentioned in this article, including hallucinations, distortions, and stimulation.

People have differing opinions on what psychedelics are, but their essence becomes clearer from a biochemical and behavioral perspective.

 
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Crystals of the neurotransmitter serotonin. Psychedelic drugs bind to serotonin receptors in the brain.

Non-hallucinogenic psychedelics could aid treatment of depression and PTSD

Scientists in search of psychedelic drug treatments have developed a way to determine whether a molecule is likely to cause hallucinations, without testing it on people or animals.

Growing evidence suggests that psychedelic compounds, which are active in the brain, have potential to treat psychiatric illnesses such as post-traumatic stress disorder (PTSD), but researchers are trying to find out whether there is a way to keep the beneficial properties of these drugs without the hallucinogenic side effects, which can complicate treatment.

It is currently almost impossible to predict whether a potential drug will cause hallucinations before it is tested on animals or people. “That really slows down drug discovery,” says David Olson, a chemical neuroscientist at the University of California, Davis.

To address this, a team led by Olson and neuroscientist Lin Tian, also at Davis, designed a fluorescent sensor to predict whether a molecule is hallucinogenic, based on the structure of a brain receptor targeted by psychedelics. Using their approach, the researchers identified a psychedelic-like molecule without hallucinogenic properties that they later found had antidepressant activity in mice.

The discovery adds “more fuel for the fire” of efforts to make drugs from psychedelic-like molecules without side effects, says Bryan Roth, a molecular pharmacologist at the University of North Carolina School of Medicine in Chapel Hill.

Psychedelic potential

Studies seem to show that some psychedelic drugs can relieve the symptoms of chronic mental illnesses, including addiction, PTSD and severe depression, possibly by helping the brain to create new connections between neurons. Ongoing clinical trials are attempting to use the magic-mushroom compound psilocybin, LSD and MDMA to treat various psychiatric disorders.

But these drugs’ hallucinogenic properties make them difficult to administer, because the recipients require constant supervision, and the hallucinatory effects can be a challenging experience. Some researchers are now looking for psychedelic-like molecules that retain the therapeutic potential without the trippy side effects.

Psychedelic drugs cause hallucinations when they interact with receptors in the brain that normally bind to serotonin, a neurotransmitter that affects mood. "But not all molecules that bind to serotonin receptors cause hallucinations," says Olson. His team’s sensor is based on the structure of a particular serotonin receptor called 5-HT2AR, which changes shape when a molecule binds to it. The degree to which it changes dictates whether hallucinations are produced.

The sensor links the receptor with a green fluorescent protein that lights up with different intensities according to the receptor’s shape. "It acts like a radar for hallucinogenic potential,” says Tian, allowing the researchers to directly interrogate how a molecule binds to 5-HT2AR, and whether that binding causes the receptor to activate.

Molecular screening

The researchers wanted to see whether they could use the sensor to predict a molecule’s hallucinogenic properties. They started by screening a group of 83 compounds with known psychedelic profiles and scoring them according to how much light the sensor emitted when bound. For all compounds, the assay reliably predicted hallucinogenic potential, says Olson.

Then the researchers applied the test to 34 compounds with unknown psychedelic profiles. They identified a molecule called AAZ-A-154 that they predicted could interact with a serotonin receptor without causing hallucinations. Mice given AAZ-A-154 did not exhibit head twitching, which is associated with hallucinations. The molecule also seemed to alleviate symptoms of depression in mice with a genetic mutation that decreases their ability to feel pleasure.

"Although it’s still unclear how AAZ-A-154 might work, the method of its discovery is an “innovative approach” to looking for non-hallucinogenic psychedelics," says Roth.

"The sensor technology is still a long way from decoupling psychedelic medicine from hallucinatory side effects," cautions Robert Malenka, a psychiatrist and neuroscientist at Stanford University in California. "It’s difficult to translate hallucinatory drug effects in mice to those in people, and although the identification of AAZ-A-154 is a good proof of the sensor concept," he said. "The use of this technique in molecular screening needs to be developed further."

doi: https://doi.org/10.1038/d41586-021-01156-y

 
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New psychedelic treats anxiety, depression

by Shamani Joshi | Vice | 15 May 2020

Imagine a psychedelic that promises you’ll never have a bad trip and resets your brain in such a way that you wouldn't have to depend on antidepressants. Vice speaks with a scientist making just that.

Learning about carbon molecules and atomic bonds may not be everyone’s preferred dose. Yet, that’s exactly what it takes to mould the Walter Whites of the world. But contrary to what Breaking Bad will have you believe, the realm of making mind-altering substances isn’t all about dodging bullets, entering into dangerous liaisons, and warding off junkies. Yes, making drugs could involve explosion-prone conical flasks and a shitload of money, but out in the real world, a drug designer is often one chained to long hours in a laboratory, calculatively toying with toxic chemicals to figure out which of its curative properties will stick. Dr Alan P Kozikowski is one of them.

Kozikowski, a US-based veteran drug designer with over 500 publications and 100 patents on his portfolio, is the co-founder of pharmaceutical research companies Actuate Therapeutics as well as HNF-Pharma. An organic chemist who trained himself to become a drug designer under the guidance of skilled scientists like Nobel prize winner EJ Corey, Kozikowski has previously established himself through drugs like Huperzine-A, a medication derived from memory-restoring Chinese herbs that is now used to treat Alzheimer’s patients. He was also part of a American government-funded research team that patented Nocaine, a safer and less addictive analog of cocaine to treat the illegal drug’s withdrawal symptoms. He currently serves as the lead scientist at a lab called Bright Minds Biosciences, where he is leading a team creating a compound similar to a psychedelic, but without the bad trip or downer.

The therapeutic potential of psilocybin, the hallucinogenic compound found in magic mushrooms, has been explored in treating anxiety, depression and post traumatic stress disorder for a few years now. However, while shrooms and LSD continue to be illegal in most places around the world, Kozikowski is currently leading a team of organic chemists and scientists to create the ultimate psychedelic cure for therapeutic purposes. His team at Bright Minds has managed to manufacture a compound that mirrors the hallucinogenic effects of psychedelics, but is relatively less harmful. While this compound is still in its testing phase, and is unlikely to be available for use for the next few years, here we catch up with Kozikowski on what it was like working on the new-and-apparently-improved psychedelic, how they managed to eliminate the bad trip, and how he feels about microdosing.

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Dr Alan Kozikowski

VICE: What gave you the idea to design a psychedelic without the bad trip?

Dr. Alan Kozikowski: It’s because of the lore that surrounds magic mushrooms as well as my long-time interest in how chemicals work on the brain. With any drug, you have to first identify an unmet medical need, a demand in the marketplace for a new drug to cure a disease or condition, in order to be able to get the funding required to create and test it. Large pharmaceutical companies have more or less abandoned research on drugs to treat central nervous system (CNS) disorders simply because they failed to achieve a return on their investment. One of the last blockbuster CNS drugs was Prozac, which was discovered about 48 years ago. Since psychedelics already existed and have been proven to help anxiety and depression when used therapeutically, we felt they had a promising future and wanted to be the ones to design new CNS drugs based largely on psilocybin.

A team of scientists including pharmacologists, organic chemists, behavioural biologists, clinicians and business managers have thus come together with an objective to improve and update a pre-existing drug. Psychedelics have the ability to impact a person’s brain in a positive way, but they also have the disadvantage of targeting certain receptor subtypes that have been linked to heart disease, thus making them potentially dangerous for anyone who takes them habitually.

The active ingredient found in magic mushrooms is psilocybin, which has proven to be an invaluable compound as it has the potential to rewire the brain and improve mental health conditions like anxiety, depression and post-traumatic stress disorder (PTSD) when taken in moderate doses in a controlled setting.

A synthetic version of psilocybin was actually sold by the drug company Sandoz up until 1966, at which point the cultural tide against these psychedelic drugs changed, and the Drug Enforcement Agency listed this as a highly controlled Schedule I drug. Nonetheless, nature has provided us with a very valuable substance, one that structurally resembles the neurotransmitter serotonin itself. The medicinal chemist can thus use this as an inspiration to create something perhaps even better. Like my business head Ian puts it: the first-generation iPhone made in 2007 was a cool creation, but it has been constantly tweaked over the years to give us the seamless experience we’re hooked on to today. This is our attempt to update magic mushrooms psilocybin or LSD so we can work out all their kinks and improve the experience of using them for a good cause.

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An illustrated model of the 5-HT2A receptor found in our brain (in red, green, white), binding with a psilocybin analog (in grey).

So how does one actually design a drug like this?

What I do first is actually look at what is known about psilocybin, how it is made, and what analogues of it have been made previously. We then use a computer and online programs as well as various patent search engines, to find all the pertinent literature, both chemistry and biology, on psilocybin and its analogs. This knowledge is then put into effect by the chemist.

Next, using all of the existing literature data plus molecular modelling studies (in which we see how psilocybin fits into the receptors in the brain it targets), we can begin to “design” newer analogs, or structures that are similar to another compound. The aim is to retain the effects of the activity caused by the desired receptor, while having little or no interactions with those receptors.

Once our design plans are in place, we can proceed to build or synthesise these molecules in the laboratory. From there, they go through various phases of clinical trials, starting with animal tests and eventually progressing to human trials.

So how is it different from a regular psychedelic?

Since we are interested in creating new compounds that can reboot the brain, we want to retain some of the psychedelic effects of psilocybin in our new compound. We anticipate being able to create compounds that may have a shorter duration of action, and that would induce a less intense trip than psilocybin itself. Of course, the key point is with the new drugs we will have removed the heart issues associated with psilocybin itself, as we will have reduced or eliminated activity at the serotonin receptor that triggers it. Defining the appropriate dose of the drug to use for various disease states will also be important. Toxicity is of course always related to the amount of the drug you take, and any drug can prove to be toxic if given at very high concentrations.

So what are the side-effects? Can you have a downer with this drug?

The chances of having a downer are highly unlikely. Generally, we see the downer happen because of the effects of serotonin releasing agents in drugs like MDMA, which trigger an overpower of emotions and a consequent comedown. But by eliminating any triggering of these receptors we also reduce the risk of the downer.

One of the side-effects that we have seen so far is that it could trigger heart attacks, and we’re working on ways to eliminate that risk. But we’re still in the testing phase and are currently doing trials, so we’re still about four years away from the FDA approving this drug for therapeutic use.

How do you envision these bad trip-proof psychedelics can be used?

We imagine that these special psychedelics will be administered in a comfortable setting like a therapist's office. The user would be sitting with eye shades on, listening to calming music while taking these drugs. We believe that once they’ve been perfected, you could go into a psychedelic session that can help your brain be reset in the sense that its receptors are altered or rewired to make you feel less clinically depressed or anxious and instead replace these feelings with positive associations. What we’re hoping is that after one to three sessions, you’re good for the next few months, unlike with current antidepressants like Prozac which have side-effects and make you develop a dependency on them, so that you can only feel normal or happy when you’re taking them. It has been said that antidepressants cause an emotional blunting or a dulling of emotions in many people that use them, whereas in contrast, psilocybin acts by enhancing emotional responsiveness in the brain. It is probably for this reason that psilocybin has proven helpful for many individuals in dealing with and healing repressed emotional trauma.

What are your thoughts on microdosing and how would this drug’s effects be different from it?

While I don’t personally take this drug, psilocybin is one of the safest and least addictive drugs out there, and has known therapeutic effects for anxiety and depression. However, with microdosing, your brain starts developing a tolerance to its positive effects, thus reducing its potential. Our drug reduces the amount of hallucinogenic effects in the compound, thus preventing the brain from developing resistance to its effects, which makes it better to use over sustained psychotherapy sessions.

 
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Methoxetamine: Cousin of Ketamine

by Alaina Jaster, BS | Psychedelic Science Review | 21 Dec 2020

The characterization of Methoxetamine, a ketamine analog, and how its action on the serotonin system sets it apart.

Ketamine has quickly risen to fame following the discovery of its antidepressant effects. Other compounds with similar pharmacology and classification have become of interest for their potential antidepressant effects as well, but their dissociative properties may lead to unwanted side effects.

New compounds tend to pop up on the black/grey market as designer drugs. Compounds that appear in these markets are considered New Psychoactive Compounds and are often reported to the United Nations Office of Drug Control and investigated for their effects to determine if they are a public health concern.

One such compound, Methoxetamine (MXE), is a hallucinogenic dissociative that is similar to phencyclidine (PCP) and ketamine. MXE appeared in the drug markets as early as 2011-2012, but since 2016 has been almost non-existent. Despite this decrease in prevalence, it has been a continued drug of interest by multiple research groups, most likely due to its close relation to PCP and ketamine.

What is methoxetamine, and what does it do in the brain?

Classified as a hallucinogenic dissociative, MXE is part of the arylcyclohexylamine class and is structurally related to ketamine and analogs of PCP. In 2013, Dr. Bryan Roth et al, investigated the neurochemical profile of MXE and found that it binds to glutamate NMDA receptors with significant affinity, as well as the serotonin transporter, SERT, but with lower affinity. Glutamate controls the excitatory signaling in the brain, specifically in areas associated with learning and memory.

The major idea behind ketamine’s antidepressant effects is that by blocking activity at these NMDA receptors, it increases the activity at other receptors, increasing plasticity. The activity of MXE at the glutamate receptor is similar to that of ketamine. Serotonin is implicated in the pathophysiology of several mood disorders, and SERT is the main target of commonly prescribed antidepressant medication.​

Physiological and psychological effects of MXE

The effects of any substance can vary depending on dose, route of administration, and other factors. Generally, small doses of MXE produce euphoria, empathy, enhanced pleasant sensory experiences, dissociation or out of body experiences, hallucinations, and some antidepressant-like effects. Physiological effects can include dizziness, increased heart rate, nausea, vomiting, paranoia, difficulty speaking, and motor effects. Higher doses or prolonged use can cause more serious aversive side effects like cardiovascular problems, respiratory issues, memory loss, speech difficulty, kidney damage, and increased anxiety and depressive symptoms. MXE also has abuse potential due to the ability to acquire tolerance and dependence.​

Investigating methoxetamine for antidepressant effects

Despite MXE being extremely rare to find through internet vendors since 2016, its existence has spiked interest in the research community. This is probably due to the finding of ketamine’s ability to produce rapid and long-lasting antidepressant effects in both humans and rodent models. Due to its structural and pharmacological similarity to ketamine, MXE been investigated for anti-depressive properties in rodent models.

Studies by multiple groups have shown that low doses of MXE produce rapid and sustained antidepressant effects in multiple behavioral experiments. These effects have been reported to be similar to ketamine, but both drugs still cause adverse side effects like dissociation. A study from 2017 found a dose-related effect of MXE on motor activity, anxiety, and depression-like behavior. One thing that sets MXE apart from ketamine is the action on the serotonin system. Since MXE binds to SERT, it may display properties similar to common pharmacotherapies to treat depression.

In 2019, one group investigated the potential anti-depressant effects of MXE and some of its analogs and their relation to ketamine. Overall, they found some antidepressant behavioral effects with these analogs and the authors believe the compounds are acting through a similar mechanism.​

Conclusion

As of now, preclinical and clinical data are not sufficient to support MXE as an antidepressant, and further research is needed to elucidate the effects on the serotonin and glutamate systems, as well as potential adverse effects. What scientists understand right now is that methoxetamine and ketamine are both closely related in their neurochemical effects, but further understanding of MXE continues to remain elusive.

 
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The Psychedelic Entourage Effect*

by Barbara E. Bauer, MS | Psychedelic Science Review | 25 Nov 2020

The entourage effect caught PSR’s eye back in early 2019. What are experts saying about the theory now and how are psychedelic research companies approaching it?

In early 2019, Psychedelic Science Review published an article titled “The Entourage Effect in Magic Mushrooms.” The article summarized three scholarly papers which brought together the first clues that the entourage effect could play a role in the effects of psychedelic mushrooms. One of the studies was conducted decades ago by the famous mushroom researcher Jochen Gartz. He hinted at the entourage effect in his data analysis from reports on accidental mushroom ingestion. Some of the mushrooms contained the compound aeruginascin, while others did not. Gartz observed that...​
"Aeruginascin seems to modify the pharmacological action of psilocybin to give an always euphoric mood during the ingestion of mushrooms."

Further investigation by researchers has yielded additional evidence suggesting there may be a synergistic relationship between the compounds in magic mushrooms and other organisms.

Finding more active compounds

In 1968, researchers Albert Leung and AG Paul isolated the compounds baeocystin and norbaeocystin from the magic mushroom Psilocybe baeocystis. Since then, scientists have discovered other active compounds in magic mushrooms beside the more familiar psilocybin and its active metabolite psilocin. For example, in 2017, Lenz et al. first identified the compound norpsilocin in Psilocybe cubensis. A study by Sherwood et al. in 2020 found that norpsilocin was not only active at the serotonin 5-HT2A receptor but was more potent than psilocin using a calcium flux assay.

In November 2019, Blei et al. reported that they had discovered compounds called ß-carbolines in four Psilocybe species. ß-carbolines are naturally occurring alkaloids more commonly known for their presence in the psychotropic beverage ayahuasca. Several ß-carbolines inhibit monoamine oxidase enzymes (MAOs). Without co-administering ß-carbolines, MAOs would break down the DMT (dimethyltryptamine) in the ayahuasca too rapidly for it to produce significant biological effects for the user. Blei et al. summarized the case for ß-carbolines participating in an analogous entourage effect in magic mushrooms, explaining...​
"We conclude that Psilocybe mushrooms produce an ayahuasca-like and potentially similarly synergistic set of metabolites that may impact upon onset and duration of their effects."

What the mushroom experts are saying

In a recent interview, psychedelic mushroom expert Paul Stamets told Joe Rogan that the “wave of the future” is making standardized formulations that include multiple psilocybin analogs, not just psilocybin. This is because combining multiple psilocybin analogs provides what Stamets calls “an entourage or symphony effect” that is not present with single active ingredients.

In April 2020, the iconic researcher, documentarian, writer, and psychonaut Hamilton Morris commented to Psychedelic Science Review in an email about the entourage effect in toad secretions. Specifically, we asked him about differences in effects between whole toad secretions versus pure 5-MeO-DMT. Morris said, “The differences are widely reported in the psychedelic community, but are not based on anything approaching a controlled double-blind experiment with a large number of subjects, which would be required to meaningfully establish a difference between the two materials.”

Speaking again about toad secretions, Morris told Joe Rogan in his podcast...​
"…maybe there’s a little bit of that sort of entourage effect that you get with almost any plant that has a variety of different alkaloids."

So, there are some conflicting opinions about the entourage effect among at least two magic mushroom experts.

What the pharmacologists are saying

Psychedelic Science Review reached out to psychedelic researchers Dr. David Nichols and Dr. Alexander Sherwood for their comments on the state of the entourage effect hypothesis in psychedelic compounds. Regarding magic mushrooms, Dr. Nichols told us...​
"I do not believe there is an entourage effect for mushrooms. The other two major tryptamines in mushrooms, baeocystin and norbaeocystin, have recently been synthesized and tested and they are not active. Pure synthetic psilocybin seems to represent the essential effect of the whole mushroom. I believe any entourage effect would be very subtle, if any."

When asked about a synergy between the compounds in toad secretions (venom), he noted...​
"…when the dried toad venom is smoked, the peptides are destroyed by the heat. It is possible that there are other volatile compounds in the toxin, but I have not seen evidence that they contribute to the effect."

For comparison purposes, Dr. Nichols pointed out how research into cannabis compounds is at a more advanced stage than other psychedelics. “Cannabis contains hundreds of compounds, most of which have not been tested. ∆9-THC is the main psychoactive component in cannabis, but it also contains ∆8-THC, cannabidiol, and a variety of terpenes and cannabinoids. It is possible that the overall effect of ingesting cannabis is a combination of its components, or an entourage effect.”

To Dr. Nichols’s point, research is indicating that there is a synergy between some of the cannabinoids found in the Cannabis plant.

Dr. Alexander Sherwood told Psychedelic Science Review, “I am excited to see that there are groups actively working to elucidate this interesting and complex phenomenon.” He offered these additional thoughts...​
"At this time, I have not seen strong evidence to support the idea [the entourage effect] one way or another. It is tempting to make an analogy between the effects produced by mixtures of lipophilic phytocannabinoids in cannabis and the various alkaloids in psychedelic mushrooms, peyote, or toad secretions, but none are directly comparable."

Looking ahead, Dr. Sherwood added...​
"The important thing to do now is design good experiments to test the entourage effect hypothesis systematically with representative mixtures of natural products."

He continued, “Discovering that a compound such as norpsilocin is an agonist at the 5-HT2A receptor is a very small piece of the puzzle. Understanding the absorption, distribution, metabolism, and excretion characteristics of the individual components in the mixture is equally, if not more, important to consider.”

There are two conclusions one can glean from this expertise provided by Drs. Nichols and Sherwood. First, there is significant skepticism among psychedelic pharmacologists about the existence of the entourage effect in psychedelic compounds (aside from cannabis). This makes sense due to the lack of proper scientific studies.

Second, it would be helpful for researchers to work toward developing a better understanding of the complete chemical composition of naturally occurring psychedelic sources like magic mushrooms (or toad secretions, ayahuasca, Salvia divinorum, etc.). This requires first identifying all the compounds they contain and understanding their chemistry and pharmacology. Then, studies can be designed to help understand how two or more of the molecules may work together to produce the entourage effect.

Examining the work of psychedelic research companies

Understandably, many experts remain unconvinced that there is a synergistic relationship between psychedelic compounds except when it comes to Cannabis. But how are commercial psychedelic research companies approaching the entourage effect? Are they treating it as an untapped opportunity or a red herring?

Over the coming weeks, this article series will review several companies that appear to be actively studying the entourage effect in their research efforts. We will summarize what they’re working on and discuss what it could mean for the future of psychedelic research. Keeping an eye on where these companies are heading and the research strategies they are using is a critical part of staying up to date with psychedelic science.

There is a lot of skepticism about whether there is an entourage effect when it comes to psychedelic compounds. So how are psychedelic research companies approaching the entourage effect? Now a closer look at Mydecine Innovations Group.

Mydecine

“Our researchers will isolate and study all of the potentially ‘magic’ molecules in mushrooms.”

In a June 2020 press release regarding their partnership with the University of Alberta, Mydecine CSO Robert Roscow stated, “We are investigating the potential of mushrooms and their compounds to improve human health and wellness. This research partnership opens up, not only investigation of single molecules from mushrooms but also more complex formulations.”

The formulations Mr. Roscow mentions could contain one or more molecules found in magic mushrooms aimed at treating a particular condition. Additional molecules not naturally occurring in these mushrooms could also be added to give a desired effect or remove one or more side effects. These formulations are in contrast to whole-mushroom extracts, which likely have different effects. In this context, another name for the entourage effect concept could be ‘mushrooms versus molecules.’

NeuroPharm, Inc., the research and development division of Mydecine, clearly states their alignment with the entourage effect on their webpage...​
"Even in the most potent psychoactive mushrooms, psilocybin is only 1-2% of the total mass. This means that as much as 99% of that mushroom is composed of other molecules. While many of those molecules may have no therapeutic value, some of them are pharmacologically active — either taken alone or in synergy with known psilocybin derivatives."

NeuroPharm also states, “Our researchers will isolate and study all of the potentially ‘magic’ molecules in mushrooms. We are studying how these molecules work both alone and in combination with other molecules like THC and CBD.”

The company makes an important observation when it comes to understanding why creating formulations is critical to accurate dosing. NeuroPharm notes that eating magic mushrooms doesn’t give a person much control over what molecules they are ingesting and how much of each compound is entering their bloodstream. The company says, “Current methods for administering psilocybin [eating mushrooms] fail to provide reliable dosing, which makes the resulting effects both inconsistent and unreliable.” They go on to say, “Formulating the active components in ‘magic mushrooms’ into reliable dosage forms will allow users to know exactly what they are taking. Formulated products will provide the desired active ingredients without any undesired compounds…”

Mydecine’s impact on psychedelic research

According to their website, Robert Roscow and his team at Mydecine/NeuroPharm are studying and applying what they understand as an entourage effect in magic mushrooms to their research and development efforts. It is too early to say what innovations may come from this work that could help people with medical conditions or those just wishing to improve their everyday lives. Based on press releases, Mydecine is currently making progress researching the single molecules psilocybin and psilocin.

NeuroPharm is conducting the first-of-its-kind clinical trial using psilocybin-assisted psychotherapy for treating PTSD (post-traumatic stress disorder) in Canadian Veterans. Also, Mydecine recently filed for a provisional patent for an ‘enhancer’ that reduces the enzymatic breakdown of psilocin in the body.

Field Trip Discovery

This company is approaching psychedelic mushroom research literally from the ground up.

Of Field Trip’s three divisions, Field Trip Discovery is focusing on the cultivation and study of magic mushrooms and the compounds they produce. As reported in Quartz, the Discovery division sees two potential business targets for the research center: quantifying the psychedelic properties of magic mushrooms to make the user experience more predictable and identifying potential intellectual property opportunities.

Field Trip Discovery made the news in October 2019 when they announced the opening of their magic mushroom research center in Jamaica. According to Discovery’s website, the lab is working identifying, isolating, and characterizing “active substances in mushrooms and related fungi.” This includes developing methods for extracting all the compounds produced by magic mushrooms. Discovery’s scientists will also look for insight and further research opportunities by studying the genetics of the mushrooms.

Field Trip Discovery sums up their research and development strategy rationale by stating, “Botanical materials are complex and diverse, and may contain many substances that modify the psychedelic experience by direct and indirect actions at serotonin, dopamine and other receptors, as well as within the cellular transport and accumulation mechanisms in the brain.”

Field Trip Founder and CEO Ronan Levy told Quartz in an interview, “One of the big challenges with fungi—and you see this with cannabis—is producing consistent product. That variability is quite profound.”

In an interview with Benzinga, Mr. Levy said, “Much like cannabis, there’s probably a lot more going on with a mushroom than just psilocybin.” He added...​
"And so really the direction of the research is to explore the potential of other molecules and the interplay of molecules within the mushrooms themselves….There’s a very good reason to believe that there are a number of interesting molecules that haven’t been studied."

Field Trip’s impact on psychedelic research

Discovery is approaching psychedelic mushroom research literally from the ground up. They appear unique in their efforts to understand how cultivation practices affect the type and amount of compounds the mushrooms produce. And concurrently, they want to know what is happening inside magic mushrooms right down to their genetics.

Field Trip Discovery also presents competition for other companies in the psychedelic intellectual property space such as CaaMTech and Cybin. So far it appears that Discovery is focusing on patenting synthetic psychedelic compounds such as FT-104. Although details on the chemistry of this molecule are vague, an article in Biospace describes it as “a novel psychedelic molecule derived from the chemical structures of known psychedelic substances.” The company’s internal pharmacology studies on FT-104 indicate that it is a serotonin 5-HT2A receptor agonist (as shown by the head twitch response test in mice) and has a potency similar to psilocybin.

CaaMTech

Patent filings indicate that CaaMTech was the first company to propose an entourage effect in psychedelic compounds.

CaaMTech states on their website that “Most conventional pharmaceutical products offer just one active ingredient in a precise dose. Natural organisms contain multiple active molecules in varying concentrations and ratios, working in harmony to produce a multitude of pharmacological effects.” The company describes the area located between understanding single molecules and all the compounds in natural organisms as a “vast and understudied territory.” Hence, CaaMTech’s research centers on creating formulations containing precise amounts of multiple active ingredients.

One of the first critical steps for creating these formulations is synthesizing and characterizing psychedelic compounds as they occur in their natural states. Since they began operating just over two years ago, CaaMTech has published over a dozen papers detailing the crystal structures of psychedelic compounds including, 4-HO-TMT iodide1 (a metabolite of aeruginascin), 4-AcO-DMT fumarate, and DMPT iodide and DMALT iodide. Their latest paper published in Acta Crystallographica, reveals the crystal structures of three psilocin prodrugs synthesized from psilacetin.

Recently, CaaMTech announced its partnership with the US National Institutes of Health to study synthetic tryptamine compounds. Also, in December 2020, CaaMTech announced they will be collaborating with the Leibniz Institute for Natural Product Research (aka the Hans Knöll Institute, HKI). A research team led by Dr. Dirk Hoffmeister will work on filling the many knowledge gaps that exist in the understanding of magic mushroom compounds. Speaking of the work with Dr. Hoffmeister and HKI, Dr. Chadeayne said in a press release...​
"Understanding the chemical composition of magic mushrooms allows us to quantifiably distinguish their effects from pure psilocybin and harness the advantages."

CaaMTech’s impact on psychedelic research

CaaMTech is impacting psychedelic research in the areas of intellectual property and solving the crystal structures of psychedelic compounds. Both of these efforts center around the entourage effect hypothesis.

Based on a 2017 priority patent filing, it appears that CaaMTech was the first company to propose making formulations of psychedelic compounds in the context of them having a synergistic or entourage effect. Specifically, the patent discusses purifying and combining psilocybin derivatives, cannabinoids, and/or terpenes for treating depression and other conditions.

Recently, they also filed a patent application pertaining to the compounds found in the plant Tabernanthe iboga (used for making ibogaine) for treating indications including addiction and treatment-resistant depression. The claims describe combining one or more purified ibogaine derivatives and, in some formulations, excluding one or more compounds to eliminate undesired effects.

In addition, CaaMTech is taking the lead in solving the crystal structures of psychedelic compounds. Doing this work is an essential first step in learning about their pharmacology and creating formulations for treating specific conditions. For example, in July 2020, Dr. Chadeayne and CaaMTech published a synthesis method and crystal structure data for the aeruginascin metabolite 4-HO TMT. Not only that, but the team generated data indicating, surprisingly, that 4-HO-TMT is active at the serotonin 5-HT2A receptor.

In a LinkedIn post, Dr. Chadeayne suggests looking to nature for inspiration and answers to questions about how to formulate and optimize psychedelic drugs...​
"Maybe the future of the psychedelic industry doesn’t need to be an either-or question. Perhaps we could have compositions that include the combinations of active compounds found in nature within reliable formulations that provide the precision and consistency expected from pharmaceutical products."

MindMed

MindMed has just started a Phase 1 trial which is studying the effects of LSD + MDMA administered together.

Partnering with Dr. Matthias Liechti and Liechti Lab, MindMed announced in August 2020 that they are planning the first clinical trial combining LSD and MDMA. News of the start of Phase 1 was announced by MindMed on January 20, 2021. One of the study goals is determining if MDMA can lessen some of the negative side effects of LSD. Instead of using one psychedelic compound like current clinical trials, the research team will investigate the therapeutic effects of a combination of two psychedelics. This work is quite unique in psychedelic research because it is examining not just the interplay between two compounds, but synthetic compounds.

In a press release from PR Newswire, Dr. Liechti said...​
"The potential of MDMALSD is to create a psychological state that may have the benefits of both substances and have longer-lasting effects than standalone psilocybin or LSD."

More specifically, the MindMed website says, “Combining MDMA and LSD may enhance the positive effects of LSD by inducing a positive psychological state with MDMA which is an empathogen to help counteract some known negative or less positive aspects of LSD."

Hand-in-hand with their MDMA-LSD research, MindMed has developed what they call their ‘Dose Optimizer’ technology. MindMed says, “This technology aims to optimize the dosing of MDMA, LSD, and other psychedelics based on a patient’s profile.” Presumably, formulations containing two or more psychedelics could be tailored to a person’s needs based on what is known about the compounds’ pharmacology and synergistic effects, i.e., the entourage effect.​

MindMed’s impact on psychedelic research

The recent partnership formed between MindMed and Liechti Labs has also yielded a patent filing for an “LSD-off switch.” This invention is aimed at stopping “bad trips” a patient may experience while undergoing LSD-assisted psychotherapy. The off-switch technology can also be used to better control the dosing of LSD to patients. From this, one could presume that MindMed is interested in not just the entourage effect between psychedelic compounds but controlling them at a molecular level.

Along with their Dose Optimizer technology mentioned earlier, MindMed is developing an entire therapeutic experience that goes beyond the psychedelic compounds themselves. Their website states that as part of their overall philosophy, “We offer a complete toolset – not just a pill.” Not only do they design “Psychedelic Inspired Medicines,” MindMed has created experimental therapies that “…have a high enough dose of a psychedelic (e.g., LSD, psilocybin) to produce a hallucinogenic effect and are administered under the supervision and guidance of a medical professional.”

The state of the art

Some scientists are skeptical of the entourage effect in psychedelics as research companies are charging ahead with the concept.

The possibility of an entourage effect with psychedelic compounds from natural sources caught PSR’s attention back in early 2019. Since then, we have been monitoring the scientific literature and news outlets to keep readers abreast of news on the theory. In November 2020, we began a series of articles on the psychedelic entourage effect (EE) as seen from the vantage point of scientists and research and development (R&D) companies. The series culminates in this article on the overall state of the art at this time. Examining this phenomenon from these two perspectives revealed an interesting and important difference of opinion.​

Two sides of the coin

Part 1 of this series recapped some studies that have hinted at the possibility of a psychedelic EE. It also examined the concept from the point of view of a few top scientists in the field including David Nichols and Alexander Sherwood. These expert pharmacologists made their stance clear; there is insufficient evidence at this time to conclude that the psychedelic EE exists. They recommend that carefully designed and controlled studies are done before making observations and drawing any conclusions.

To capture the other perspective, this report profiled four companies exploring the EE phenomenon as part of their R&D activities — Mydecine, Field Trip Discovery, CaaMTech, and MindMed. According to public comments from C-Level executives and the information on their websites, the validity of the psychedelic EE has been established and is providing the rationale and basis for multi-million dollar R&D investments.​

Differing opinions give rise to new discoveries

Therefore, taken as a whole, this small opinion survey concludes that the scientific validity of the psychedelic entourage effect remains open to debate. It also indicates that it’s an exciting time to be involved in psychedelic research. The healthy skepticism of scientists coupled with innovation and risk-taking by psychedelic research companies continues to propel psychedelic science as never before.

Emerging scientific fields like psychedelic science are fertile ground for new and exciting theories about how and why things work the way they do in the natural world. As is the nature of science, theories come and go. They are subjected to scrutiny by peers and testing in the lab. Those that fail in proving their validity are set aside. Other theories meeting the challenge will spark curious minds to take them further down the path of discovery and understanding.

So far, the psychedelic EE is meeting that challenge in the eyes of R&D companies. But there is so much more to learn before the theory has the opportunity of entering the mainstream of psychedelic science research.

*From the articles here :
 
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Albert and Anita Hofmann

How LSD affects the brain

by Joshua Krisch | The Scientist

The psychedelic drug LSD is known for its euphoric effects, and for inducing long “trips.” Now, in two studies published last week (one in Current Biology, the other in Cell), scientists have examined how LSD produces such diverse effects and why the drug takes so long to wear off. The results of both studies suggest that LSD’s effects are mediated by the serotonin 2A receptor, and that the drug is just the right shape to bind this receptor for extended periods of time.

For the Current Biology study, 21 volunteers were given a placebo, a small dose of LSD alone, or the same dose of LSD but with kentaserin, a serotonin 2A antagonist. Study participants who took the kentaserin reported virtually the same experiences as those who took the placebo, and fMRI brain scans confirmed similar brain activities across participants in both groups. "The serotonin 2A antagonist blocked all the effects of LSD, so it was like if people didn’t take any drugs,” coauthor Katrin Preller, neuroscientist at the Zurich University Hospital in Switzerland told The Verge. “All the typical symptoms—hallucinations, everything—were gone.”

For the Cell study, researchers imaged LSD binding various serotonin receptors, observing that the drug clings to these structures in a unique way. This could explain why the effects of LSD take some time to wear off. “What we saw is that the receptor is shaped a little bit like a vase, and it has a space in the middle where the LSD binds and there’s a lid above it,” coauthor Daniel Wacker of the University of North Carolina, Chapel Hill, told The Verge. “LSD has this unique property that it actually holds onto the lid. For many other compounds like serotonin, the lid remains rather flexible. Because LSD holds onto it, it really stays in there.”

According to The Guardian, “In future, the findings could help chemists produce shorter-acting versions of the drug that may be more suited to clinical use for anxiety or post traumatic stress disorder.”

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Psychedelic neuroimaging

Two papers—one published in PNAS and another in Current Biology—report how brain activity is altered in people given doses of LSD. Using two different brain imaging approaches, the authors of both studies detailed the particular changes in activity that associate with arguably the best-known effects of LSD: visual hallucinations and an increased sense of unity with one’s surroundings—referred to in the Current Biology paper as “ego dissolution.”

“This work is very important with regards to the insights it gives us on how hallucinogens, specifically LSD, affect the brain,” said psychiatrist and behavioral scientist Charles Grob of UCLA. “Now we have a better understanding of the neurobiological substrate for the psychedelic experience.”

Research into psychedelic drugs, such as LSD and psilocybin—the hallucinogenic component in magic mushrooms—took a nosedive in the 1960s and 70s, following the banning of these substances. “Research with humans was not occurring in the United States and Europe from [then on],” said Grob. By the 90s and 2000s, research on these drugs started to slowly pick up," Grob said, "reflecting a greater receptivity on the part of the regulatory agencies to allow this sort of research.”

Previous studies have suggested that compounds like LSD, in combination with psychotherapy, could be effective treatments for alcoholism, anxiety, and tobacco addiction, among other things.

Aside from their potential clinical use, the drugs also offer insight into the nature of consciousness itself, said cognitive and computational neuroscientist Anil Seth of the University of Sussex, U.K. “One of the main ways to try to understand the neural basis of consciousness is to try to induce different kinds of experience and see what happens in the brain,” he said, and “LSD is a very potent way of manipulating somebody’s experience of the world and of themselves.”

To examine LSD’s effects, Imperial College London’s David Nutt and Robin Carhart-Harris together with their colleagues recruited 20 healthy volunteers, all of whom had reported taking a psychedelic drug at least once before. "The subjects were given injections of 75 micrograms of LSD—equivalent to about one blotter of LSD taken orally and recreationally,” said Carhart-Harris—and then their brains were analyzed by functional magnetic resonance imaging (fMRI) and magnetoencephalographies (MEG). In addition, the volunteers were asked to rate various aspects of their experiences and to answer an Altered States of Consciousness questionnaire. As a control, the subjects’ brains were analyzed a couple of weeks before or after the LSD analyses, at which point they were given a saline placebo injection.

Connecting the participants’ ratings and questionnaire answers to the imaging data, the team found that LSD-induced visual hallucinations correlated with an increase in cerebral blood flow to the visual cortex, a pronounced increase in connectivity between the visual cortex and other brain regions, and a decrease in the power of visual cortex alpha waves, which are thought to generally inhibit neural activity. The authors suggested that this reduced alpha power may allow uninhibited visual cortex activity, which—together with the increased connectivity between normally unrelated brain regions—could help explain the subjects’ ability to visualize unusual images even with their eyes closed.

Aside from the increased connections with the visual cortex, LSD induced a global increase in connectivity across the brain, which was correlated with the participants’ sense of ego dissolution. In contrast, connections within specific systems, such as the default mode network, appeared to reduce.

“If you look at connectivity within [known] systems, what you see with both psilocybin and LSD is a weakening of connections,” said Carhart-Harris. “But when you look at the relationships between the different systems . . . they relate to each other much more.” Overall, the result appears to be a “unified, more integrated brain,” he said.

"Understanding the neurobiological basis of ego dissolution is particularly interesting, because this break down of self-referential processing may be the driver of clinical change,” said cognitive neuroscientist Fred Barrett of the Johns Hopkins School of Medicine in Baltimore who was not involved in the work. "Put another way, it is this ego-dissolving, mind-expanding aspect of the psychedelic experience that seems to be associated with the drugs’ treatment successes."

"It’s possible that psychedelic drugs offer a 're-equilibration of connectivity,' ”
said Grob. “Patterns of a psychiatric disorder are often entrenched,” he added, “and there may be some value in loosening things up.”

*From the articles here :
 
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Antidepressant Mechanisms of Psilocybin and Ketamine*

Ketamine and psilocybin both exert rapid antidepressant effects. Could these effects be explained by a common mechanism that promotes neurogenesis?

by Matthew Gallenstein | Psychedelic Science Review | 24 Aug 2021

Depression is the single largest contributor to global disability, affecting approximately 322 million people worldwide. In addition to its high prevalence, depression can impair functionality, impact the quality of life, and lead to suicide in more severe cases. Conventional antidepressant treatments have a delayed onset of action, taking weeks to exert their effects, and individuals with depression who are suicidal are at particular risk during that time.

Novel treatment approaches for depression, such as ketamine and psilocybin, are notable for their rapid-acting onset, prompting reductions in suicidality and depressive symptoms shortly after administration. Both of these rapid-acting antidepressants (RAADs) have displayed preliminary efficacy in treating depression in clinical trials, as well as efficacy in addressing depression that has failed to respond to conventional antidepressants, also known as treatment-resistant depression.

Although ketamine and psilocybin are characterized by distinct pharmacodynamics, they share common mechanisms that may partially explain their rapid antidepressant effects.

The neurogenic theory of depression

There are many explanatory models of depression, from the psychological to the biological, but the neurogenic theory of depression may be useful when considering the antidepressant mechanisms of ketamine and psilocybin. The neurogenic theory conceives of depression as an impairment in adult neurogenesis, or the brain’s ability to repair existing neurons and make new neurons throughout the lifespan.

New neurons are produced in the hippocampus and the frontal cortex, two areas that are atrophied by chronic stress, which induces dysregulation of the HPA axis via increased levels of glucocorticoids (stress hormones). Furthermore, depression is marked not only by increased glucocorticoids but decreased levels of brain-derived neurotrophic factor (BDNF), a neurotrophin correlated with the brain’s capacity for neurogenesis. As such, stress (and by extension, depression) causes the destruction of neurons but also impairs the brain’s ability to repair such damage. Conventional antidepressant treatment can increase BDNF levels, thereby reversing hippocampal atrophy and resulting in the neurons’ increased ability to repair and grow, but this process takes weeks. Ketamine and psilocybin also affect neurogenesis via increasing BDNF but do so rapidly, suggesting a potential shared mechanism for their antidepressant effects.

Ketamine

Ketamine’s antidepressant mechanism of action is not yet fully understood, though one hypothesis proposes that it may be attributed to a ketamine-induced glutamate surge in the prefrontal cortex (PFC). Glutamate is the primary excitatory neurotransmitter in the brain, and ketamine modulates glutamate transmission by acting as a non-competitive antagonist at N-methyl-D-aspartate (NMDA) receptors. Ketamine blocks inhibitory γ-aminobutyric acid (GABA)-nergic interneurons in both cortical and subcortical regions, resulting in the increased firing of glutamatergic neurons and a “surge” of extracellular glutamate in the PFC. At the same time, ketamine blocks NMDA receptors in the PFC and activates alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors.

This surge is thought to shift the proportion of AMPA to NMDA activation in the cortex in favor of AMPA activation, with AMPA activation triggering intracellular mechanisms that promote the release of brain-derived neurotrophic factor (BDNF).2 Since BDNF levels are correlated with the brain’s capacity for neurogenesis, AMPA activation may be a key aspect of ketamine’s antidepressant effect.

The pharmacodynamics of the ketamine-induced glutamate surge as compiled by Vollenweider and Kometer. Ketamine blocks NDMA receptors on GABA-ergic neurons in subcortical and cortical regions. This leads to increased glutamate release, blocking NDMA receptors and activating AMPA receptors on pyramidal neurons in the PFC, which prompts intracellular mechanisms resulting in the release of BDNF.

Psilocybin

Similarly, psilocybin’s antidepressant mechanism of action is not fully understood, but it is mediated by its effect on the serotonin (5-HT) system and activation of 5-HT receptors. Psilocybin is metabolized to psilocin, which then inhibits the 5-HT transporter and binds to the 5-HT2A, 5-HT2C, 5-HT1A, and 5-HT1B receptors. Psilocin stimulates postsynaptic 5-HT2A receptors on pyramidal cells in layer V of the PFC, which leads to a similar “surge” of glutamate and activation of AMPA receptors on pyramidal neurons in the cortex. Furthermore, psilocin directly activates 5-HT2A receptors on cortical pyramidal neurons as well. Both AMPA and 5-HT2A activation on cortical pyramidal neurons prompt intracellular processes that result in an increase in BDNF.

The pharmacodynamics of the psilocybin-induced glutamate surge as compiled by Vollenweider and Kometer. Psilocin binds to 5-HT2A receptors in deep cortical layers, leading to increased glutamate release in the PFC. This glutamate surge produces NMDA antagonism and AMPA activation, which prompts intracellular mechanisms resulting in BDNF release. Direct agonism of 5-HT2A receptors by psilocin on layer V pyramidal neurons in the PFC prompts intracellular mechanisms resulting in BDNF release as well.

Common mechanisms

As noted, ketamine and psilocybin both prompt a glutamate surge in the PFC, albeit by different means. This surge leads to AMPA activation and intracellular mechanisms promoting the release of BDNF. The end result is a rapid change in neuroplasticity which, according to the neurogenic theory of depression, would correlate with a rapid remission in depressive symptoms. This provides a rationale for the acute antidepressant effects of ketamine and psilocybin, but these effects continue after the drugs have been eliminated from the body.

One potential explanation is that ketamine and psilocybin both increase the expression of neuroplasticity-regulating genes, leading to continued increases in BDNF for a period of time afterward. Other theories posit that changes in brain network connectivity and functionality brought about by ketamine and psilocybin may underlie their antidepressant benefits. For example, their shared glutamate surge may normalize dysregulation between the PFC and the limbic system. The PFC is correlated with “top-down” control of emotion and stress responses mediated by the amygdala, so ketamine and psilocybin may help restore the brain’s ability to regulate stress and emotion, which is impaired in depression. Taken together, these explanations provide a rationale for the mechanisms behind ketamine and psilocybin’s acute and sustained antidepressant benefits.

Another illustration of the pharmacodynamics of ketamine and serotonergic psychedelics (such as psilocybin) as compiled by Kadriu et al. 2021. Both compounds prompt a surge in glutamate, increased AMPA throughput, and intracellular mechanisms that lead to increased BDNF. Increased BDNF results in spine growth, neurite growth, and synaptogenesis, all aspects of neuroplasticity that may bolster the antidepressant effects of ketamine and psilocybin.

Looking forward

Ketamine and psilocybin are intriguing treatments for depression in part because of their RAAD properties. Ketamine and psilocybin share common mechanisms that may explain these properties, yet their full pharmacodynamics are distinct and complex, which may explain the differences in treatment response between the two. Ketamine’s antidepressant response is sustained for two to three weeks at most, with some individuals failing to respond to ketamine at all. In contrast, numerous clinical trials using psilocybin to treat depression have reported sustained antidepressant effects for weeks, months, or even years after a single dose. Additional research is required to tease apart the reasons for these differences, but ketamine and psilocybin remain promising treatments for depression worthy of further investigation.

*From the article here :
 
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Cambridge

Are prodrugs the next wave of psychedelic drug development?

The path toward therapeutic psychedelic-based drugs is becoming clearer as scientists understand more about how they are processed in the body.

by Barbara E. Bauer, MS | Psychedelic Science Review | 21 Sep 2021

Last week, COMPASS Pathways announced that it acquired an intellectual property (IP) portfolio of novel psychedelic compounds and prodrugs. According to the press release, “The substances covered in the IP portfolio include a variety of psychedelic and empathogenic compounds, some of which are prodrugs.”

What are prodrugs?

COMPASS’s press release defined prodrugs as “pharmacologically inactive compounds which are metabolized inside the body to produce an active drug.” As discussed below, COMPASS’s lead candidate (psilocybin, “COMP360”) is a prodrug of psilocin. According to a review article by Jarkko Rautio et al. in Nature Reviews Drug Discovery, “Prodrugs are molecules with little or no pharmacological activity that are converted to the active parent drug in vivo by enzymatic or chemical reactions or by a combination of the two.”

As the simple scheme above illustrates, there are three key questions to answer about how a prodrug converts into an active drug:​
  1. What is the prodrug molecule that is administered to the subject and what are its properties (stability, crystallinity, ease of synthesis, etc.)?​
  2. What active ingredient is the prodrug designed to deliver and what are the properties of that compound, its metabolites, etc.?​
  3. How is the prodrug converted into the active (e.g., metabolism or hydrolysis), and how does that mechanism affect the prodrugs’ ability to provide the active? (A basic question here could be is psilocybin the most efficient means for administering psilocin compared to other psilocin prodrugs?).​
Prodrugs represent an important class of pharmaceutical development. In the ten-year period between 2008 – 2018, the US Food and Drug Administration approved at least 30 prodrugs, which accounted for more than 12% of all approved small-molecule new chemical entities.

Psilocybin is the most well-known psychedelic prodrug

Prodrugs are important within the field of psychedelic research and drug development. For example, psilocybin is most frequently described as the active component in magic mushrooms. But, psilocybin is technically a prodrug of psilocin. When consumed, psilocybin is rapidly metabolized into psilocin. Psilocin is the active drug: The data from receptor binding studies at serotonin 5-HT receptors confirms psilocybin’s role as a psilocin prodrug.

The metabolism of psilocybin to psilocin proceeds via a hydrolysis reaction. The 4-phosphate ester of psilocybin is hydrolyzed, resulting in psilocin. (The term hydrolysis refers to any chemical reaction in which a molecule of water breaks one or more chemical bonds. For example the oxygen-phosphorus bond in psilocybin. Other psilocybin derivatives present in magic mushrooms probably follow analogous metabolic pathways (hydrolysis of a 4-phosphate ester into a 4-hydroxy group) when ingested. Examples include:​
Synthetic psychedelic prodrugs

In addition to these four naturally occurring psilocybin derivatives in magic mushrooms, other synthetic prodrugs of psilocin have been designed. For example, in 1963, chemists Albert Hofmann and Franz Troxler patented 4-AcO-DMT (aka psilacetin) along with other indole esters, which were all synthesized and described as their free base or zwitterionic forms. In 1999, David Nichols reported the fumarate salt of 4-AcO-DMT, first describing the compound as a prodrug, i.e. the “O-Acetyl Prodrug of Psilocin”6.

Using the same chemical reaction as the above described naturally occurring psilocybin derivatives (psilocybin, baeocystin, norbaeocystin, and aeruginascin), 4-AcO-DMT is converted into psilocin via a hydrolysis reaction. More scientific papers describing 4-AcO prodrugs are appearing in the current literature.

Similar prodrugs have been designed for structurally similar active compounds. For example, in December 2020, Adam Klein et al. published work on the Structure-Activity Relationship of Psilocybin Analogues, including eight 4-Acetoxy-N,N–dialkyltryptamines, which were used as fumarate or acetate salts. They found that the 4-acetoxy-N,N-dialkyltryptamines were significantly less potent as 5-HT2 receptor agonists, noting that “the potency of the O-acetylated tryptamine was about an order of magnitude weaker (ranging from 10- to 40-fold) compared to their 4-hydroxy counterparts.”

However, despite their substantially reduced potency in vitro, Klein et al. demonstrated that the 4-acetoxy-N,N–dialkyltryptamines were equally active in vivo in the Head Twitch Response assay. Taken together, Klein et al.’s results show that the 4-acetoxy-N,N–dialkyltryptamines “are likely serving as prodrugs for the corresponding 4-hydroxytryptamines.”

Using the same chemical reaction for the above described naturally occurring psilocybin derivatives, it follows that other 4-acetoxy-N,N–dialkyltryptamines are hydrolyzed into their 4-hydroxy-N,N–dialkyltryptamine counterparts, which serve as the active drugs.

The future of psychedelic prodrugs

COMPASS’s recent press release illustrates the potential for developing new psychedelic prodrugs– even when the active compound was previously known. Dr. Matthias Grill noted that the technology acquired by COMPASS was “Inspired by the work of chemists like Albert Hofmann and Alexander Shulgin” and that he was “proud to be developing these evolved compounds,” alluding to improvements made in prodrug design.

Dr. Grill also pointed out that “Chemistry still happens inside the flask and not on paper,” highlighting the amount of experimental work required to design, synthesize, and test novel prodrugs– even where the active compound was previously known. Here, Lars Wilde, Chief Business Officer, President and Co-founder of COMPASS Pathways, touches on the commercial incentives for developing prodrugs and “novel derivatives of known compounds,” namely the ability to create patentable compounds: “This agreement will strengthen and expand our IP and development portfolio with new compounds.”

Prodrug compounds can be administered to the subject, where they are converted in vivo via an enzymatic or non-enzymatic reaction, e.g., hydrolysis, into a known active compound. Accordingly, prodrugs offer an alternative means for administering an active compound. And, unlike the active compound, a prodrug’s physical properties (solubility, stability, crystallinity, melting point, etc.) and biological properties (e.g., rate of conversion into the active, absorption, distribution, etc.) can be optimized. For these reasons, prodrugs of known active psychedelic compounds are an exciting area for future research and development.

Barbara E. Bauer, MS
Barb is Editor and one of the founders of Psychedelic Science Review. Her goal is making accurate and concise psychedelic science research assessable so that researchers and private citizens can make informed decisions.

 
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The Compounds in Psychedelic Cacti

Mescaline is the best-known phenethylamine in psychedelic cacti; but what about the other “minor” compounds in those cacti?

by Barbara E. Bauer, MS | Psychedelic Science Review | 1 Nov 2021

Scientists are learning that psychedelic compounds abound in nature. In addition to tryptamine compounds found in magic mushrooms and toad venom, psychedelic cacti provide a source of naturally occurring psychoactive phenethylamine compounds. The image below illustrates the difference in the chemical structures of tryptamine and phenethylamine.

Mescaline is probably the most well-known compound in psychedelic cacti. Species that contain it include the San Pedro cactus (Echinopsis pachanoi), Peyote cactus (Lophophora williamsii), and the Peruvian Torch cactus (Echinopsis peruviana). Peyote, in particular, is unique because archaeologists have found evidence of its use by Native Americans as far back as 5,700 years ago, making it the oldest known plant containing a bioactive drug compound. Mescaline was first synthesized by Ernst Späth in 1918.

In their classic book “PiHKAL: A Chemical Love Story,” Alexander and Ann Shulgin called mescaline one of the “Magical Half Dozen” compounds that they considered the most important out of all those they synthesized and studied.

Other Compounds in Psychedelic Cacti

In addition to mescaline, psychedelic cacti contain other psychoactive compounds. Many of those compounds remain untested (and probably many still undiscovered) so researchers don’t have a clear picture of which ones may have psychedelic/therapeutic effects and may be involved in entourage effects and/or allosteric modulation.

In 1969, Richard Evans Schultes stated in a paper in Science that, “Peyote contains at least 15 ß-phenethylamine and isoquinoline alkaloids.” He went on to say,

"The intoxications induced by mescaline and by Peyote itself are very different, but they have unfortunately been confused in the literature."
Research done in the 1970s identified compounds in the Peyote cactus including isopellotine, anhalamine, and tyramine.

In 2015, Ibarra-Laclette et al. detected the following compounds in Peyote (and others identified previously) using GC-MS (gas chromatography-mass spectrometry):
  • Mescaline​
  • Hordenine​
  • N-Methylmescaline​
  • N-Acetylmescaline​
  • Pellotine​
  • Anhalonine​
  • Anhalidine​
  • Anhalonidine​
  • Lophophorine​

Interestingly, the authors found that, while abundant in the “buttons,” mescaline was “barely present” in extracts obtained from Peyote roots, while hordenine (which has antibacterial properties) was found only in the roots.

Further, based on their literature review, Ibarra-Laclette et al. stated, “Not all of these substances exhibit psychopharmacological activity when administered singly, but in combination, they apparently potentiate the effects of the mescaline and definitely alter some characteristics for the experience.”

In addition to those listed so far, in the 1977 book “Peyote and Other Psychoactive Cacti,” Adam Gottlieb listed the following compounds in his ‘Dictionary of Cactus Alkaloids.’​
  • Dolichotheline​
  • Homoveratrilamine​
  • Macromerine​
  • Metanephrine​
  • 3-Methoxytyramine​
  • N-Methylphenethylamine​
  • N-Methyltyramine​
  • Candicine​
  • Normacromerine​

Here, the compound candicine is particularly interesting because it is a quaternary ammonium compound. The magic mushroom compounds aeruginascin and 4-HO-TMT also have this functional group.

Like magic mushrooms, the chemical composition of naturally occurring cacti appears to be highly variable. In 2010, Ogunbodede et al. analyzed the mescaline levels in the cortical stem from several San Pedro cactus samples. The observed that “The range of mescaline concentrations across the 14 taxa/cultivars spanned two orders of magnitude, from 0.053% to 4.7% by dry weight.” These data may bring to mind how much the levels of a single compound can vary in magic mushrooms and toad venom, and likely in other organisms.

Continuing Research on Psychedelic Cacti

Clearly, there is much mystery still surrounding the chemical composition of psychoactive cacti– including the identity of all the active compounds and the concentrations of those compounds. Just like magic mushrooms and toad venom, it is feasible that these compounds have synergistic effects on the body. But it’s all speculation until scientists identify all the compounds in these cacti, elucidate their pharmacology, and understand how they work together to produce certain effects.

 
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The Serotonin 5-HT2A Receptor*

Although there are distinct differences between our species, the mouse serotonin 2A receptor plays a crucial role in human psychedelic drug research.

by Ian Liddle, MSci | Psychedelic Science Review | 21 Nov 2021

The serotonin 5-HT2A receptor plays a crucial role in learning and cognition and is one of the primary targets of the psychedelic drug lysergic acid diethylamide (LSD). Mice (murine) models have been used extensively to understand the complex neuropharmacology of the 5-HT2A receptor. This article is an overview of the similarities and differences between human and mouse 5-HT2A receptors and the implication for psychedelic research.

The Serotonin 5-HT2A Receptor

The serotonin 5-HT2A receptor (5-HT2AR) is a G protein-coupled receptor (GPCR) modulated by the excitatory monoamine neurotransmitter 5-hydroxytryptamine (5-HT), commonly referred to as serotonin. The 5-HT2ARs are distributed throughout the periphery in the smooth muscle and the mammalian brain with the highest receptor densities found in the cortex and frontal cortex thought to form functions in memory and learning. Clinically 5-HT2AR is implicated in several psychiatric disorders, including schizophrenia, depression, obsessive-compulsive disorder, and autism, with treatment accompanied by 5-HT2AR antagonists. The main target for several psychoactive drugs acting as 5-HT2AR agonists include the indoleamines, LSD and DMT, and the substituted phenylethylamines such as DOM and 25I-NBOMe.

Murine Models for the 5-HT2A Receptor

To understand the complex pharmacology of 5-HT2AR and to ensure the clinical success of developing therapeutics, mice (Murine) are often used as a first model organism. Drugs acting as 5-HT2AR agonists can be identified in mice through the head twitch response (HTR). When a mouse is administered a 5-HT2AR selective agonist there is a paroxysmal rotational movement of the head. This action is blocked by the treatment of selective 5-HT2AR antagonists or mice lacking the 5-HT2AR gene. While there is evidence the 5-HT2C receptor can also be responsible for the HTR, the 5-HT2AR induced HTR is a quantifiable model that often correlates with drugs inducing hallucinogenic experiences in humans and has been extended to correlate with a human–drug dosage.

Mouse models have been useful to distinguish ligand effects on different 5-HT receptor subtypes. For instance, the indoleamine psilocin was shown to act as a nonselective 5-HT receptor agonist with activity against the 5-HT1A, 5-HT2A, and 5-HT2C receptors, whereas 1-methyl psilocin was shown to act selectivity to 5-HT2A. The psychedelic compound 25CN-NBOH has been shown to be highly selective for the 5-HT2AR over other serotonin receptors. However, as demonstrated through in vivo mouse models, 25CN-NBOH selectivity does not correspond to a high efficacy matched by the nonselective agonist DOI, suggesting potential pharmacokinetic factors such as metabolism, absorption, and/or distribution. Both compounds, DOI and 25CN-NBOH, have also been implicated in temporal and spatial perception in mice by acting selectivity through 5-HT2AR.

The 5-HT2AR amino acid sequence is highly conserved between species, with the mouse and human receptor sharing 91% sequence identity. Only a single amino acid residue differs within the orthosteric binding pocket; in the human 5-HT2AR there is a serine amino acid, whilst in the mouse 5-HT2AR this position is replaced with alanine.

In the human 5-HT2AR crystal structure, the serine2425.46 hydroxyl side chain forms specific hydrogen bonding interactions with LSD (Figure 3). Replacing serine with alanine would abrogate this hydrogen bonding interaction which was supported through mutagenesis studies. Mutating serine 2425,46 to alanine was able to maintain the binding affinity of LSD but resulted in an increased dissociation rate from the receptor suggesting a role of serine242 in the long binding kinetics to LSD. This interaction may be ligand-specific as other 5-HT2AR agonists and antagonists do not form the hydrogen bond interaction.

Even prior to the 5-HT2AR crystal structure, Canal et al. showed the importance of the human 5-HT2AR interaction with the serine242 residue for binding trans-4-phenyl-2-dimethyl aminotetralin (PAT) compounds (Figure 4). Specifically, (+)-6-OH-7-Cl-PAT had a 40-fold-lower binding affinity at the mouse receptor compared to the human and was inactive against the mouse 5-HT2AR, but a partial agonist to the human 5-HT2AR. Mutating the human 5-HT2AR serine 242 to alanine residue resulted in decreased binding affinity which was comparable to the wild type mouse 5-HT2AR. Molecular docking showed the (+)-6-OH-7-Cl-PAT to interact specifically with serine 242. The presence of two chiral centers in the PAT compounds highlights the importance of three-dimensional complementarity in receptor binding and activation.

In a related study, Dougherty et al. showed the receptor binding affinity for several compounds was not correlated between mice and human 5-HT2AR, this difference was most pronounced in 5-HT2AR antagonists. Daugherty et al. also demonstrated the importance of 5-HT2A receptor density within the frontal cortex. Receptor density accounts for the number of responding units (receptors) within a target, and a high receptor density can elicit a greater dose-response. Understanding receptor density is important as it can explain agonist-induced effects between different species and diseases. Daugherty et al. showed the 5-HT2A receptor density is similar between mice and humans in native systems. Mice chronically treated with the agonist DOI had reduced receptor density which was correlated with a reduction in head twitch response; in contrast, treatment with a 5-HT2AR antagonist resulted in an up-regulation of the receptor.

Understanding the drug effects on receptor density can be surrogate as disease models in humans. For instance, a recent study involving schizophrenic post-mortem samples suggested the number of available binding 5-HT2AR is increased compared to non–schizophrenic patients. Comparatively, at post-mortem, schizophrenic patients treated with antipsychotics had reduced 5-HT2AR density suggesting a role of hyperactive 5-HT2AR in schizophrenia. Increased 5-HT2AR density or hyperactive receptors have also been implicated in the pathogenesis of major depressive disorders and treatment with antidepressants may lead to their downregulation, resulting in antidepressant effects.

The role of mouse models can also help identify new psychoactive compounds. Recently, quipazine and 2-naphthalene piperazine (2-NP) had been shown to be agonists of 5-HT2AR and induced a HTR in mice that were blocked by 5-HT2AR antagonist M100907. For quipazine, binding affinity was similar across species. Interestingly, the related analogues isoquipazine and 1-naphthalene piperazine (1-NP) acted as antagonists on the 5-HT2AR. The authors go on to suggest that quipazine and 2-NP belong to classical psychedelics outside core phenylethylamine structure and point to the relatively unexplored psychedelic chemical space.

Conclusion

Murine models have provided some key insights into the function of the 5-HT2AR and its ability to bind agonist compounds by inducing the head twitch response. Important developments have been in understanding the species differences in receptor binding affinities and receptor densities which can then be applied to disease (mice) models to support translational medicine. Mice models have also been used to help identify 5-HT2AR agonists which could potentially be psychoactive in humans. As with any scientific or animal model, it is essential to clearly and explicitly identify the purpose of the model which then must be validated.

*From the article here :
 
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Editor’s Choice Award 2021 ~ Best Study on Psychedelics and Pharmacology*

by Barbara E. Bauer, MS | Psychedelic Science Review | 9 Dec 2021

The pace of psychedelic research continued its acceleration during 2021, culminating in several fascinating and groundbreaking studies. As the year comes to a close, Psychedelic Science Review is acknowledging some of the outstanding research papers of 2021.

This year, the Editor’s Choice Award for the best study on psychedelics and pharmacology goes to Dr. Adam Klein of the Department of Psychiatry at the Unversity of California San Diego and his research team, Muhammad Chatha, Lauren Laskowski, Emilie Anderson, Simon Brandt, Stephen Chapman, John McCorvy, and Adam Halberstadt. Their paper reported on the results of their work studying the SAR (structure-activity relationship) of 17 structurally related tryptamine compounds, all analogs of the magic mushroom compound psilocybin.1

The tryptamines used in the study were all 4-substituted N,N-di-alkyltryptamines. Chemically, these compounds can be further divided into two categories, 4-acetoxy (4-AcO) substituted and, 4-hydroxy (4-HO) substituted. The compounds they tested included 4-AcO-DMT (psilacetin), 4-HO-DMT (psilocin), 4-HO-DPT, and 4-HO-MiPT.

SARs are essential in medical and pharmaceutical research because they show how the chemical structure of a compound relates to its biological activity. Earlier this year, Psychedelic Science Review ran an article summarizing the findings of the Klein et al. study. Here are the highlights:​
  • All compounds behaved as full or partial agonists at the serotonin receptors, displaying similar potencies at 5-HT2A and 5-HT2B.​
  • Some compounds with bulkier N-alkyl groups (e.g., N,N-diisopropyl) had lower potency at 5-HT2C and higher 5-HT2B receptor efficacy.​
  • Compared to their 4-HO analogs, the 4-AcO compounds exhibited reduced in vitro 5-HT2A potency by about 10- to 20-fold.​
  • In contrast, the 4-AcO and 4-HO compounds exhibited similar agonist efficacy in vivo, as shown in the HTR (head-twitch response) experiments, “suggesting that O-acetylated tryptamines may be deacetylated in vivo, acting as prodrugs.”​
In concluding, Dr. Klein and the research team stated, “…the tryptamine derivatives have psilocybin-like pharmacological properties, supporting their classification as psychedelic drugs.”

Barbara E. Bauer, MS

Barb is Editor and one of the founders of Psychedelic Science Review. Her goal is making accurate and concise psychedelic science research assessable so that researchers and private citizens can make informed decisions.

*From the article here :
 
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Editor’s Choice Award 2021 ~ Best Study on Psychedelics and Nature

by Barbara E. Bauer | Psychedelic Science Review | 7 Dec 2021

Authors: Fricke J, Sherwood AM, Halberstadt AL, Kargbo RB, Hoffmeister D.
Chemoenzymatic Synthesis of 5-Methylpsilocybin: A Tryptamine with Potential Psychedelic Activity
J Nat Prod. 2021;84(4):1403-1408.
doi:10.1021/acs.jnatprod.1c00087

The pace of psychedelic research continued its acceleration during 2021, culminating in several fascinating and groundbreaking studies. As the year comes to a close, Psychedelic Science Review is acknowledging some of the outstanding research papers of 2021.

This year, the Editor’s Choice Award for the best study on psychedelics and nature goes to Dr. Janis Fricke of the Hans Knöll Institute and his research team consisting of Alexander Sherwood, Adam Halberstadt, Robert Kargbo, and Dirk Hoffmeister. Their paper titled, “Chemoenzymatic Synthesis of 5‑Methylpsilocybin: A Tryptamine with Potential Psychedelic Activity” describes the chemoenzymatic process they developed for synthesizing usable quantities of 5-methylpsilocybin.1 They also tested the compound for psychedelic activity using the mouse head twitch response (HTR).

The team was interested in studying 5-methylpsilocybin because, as they explained, “While individual substitutions at either the C4 or C5 position of the N,N-dialkyltryptamine core have been explored for potential psychedelic like activity, few examples exist where compounds with combined C4 and C5 substitutions were explored.”

The first step in the process involved chemically synthesizing (the ‘chemo’ part) the precursor compound 5-methylpsilocin. Then, in the ‘enzymatic’ part of the method, the team used an enzyme called 5-hydroxytryptamine kinase, which they isolated from the magic mushroom Psilocybe cubensis and then purified. The enzyme phosphorylated 5-methylpsilocin to 5-methylpsilocybin. The authors said, “The zwitterionic product was isolated from the enzymatic step with high purity utilizing a solvent−antisolvent precipitation approach.”

Dr. Fricke and his colleagues reported that the HTR data “indicated activity [for 5-methylpsilocbyin] that was more potent than the psychedelic dimethyltryptamine (DMT), but less potent than that of psilocybin.”

Barb is Editor and one of the founders of Psychedelic Science Review. Her goal is making accurate and concise psychedelic science research assessable so that researchers and private citizens can make informed decisions.

 
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Unifying Theories of Psychedelic Drug Effects

Link R. Swanson 1,2,3*​
  • 1Center for Cognitive Sciences, University of Minnesota, Minneapolis, MN, United States​
  • 2Department of Philosophy, University of Minnesota, Minneapolis, MN, United States​
  • 3Minnesota Center for Philosophy of Science, University of Minnesota, Minneapolis, MN, United States​
How do psychedelic drugs produce their characteristic range of acute effects in perception, emotion, cognition, and sense of self? How do these effects relate to the clinical efficacy of psychedelic-assisted therapies? Efforts to understand psychedelic phenomena date back more than a century in Western science. In this article I review theories of psychedelic drug effects and highlight key concepts which have endured over the last 125 years of psychedelic science. First, I describe the subjective phenomenology of acute psychedelic effects using the best available data. Next, I review late 19th-century and early 20th-century theories—model psychoses theory, filtration theory, and psychoanalytic theory—and highlight their shared features. I then briefly review recent findings on the neuropharmacology and neurophysiology of psychedelic drugs in humans. Finally, I describe recent theories of psychedelic drug effects which leverage 21st-century cognitive neuroscience frameworks—entropic brain theory, integrated information theory, and predictive processing—and point out key shared features that link back to earlier theories. I identify an abstract principle which cuts across many theories past and present: psychedelic drugs perturb universal brain processes that normally serve to constrain neural systems central to perception, emotion, cognition, and sense of self. I conclude that making an explicit effort to investigate the principles and mechanisms of psychedelic drug effects is a uniquely powerful way to iteratively develop and test unifying theories of brain function.

Introduction

Lysergic acid diethylamide (LSD), N,N-dimethyltryptamine (DMT), psilocybin, and mescaline—the ‘classic’ psychedelic drugs—can produce a broad range of effects in perception, emotion, cognition, and sense of self. How do they do this? Western science began its ‘first wave’ of systematic investigations into the unique effects of mescaline 125 years ago. By the 1950s, rising interest in mescaline research was expanded to include drugs like DMT, LSD, and psilocybin in a ‘second wave’ of psychedelic science. Because of their dramatic effect on the character and contents of subjective awareness, psychedelic drugs magnified the gaps in our scientific understanding of how brain chemistry relates to subjective experience commented that our understanding circa 1954 was “absurdly inadequate” and amounted to a mere “clue” that he hoped would soon develop into a more robust understanding. “Meanwhile the clue is being systematically followed, the sleuths—biochemists, psychiatrists, psychologists—are on the trail." A ‘third wave’ of psychedelic science has recently emerged with its own set of sleuths on the trail, sleuths who now wield an arsenal of 21st-century scientific methodologies and are uncovering new sets of clues.

Existing theoretical hurdles span five major gaps in understanding. The first gap is that we do not have an account of how psychedelic drugs can produce such a broad diversity of subjective effects. LSD, for example, can produce subtle intensifications in perception—or it can completely dissolve all sense of space, time, and self. What accounts for this atypical diversity?

The second gap is that we do not understand how pharmacological interactions at neuronal receptors and resulting physiological changes in the neuron lead to large-scale changes in the activity of neural populations, or changes in brain network connectivity, or at the systems-level of global brain dynamics. What are the causal links in the multi-level pharmaco-neurophysiological chain?

The third gap is that we do not know how psychedelic drug-induced changes in brain activity—at any level of description—map onto the acute subjective phenomenological changes in perception, emotion, cognition, and sense of self. This kind of question is not unique to psychedelics, but our current understanding of psychedelic drug effects clearly magnifies the disconnect between brain science and subjective experience.

Fourth, there is a gap in our understanding of the relationships between psychedelic effects and symptoms of psychoses, such as perceptual distortion, hallucination, or altered self-reference. What is the relationship between psychedelic effects and symptoms of chronic psychotic disorders?

Fifth and finally, there is a gap in our clinical understanding of the process by which psychedelic-assisted therapies improve mental health. Which psychedelic drug effects (in the brain or in subjective experience) enable clinical improvement? How?

Scientific efforts to understand diverse natural phenomena aim to produce a single theory that can account for many phenomena using a minimal set of principles. Such theories are sometimes called unifying theories. Not everyone agrees on the meaning of ‘unification’ or ‘unifying theory’ in science. Morrison observed that, although theory unification is a messy process which may not have discernible universal characteristics, historically successful unifying scientific theories tend to have two common features: (1) a formalized framework (quantitative mathematical descriptions of the phenomena) and (2) unifying principles (abstract concepts that unite diverse phenomena). On this conception, then, a unifying theory of psychedelic drug effects would offer a single formalized (mathematical or computational) framework capable of describing diverse psychedelic phenomena using a minimal set of unifying principles. Unfortunately, the survey of literature in this review does not locate an existing unifying theory of psychedelic drug effects. It does, however, highlight enduring abstract principles that recur across more than a century of theoretical efforts. Furthermore, it reviews recent formalized frameworks which, although currently heterogeneous and divergent, hint at the possibility of a quantitative groundwork for a future unifying theory.

The field of cognitive neuroscience offers formalized frameworks and general principles designed to track and model the neural correlates of perception, emotion, cognition, and consciousness. These broad frameworks span major levels of description in the brain and attempt to map them onto behavioral and phenomenological data. Corlett et al. argue that until this is done “our understanding of how the pharmacology links to the symptoms will remain incomplete.” Montague et al. argue that ‘computational psychiatry’ can remedy the “lack of appropriate intermediate levels of description that bind ideas articulated at the molecular level to those expressed at the level of descriptive clinical entities.” Seth argues that “computational and theoretical approaches can facilitate a transition from correlation to explanation in consciousness science” and explains how a recent LSD, psilocybin, and ketamine study was motivated by a need to elucidate descriptions at intermediate levels somewhere between pharmacology and phenomenology: “We know there’s a pharmacological link, we know there’s a change in experience and we know there’s a clinical impact. But the middle bit if you like, what are these drugs doing to the global activity of the brain, that’s the gap we’re trying to fill with this study." Taken together, the above quotations point to an emerging sense that cognitive neuroscience frameworks can address gaps in our understanding of psychedelic drug effects.

In this article I review theories of psychedelic drug effects. First, making an effort to clearly define the target explananda, I review the acute subjective phenomenological properties of psychedelic effects as well as long-term clinical outcomes from psychedelic-assisted therapies. Second, I review theories from first-wave and second-wave psychedelic science—model psychoses theory, filtration theory, and psychoanalytic theory—and identify core features of these theories. Third, I review findings from recent neurophysiological research in humans under psychedelic drugs. Finally, I review select 21st-century theories of psychedelic effects that have been developed within cognitive neuroscience frameworks; namely, entropic brain theory, integrated information theory, and predictive processing. My analysis of recent theoretical efforts highlights certain features, first conceptualized in 19th- and 20th-century theories, which remain relevant in their ability to capture both the phenomenological and neurophysiological dynamics of psychedelic effects. I describe how these enduring theoretical features are now being operationalized into formalized frameworks and could serve as potential unifying principles for describing diverse psychedelic phenomena.​

Psychedelic Drug Effects

There are dozens of molecules known to cause psychedelic-like effects. This review focuses only on a limited set of drugs dubbed ‘classical hallucinogens’ or ‘classic psychedelics’ which are: LSD, DMT, psilocybin, and mescalin. Importantly, there are qualitative inter-drug differences between the effects of the four classic psychedelic drugs. Drug dosage is a primary factor in predicting the types of effects that will occur. Effects unfold temporally over a drug session; onset effects are distinct from peak effects and some effects have a higher probability of occurring at specific timepoints over the total duration of drug effects. Furthermore, effects are influenced by non-drug factors traditionally referred to as set and setting, such as personality, pre-dose mood, drug session environment, and external stimuli (Figure 1).

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FIGURE 1. ‘Extra-pharmacological’ factors that can determine psychedelic drug effects may be biological [e.g., receptor polymorphisms or psychological in nature [e.g., personality or suggestibility. The pre-state refers to such things as anticipatory anxiety, expectations and assumptions (which account for so-called ‘placebo’ and ‘nocebo’ effects), and readiness to surrender resistances and ‘let go’ to the drug effects. In the context of psychedelic research, the pre-state is traditionally referred to as the ‘set’. State refers to the acute subjective and biological quality of the drug experience and may be measured via subjective rating scales or brain imaging. Dose relates to the drug dosage—which may be a critical determinant of state—as well as long-term outcomes. Environment relates to the various environmental influences. In the context of psychedelic research this is traditionally referred to as ‘setting’. We recognize that the environment can be influential at all stages of the process of change associated with drug action. The long-term outcomes may include such things as symptoms of a specific psychiatric condition such as depression—measured using a standard rating scale as well as relatively pathology-independent factors such as personality and outlook.

The above variables, while crucial, do not completely prohibit meaningful characterization of general psychedelic effects, as numerous regularities, patterns, and structure can still be identified. Indeed, common psychedelic effects can be reliably measured using validated psychometric instruments consisting of self-report questionnaires and rating scales, though some of these rating scales may be in need of further validation using modern statistical techniques. Items from these rating scales are wrapped in ‘scare quotes’ in the following discussion in an effort to characterize the subjective phenomenology of psychedelic effects from a first-person perspective. An example of rating scale results is given in (Figure 2).

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FIGURE 2. Subjective rating scale items selected after psilocybin (blue) and placebo. “Items were completed using a visual analog scale format, with a bottom anchor of ‘no, not more than usually’ and a top anchor of ‘yes, much more than usually’ for every item, with the exception of ‘I felt entirely normal,’ which had bottom and top anchors of ‘No, I experienced a different state altogether’ and ‘Yes, I felt just as I normally do,’ respectively. Shown are the mean ratings for 15 participants plus the positive SEMs. All items marked with an asterisk were scored significantly higher after psilocybin than placebo infusion at a Bonferroni-corrected significance level of p < 0.0022.

Perceptual Effects

Perceptual effects occur along a dose-dependent range from subtle to drastic. The range of different perceptual effects includes perceptual intensification, distortion, illusion, mental imagery, elementary hallucination, and complex hallucination. Intensifications of color saturation, texture definition, contours, light intensity, sound intensity, timbre variation, and other perceptual characteristics are common. The external world is experienced as if in higher resolution, seemingly more crisp and detailed, often accompanied by a distinct sense of ‘clarity’ or ‘freshness’ in the environment. Sense of meaning in percepts is altered, e.g., ‘Things around me had a new strange meaning for me’ or ‘Objects around me engaged me emotionally much more than usual’.

Perceptual distortions and illusions are extremely common, e.g., ‘Things looked strange’ or ‘My sense of size and space was distorted’ or ‘Edges appeared warped’ or ‘I saw movement in things that weren’t actually moving’. Textures undulate in rhythmic movements, object boundaries warp and pulsate, and the apparent sizes and shapes of objects can shift rapidly. Controlled psychophysical studies have measured various alterations in motion perception, object completion, and binocular rivalry.

In what are known as elementary hallucinations—e.g., ‘I saw geometric patterns’—the visual field can become permeated with intricate tapestries of brightly colored, flowing latticework and other geometric visuospatial ‘form constants’. In complex hallucinations visual scenes can present elaborate structural motifs, landscapes, cities, galaxies, plants, animals, and human (and non-human) beings. Complex hallucinations typically succeed elementary hallucinations and are more likely at higher doses especially under DMT. Both elementary and complex hallucinations are more commonly reported behind closed eyelids (‘closed eye visuals’; CEVs) but can dose-dependently occur in full light with eyes open (‘open eye visuals’; OEVs). CEVs are often described as vivid mental imagery. Under psychedelic drugs, mental imagery becomes augmented and intensified—e.g., ‘My imagination was extremely vivid’—and is intimately linked with emotional and cognitive effects. “Sometimes sensible film-like scenes appear, but very often the visions consist of scenes quite indescribable in ordinary language, and bearing a close resemblance to the paintings and sculptures of the surrealistic school." Psychedelic mental imagery can be modulated by both verbal and musical auditory stimuli. Synaesthesia has been reported, especially visual phenomena driven by auditory stimuli—‘Sounds influenced the things I saw’—but classification of these effects as ‘true’ synaesthesia is actively debated.

Somatosensory perception can be drastically altered—e.g., ‘I felt unusual bodily sensations’—including body image, size, shape, and location. Sense of time and causal sequence can lose their usual linear cause-effect structure making it difficult to track the transitions between moments.

Overall the perceptual effects of psychedelics are extremely varied, multimodal, and easily modulated by external stimuli. Perceptual effects are tightly linked with emotional and cognitive effects.

Emotional Effects

Emotional psychedelic effects are characterized by a general intensification of feelings, increased (conscious) access to emotions, and a broadening in the overall range of emotions felt over the duration of the drug session. Psychedelics can induce unique states of euphoria characterized by involuntary grinning, uncontrollable laughter, silliness, giddiness, playfulness, and exuberance. Negatively experience emotions—e.g., ‘I felt afraid’ or ‘I felt suspicious and paranoid’—are often accompanied by a general sense of losing control, e.g., ‘I feared losing control of my mind’.

However, the majority of emotional psychedelic effects in supportive contexts are experienced as positive. Both LSD and psilocybin can bias emotion toward positive responses to social and environmental stimuli. Spontaneous feelings of awe, wonder, bliss, joy, fun, excitement (and yes, peace and love) are also consistent themes across experimental and anecdotal reports. In supportive environments, classic psychedelic drugs can promote feelings of trust, empathy, bonding, closeness, tenderness, forgiveness, acceptance, and connectedness. Emotional effects can be modulated by all types of external stimuli, especially music.

Cognitive Effects

Precise characterization of cognitive psychedelic effects has proven enigmatic and paradoxical. Acute changes in the normal flow of linear thinking—e.g., ‘My thinking was muddled’ or ‘My thoughts wandered freely’—are extremely common. This is reflected in reduced performance on standardized measures of working memory and directed attention; however, reductions in performance have been shown to occur less often in individuals with extensive past experience with the drug’s effects. Crucially, cognitive impairments related to acute psychedelic effects are dose-dependent. Extremely low doses, known as microdoses, have been anecdotally associated with improvements in cognitive performance “a claim that urgently requires empirical verification through controlled research." Theoretical attempts to account for the reported effects of microdosing have yet to emerge in the literature and therefore present an important opportunity to future theoretical endeavors.

Certain cognitive traits associated with creativity can increase under psychedelics such as divergent thinking, use of unlikely language patterns or word associations, expansion of semantic activation, and attribution of meaning to perceptual stimuli especially musical stimuli. Primary-process thinking—a widely validated psychological construct associated with creativity—is characterized phenomenologically by “image fusion; unlikely combinations or events; sudden shifts or transformations of images; and contradictory or illogical actions, feelings, or thoughts." Psilocybin and LSD have been shown to increase primary-process thinking as well as the subjective bizarreness and dreamlike nature of mental imagery associated with verbal stimuli. Cognitive flexibility (or ‘loosening’ of cognition) and optimism can remain for up to 2 weeks after the main acute drug effects have dissipated. Furthermore, long-term increases in creative problem-solving ability (Sweat et al., 2016) and personality trait openness have been measured after just one psychedelic experience.

Ego Effects and Ego Dissolution Experiences

Klüver observed that under peyote “the line of demarcation drawn between ‘object’ and ‘subject’ in normal state seemed to be changed. The body, the ego, became ‘objective’ in a certain way, and the objects became ‘subjective.”’ Similar observations continued throughout first-wave and second-wave psychedelic science. Importantly, effects on sense of self and ego occur along a dose-dependent range spanning from subtle to drastic. Subtle effects are described as a ‘softening’ of ego with increased insight into one’s own habitual patterns of thought, behavior, personal problems, and past experiences; effects which were utilized in ‘psycholytic’ psychotherapy. Drastic ego-effects, known as ego dissolution3, are described as “the dissolution of the sense of self and the loss of boundaries between self and world” —e.g., ‘I felt like I was merging with my surroundings’ or ‘All notion of self and identity dissolved away’ or ‘I lost all sense of ego’ or ‘I experienced a loss of separation from my environment’ or ‘I felt at one with the universe’. These descriptions resemble non-drug ‘mystical-type’ experiences; however, the extent of overlap here remains an open question. Ego dissolution is more likely to occur at higher doses. Furthermore, certain psychedelic drugs cause ego dissolution experience more reliably than others; psilocybin, for example, was found to produce full ego dissolution more reliably compared with LSD. Ego dissolution experiences can be driven and modulated by external stimuli, most notably music. Interestingly, subjects who experienced ‘complete’ ego dissolution in psychedelic-assisted therapy were more likely to evidence positive clinical outcomes as well as long-term changes in life outlook and the personality trait openness.

Clinical Efficacy and Long-Term Effects

Mescaline-assisted therapies showed promising results during first-wave psychedelic science and this trend continued through second-wave psychedelic research on LSD-assisted therapies. Recent studies have produced significant evidence for the therapeutic utility of psychedelic drugs in treating a wide range of mental health issues, including anxiety and depression, obsessive-compulsive disorder, and addiction to alcohol and tobacco. In many clinical studies, ego-dissolution experience has correlated with positive clinical outcomes.

Remarkably, as mentioned above, a single psychedelic experience can increase optimism for at least 2 weeks after the session and can produce lasting changes in personality trait openness. A study of regular (weekly) ayahuasca users showed improved cognitive functioning and increased positive personality traits compared with matched controls. Interestingly, these outcomes may expand beyond sanctioned clinical use, as illicit users of classic psychedelic drugs within the general population self-report positive long-term benefits from their psychedelic experiences, are statistically less likely to evidence psychological distress and suicidality, and show an overall lower occurrence of mental health problems in general.

Summary

The above evidence demonstrates the broad diversity of acute subjective effects that classic psychedelic drugs can produce in perceptual, emotional, and cognitive domains. Unique changes in sense of self, ego, body image, and personal meaning are particularly salient themes. How do these molecules produce such dramatic effects? What are the relationships between acute perceptual, emotional, cognitive, and self-related effects? What is the link between acute effects and long-term changes in mental health, personality, and behavior? Theories addressing these questions emerged as soon as Western science recognized the need for a scientific understanding of psychedelic drug effects beginning in the late 19th century.

 
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Cambridge

Unifying Theories of Psychedelic Drug Effects, cont'd

Link R. Swanson 1,2,3*
  • 1Center for Cognitive Sciences, University of Minnesota, Minneapolis, MN, United States
  • 2Department of Philosophy, University of Minnesota, Minneapolis, MN, United States
  • 3Minnesota Center for Philosophy of Science, University of Minnesota, Minneapolis, MN, United States

19th and 20th Century Theories of Psychedelic Drug Effects

The effects described above are what captured the interest of first-wave and second-wave psychedelic scientists, and the theories they developed in their investigations have two central themes. The first theme is the observation that psychedelic effects share descriptive elements with symptoms of psychoses, such as hallucination, altered self-reference, and perceptual distortions. This theme forms the basis of model psychoses theory and is what motivated the adoption of the term ‘psychotomimetic’ drugs. The second theme is the observation that psychedelic drugs seem to expand the total range of contents presented subjectively in our perceptual, emotional, cognitive, and self-referential experience. This theme forms the basis of filtration theory and is what motivated the adoption of the term ‘psychedelic’ drugs. A third theoretical account uses psychoanalytic theory to address the expanded range of mental phenomena produced by psychedelic drugs as well as the shared descriptive elements with symptoms of psychoses. The next section reviews these themes along with their historically associated theories before tracing their evolution into third-wave (21st-century) psychedelic science.

Model Psychoses Theory

When Lewin ‘discovered’ the peyote cactus, his reports caught the attention of adventurous 19th-century scientists like, and Ellis, who promptly obtained samples and began consuming the cactus and observing its effects on themselves. When Heffter (1898] isolated mescaline from the peyote cactus and Späth paved the way for laboratory synthesis, scientists began systematically dosing themselves (along with their colleagues and students) with mescaline and publishing their findings in medical journals, intrigued by the approach of Knauer and Maloney, ingested peyote at the University of Minnesota Psychological Laboratory and, after the effects had taken hold, completed standard psychophysical measures. Klüver argued that systematic investigations into the neural mechanisms of mescaline effects would help neurology “elucidate more general questions of the psychology and pathology of perception.” However, it was the pathology aspect, not the general psychology questions, which became the dominant focus of ensuing mescaline research paradigms.

Model psychoses theory began long before any of the classic psychedelic drugs became known to Western science. Moreau linked hashish effects with mental illness and Kraepelin founded “pharmacopsychology” by dosing himself and his students with various psychoactive drugs in the laboratory of Wilhelm Wundt. These scientists hoped to study psychotic symptoms using drugs to induce ‘model psychoses’ (1) in themselves, to gain first-person knowledge of the phenomenology of psychotic symptoms "by administering to one another such substances as will produce in us transitory psychoses," and (2) in normal research subjects, allowing for laboratory behavioral observations on how the symptoms emerge and dissipate. Kraepelin and colleagues attempted to model psychoses using many drugs—“tea, alcohol, morphine, trional, bromide, and other drugs”—yet Kraepelin’s pupils Knauer and Maloney argued that these drugs unfortunately “produce mental states which have little similarities to actual insanities” and argued instead that mescaline was unique in its ability to truly model psychoses. The dramatic subjective effects of mescaline invigorated the model psychoses paradigm. Growing demand for the ideal chemical agent for model psychoses eventually motivated Sandoz Pharmaceuticals to bring LSD to market in the 1940s.

Importantly, model psychoses theory was not initially a theory of drug effects; it was an idealistic paradigm for researching psychoses that was already in use before Western science ‘discovered’ classic psychedelic drugs. Nonetheless, it seeded the idea that psychedelic effects themselves could be explained in terms of psychopathology and motivated a search for common neural correlates. The founding figures of neuropharmacology were driven by questions regarding the relationship between psychoactive drugs and endogenous neurochemicals. The putative psychoses-mimicking effects of LSD and mescaline inspired the idea that psychotic symptoms might be caused by a “hypothetical endotoxin” or some yet-unknown endogenous neurochemical gone out of balance. The discovery that LSD can antagonize serotonin led to the hypothesis that the effects of LSD are serotonergic and simultaneously to the historic hypothesis6 that serotonin might play a role in regulating mental function.

At the 1955 Second Conference on Neuropharmacology the whole class of drugs was dubbed psychotomimetic. Interestingly, the word mimetic means to “imitate” “mimic” or “exhibit mimicry” which is the act of appearing as something else—for example, when one species mimics the appearance or behavior of another (e.g., the non-venomous bullsnake rattles its tail against dry leaves to mimic a venomous rattlesnake). Psychotomimetic drug effects, on this literal reading of the term, would merely mimic or imitate—appear as if they are—psychoses. However, to mimic is not to model. A model intends to capture important structural or functional principles of the entity or phenomena that it models. A mimic, by contrast, merely creates the illusion that it possesses the properties it mimics. Thus, the term psychotomimetic implies that the effects of these drugs merely resemble psychoses but do not share functional or structural properties in their underlying biology or phenomenology. Nonetheless, LSD and mescaline were used as models to investigate psychotic symptoms. Yet the scientific utility of drug models hinges on our understanding of the mechanisms underpinning the drugs’ effects; we still need a theory of how psychotomimetic drugs work. A subtle explanation-explananda circularity can come into play here, in which psychoses are explained using drug models yet the drug effects are explained using theories of psychoses. Further complicating the matter is the clear difference between acutely induced drug effects and the gradual development of a chronic mental illness. This cluster of conceptual challenges poured fuel on the flaming debates about the merits of drug-induced model psychoses, which in 1957 had already “smoldered for nearly 50 years." An additional conceptual challenge was the fact that mescaline had for years shown promise in treating psychopathologies, and LSD was gaining popularity for pharmaceutically enhanced psychotherapy. Model psychoses theory needed to explain how it was the case that drugs putatively capable of inducing psychotic symptoms could simultaneously be capable of treating them—What Osmond termed "the hair of the dog” problem. In fact, to this day “the apparent paradox by which the same compound can be both a model of, and yet a treatment for, psychopathology has never been properly addressed." Taken together, the above cluster of conceptual challenges drove Osmond to doubt his own prior work on model psychoses, and he declared ‘psychotomimetic’ an outmoded term, arguing that the effects of these drugs could not be captured wholly in terms of psychopathology. “If mimicking mental illness were the main characteristic of these agents, ‘psychotomimetics’ would indeed be a suitable generic term. It is true that they do so, but they do much more."

Filtration Theory

Osmond (1957) argued that the ‘psychotomimetic’ class of drugs needed a more appropriate name. “My choice, because it is clear, euphonious, and uncontaminated by other associations, is psychedelic, mind-manifesting." But how exactly should we understand psychedelic effects as ‘mind-manifesting’? Osmond’s nomenclature legacy was directly influenced by his friend Aldous Huxley, who described the core idea to Osmond in the following personal letter dated April 10, 1953:

Dear Dr. Osmond,
It looks as though the most satisfactory working hypothesis about the human mind must follow, to some extent, the Bergsonian model, in which the brain with its associated normal self, acts as a utilitarian device for limiting, and making selections from, the enormous possible world of consciousness, and for canalizing experience into biologically profitable channels. Disease, mescaline, emotional shock, aesthetic experience and mystical enlightenment have the power, each in its different way and in varying degrees, to inhibit the function of the normal self and its ordinary brain activity, thus permitting the ‘other world’ to rise into consciousness.
Yours sincerely,
Aldous Huxley


Huxley’s letter can help unpack the intended ‘mind-manifesting’ etymology of Osmond’s new term psychedelic. Huxley saw the biological function of the brain as a “device” engaged in a continuous process of elimination and inhibition to sustain the “normal self” of everyday waking experience to maximize adaptive fit. Huxley’s choice metaphor for visualizing this was the cerebral reducing valve (Figure 3).


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FIGURE 3. Aldous Huxley’s “cerebral reducing valve.” On the ‘inlet’ (right) side of the cerebral reducing valve is a vast ocean of all possible perceptual, emotional, and cognitive experiences. On the ‘outlet’ (left) side is our moment-to-moment stream of experience in normal waking life. Mechanisms inside the valve ‘reduce’ the character and contents of experience, ‘canalizing’ the ocean of possible experience into a more limited stream of waking consciousness aimed at maximum biological utility.

“What I have called the cerebral reducing valve [is a] normal brain function that limits our mental processes to an awareness, most of the time, of what is biologically useful” (Huxley) argued that this “normal brain function” emerges developmentally during the course of psychological maturity, so for a period during childhood, before the cerebral reducing valve has fully developed, “there is this capacity to live in a kind of visionary world.” Once the valve is fully developed, however, normal waking life becomes restricted to "a world fabricated by our everyday, biologically useful and socially conditioned perceptions, thoughts and feelings."

Huxley borrowed the core idea from 19th-century filtration theory accounts of various mental phenomena: “According to filtration theorists, consciousness is ordinarily kept narrow by biological and psychological selection processes that exclude a great deal of subconscious material." Filtration theorists include founding figures of psychopharmacology, psychology, and parapsychology, along with early 20th-century philosophers Bergson and Broad. Bergson applied his own filtration framework to drug effects in his brief response to James’ glowing descriptions of what it is like to inhale nitrous oxide. James’ peculiar state of mind, explained Bergson, should be thought of as a latent potential of the brain/mind, which nitrous oxide simply “brought about materially, by an inhibition of what inhibited it, by the removing of an obstacle; and this effect was the wholly negative one produced by the drug." Huxley picked up Bergson’s line of thinking and eventually convinced Osmond that it was important to reflect this principle in scientific descriptions of the effects of LSD and mescaline. Smythies also subscribed to this idea, stating that “mescaline may be supposed to inhibit that function in the brain which specifically inhibits the mescaline phenomena from developing in the sensory fields.”

Thus, Osmond’s proposed name-change—psychedelic—was intended to capture the spirit of filtration theory. In this new descriptive model, psyche (mind) delic (manifesting) drugs manifest the mind by inhibiting certain brain processes which normally maintain their own inhibitory constraints on our perceptions, emotions, thoughts, and sense of self. Osmond and Huxley both found this principle highly applicable to their own direct first-person knowledge of what it is like to experience the effects of mescaline and LSD—the expanded range of feelings, intensification of perceptual stimuli, vivid vision-like mental imagery, unusual thoughts, and expanding (or dissolving) sense of self and identity.

Osmond argued that his ‘mind-manifesting’ description had further theoretical virtues that could address the conceptual challenges of model psychoses theory and improve our understanding of (1) the diverse range of psychedelic effects, (2) their relationship to psychotic symptoms, and (3) their role in psychedelic-assisted therapies. First, the pharmacological disruption of hypothetical inhibitory brain mechanisms that normally attenuate internal and external stimuli suggested that the kinds of effects produced by the drug would depend on the kinds of stimuli in the system, which is consistent with the diverse range of effects on multiple perceptual modalities, emotional experience, and cognition.

Second, the brain’s selective filtration mechanisms, while evolutionarily adaptive and biologically useful, could develop pathological characteristics in two fundamentally distinct ways. First, a chronically overactive filter limits too much of the mind, causing a rigid, dull, neurotic life in which mental contents become overly restricted to “those enumerated in the Sears-Roebuck catalog which constitutes the conventionally ‘real’ world." Second, a chronically underactive or ‘leaky’ filter places too few constraints on the mind and allows too much ‘Mind at Large’ to enter conscious awareness, potentially resulting in perceptual instability, cognitive confusion, or hallucination. This picture helped Huxley and Osmond understand the relationship between psychedelic phenomena and psychotic phenomena: temporarily opening the cerebral reducing valve with psychedelics could produce mental phenomena that resembled symptoms of chronic natural psychoses precisely because both were the result of (acute or chronic) reductions in brain filtration mechanisms.

Third and finally, filtration theory addressed the paradoxical “hair of the dog” issue—why drugs that ‘mimic’ psychoses can aid psychotherapy—which, as described in the previous section, was a conceptual challenge for model psychoses theory. The solution to the paradox was in the filtration theory idea that psychedelic drugs temporarily ‘disable’ brain filtration mechanisms, which could allow patients and therapists to work outside of the patient’s everyday (pathological) inhibitory mechanisms. Thus, filtration theory offered a way to understand psychedelic effects that was consistent with both their psychotomimetic properties and their therapeutic utility.

Osmond and Huxley argued that filtration theory concepts were fully consistent with the subjective phenomenology, psychotomimetic capability, and therapeutic efficacy of psychedelic drugs. However, it remains unclear exactly what it is that the brain is filtering and consequently what it is that emerges when the filter is pharmacologically perturbed by a psychedelic drug. According to Huxley, LSD and mescaline “inhibit the function of the normal self and its ordinary brain activity, thus permitting the ‘other world’ to rise into consciousness." Huxley (and Bergson) spoke of the brain as a device that filters the world and when the filter is removed we experience ‘more’ of reality. Osmond’s ‘mind-manifesting’ (psyche) (delic) name, by contrast, suggests that these drugs permit latent aspects of mind to rise into conscious awareness. So which is it? Do psychedelic drugs manifest latent aspects of mind or of world? How we answer this question will crucially determine our ontological and epistemological conclusions regarding the nature of psychedelic experience. Huxley and Osmond did not make this clear. Huxley seems to favor the position that psychedelic experience reveals a wider ontological reality and grants epistemic access to greater truth. Osmond’s view, on which these drugs reveal normally hidden aspects of mind, seems less radical, more compatible with materialist science, and less epistemically and ontologically committed. Still, if mind provides us with access to world, then lifting restrictions on mind could in principle expand our access to world. This important point resurfaces in section “Predictive Processing” below.

Psychoanalytic Theory

Freud developed an elaborate theoretical account of mental phenomena which, like filtration theory, placed great emphasis on inhibition mechanisms in the nervous system.8 Freud divided the psyche into two fundamentally distinct modes of activity: the primary process and the secondary process. In the primary process, the exchange of “neuronal energy” is “freely mobile” and its psychological dynamics are characterized by disorder, vagueness, conceptual paradox, symbolic imagery, intense emotions, and animistic thinking. In the secondary process, by contrast, the exchange of neuronal energy is “bound” and its psychological dynamics are characterized by order, precision, conceptual consistency, controlled emotions, and rational thinking. Freud hypothesized that the secondary process is maintained by an organizing neural “mass” called the ego which “contains” and exerts control over the primary process by binding primary process activity into its own pattern of activity. Freud hypothesized that secondary process neural organization, sustained by the ego, is required for certain aspects of perceptual processing, directed attention, reality-testing, sense of linear time, and higher cognitive processes. When Freud’s ego is suppressed, such as during dream sleep, wider worlds of experience can emerge, but secondary process functions are lost. The secondary process and its supporting neural organizing pattern—the ego—emerges during ontogenetic development and solidifies with adult maturity: “A unity comparable to the ego cannot exist from the start; the ego has to be developed." Furthermore, pathological characteristics can emerge when Freud’s ego restricts either too much or too little of the primary process.

Freud himself was apparently uninterested in psychedelic drugs and instead emphasized dreams as “the royal road to a knowledge of the unconscious activities of the mind." Nonetheless, psychedelic drugs produce dreamlike visions and modes of cognition that feature symbolic imagery, conceptual paradox, and other hallmark characteristics of the primary process. How did other psychoanalytic theorists describe psychedelic drug effects? The core idea is that psychedelic drugs interfere with the structural integrity of the ego and thereby reduce its ability to suppress the primary process and support the secondary process. This ‘frees’ the primary process which then spills into conscious awareness, resulting in perceptual instability, wildly vivid imagination, emotional intensity, conceptual paradox, and loss of usual self-boundaries. Due in part to the close resemblance between psychedelic effects and primary process phenomena, psychoanalytic theory became the framework of choice during the mid 20th-century boom in psychedelic therapy. Psychedelic ego effects, which range from a subtle loosening to a complete dissolution of ego boundaries, were found to be great tools in psychotherapy because of their capacity to perturb ego and allow primary process phenomena to emerge.

But how do psychedelic drugs disrupt the structure of the ego? Freud hypothesized that the organizational structure of ego rests upon a basic perceptual schematic of the body and its surrounding environment. Perceptual signals are continuously ‘bound’ and integrated into the somatic boundaries of the ego. Savage speculated that the LSD’s perceptual effects and ego effects are tightly linked. “LSD acts by altering perception. Continuous correct perception is necessary to maintain ego feeling and ego boundaries. … Perception determines our ego boundaries. … disturbances in perception caused by LSD make it impossible for the ego to integrate the evidence of the senses and to coordinate its activities …” Savage’s insights into a set of hypotheses were aimed at elucidating the neurobiological mechanisms of a Freudian ‘stimulus barrier’ and its dissolution under LSD:

Such barriers would presumably consist of processes limiting the spread of excitation between different functional areas of the brain. The indications are that LSD, in some manner, breaks down these stimulus barriers of which Freud spoke. Nor is this merely a figure of speech. There is some reason to suspect that integrative mechanisms within the central nervous system (CNS) which handle inflowing stimuli are no longer able to limit the spread of excitation in the usual ways. We might speculate that LSD allows greater energy exchanges between certain systems than normally occurs, without necessarily raising the general level of excitation of all cortical and subcortical structures.

Freud hypothesized that ego is sustained by a delicate balance of ‘neuronal energy’ which critically depends on integrative mechanisms to process inflowing sensory stimuli and to ‘bind’ neural excitation into functional structures within the brain. Psychedelic drugs, according to Savage and Klee, perturb integrative mechanisms that normally bind and shape endogenous and exogenous excitation into the structure of the ego. As we will see below, Klee’s ideas strongly anticipate many neurophysiological findings and theoretical themes from 21st-century psychedelic science.

Summary

From the above analysis of first-wave and second-wave theories I have identified four recurring theoretical features which could potentially serve as unifying principles. One feature is the hypothesis that psychedelic drugs inhibit a core brain mechanism that normally functions to ‘reduce’ or ‘filter’ or ‘constrain’ mental phenomena into an evolutionarily adaptive container. A second feature is the hypothesis that this core brain mechanism can behave pathologically, either in the direction of too much, or too little, constraint imposed on perception, emotion, cognition, and sense of self. A third feature is the hypothesis that psychedelic phenomena and symptoms of chronic psychoses share descriptive elements because they both involve situations of relatively unconstrained mental processes. A fourth feature is the hypothesis that psychedelic drugs have therapeutic utility via their ability to temporarily inhibit these inhibitory brain mechanisms. But how are these inhibitory mechanisms realized in the brain?​

Neuropharmacology and Neurophysiological Correlates of Psychedelic Drug Effects

Klee recognized that his above hypotheses, inspired by psychoanalytic theory and LSD effects, required neurophysiological evidence. “As far as I am aware, however, adequate neurophysiological evidence is lacking … The long awaited millennium in which biochemical, physiological, and psychological processes can be freely correlated still seems a great distance off." What clues have recent investigations uncovered?

A psychedelic drug molecule impacts a neuron by binding to and altering the conformation of receptors on the surface of the neuron . The receptor interaction most implicated in producing classic psychedelic drug effects is agonist or partial agonist activity at serotonin (5-HT) receptor type 2A (5-HT2A). A molecule’s propensity for 5-HT2A affinity and agonist activity predicts its potential for (and potency of) subjective psychedelic effects. When a psychedelic drug’s 5-HT2A agonist activity is intentionally blocked using 5-HT2A antagonist drugs (e.g., ketanserin), the subjective effects are blocked or attenuated in humans under psilocybin, LSD, and ayahuasca. Importantly, while the above evidence makes it clear that 5-HT2A activation is a necessary (if not sufficient) mediator of the hallmark subjective effects of classic psychedelic drugs, this does not entail that 5-HT2A activation is the sole neurochemical cause of all subjective effects. For example, 5-HT2A activation might trigger neurochemical modulations ‘downstream’ (e.g., changes in glutamate transmission) which could also play causal roles in producing psychedelic effects. Moreover, most psychedelic drug molecules activate other receptors in addition to 5-HT2A, and these activations may importantly contribute to the overall profile of subjective effects even if 5-HT2A activation is required for their effects to occur.

How does psychedelic drug-induced 5-HT2A receptor agonism change the behavior of the host neuron? Generally, 5-HT2A activation has a depolarizing effect on the neuron, making it more excitable (more likely to fire). Importantly, this does not necessarily entail that 5-HT2A activation will have an overall excitatory effect throughout the brain, particularly if the excitation occurs in inhibitory neurons. This important consideration (captured by the adage ‘one neuron’s excitation is another neuron’s inhibition’) should be kept in mind when tracing causal links in the pharmaco-neurophysiology of psychedelic drug effects.

In mammalian brains, neurons tend to ‘fire together’ in synchronized rhythms known as temporal oscillations (brain waves). MEG and EEG equipment measure the electromagnetic disturbances produced by the temporal oscillations of large neural populations and these measurements can be quantified according to their amplitude (power) and frequency (timing). Specific combinations of frequency and amplitude can be correlated with distinct brain states, including waking ‘resting’ state, various attentional tasks, anesthesia, REM sleep, and deep sleep). In what ways do temporal oscillations change under psychedelic drugs? MEG and EEG studies consistently show reductions in oscillatory power across a broad frequency range under ayahuasca, psilocybin, and LSD. Reductions in the power of alpha-band oscillations, localized mainly to parietal and occipital cortex, have been correlated with intensity of subjective visual effects—e.g., ‘I saw geometric patterns’ or ‘My imagination was extremely vivid’—under psilocybin and ayahuasca. Under LSD, reductions in alpha power still correlated with intensity of subjective visual effects but associated alpha reductions were more widely distributed throughout the brain. Furthermore, ego-dissolution effects and mystical-type experiences (e.g., ‘I experienced a disintegration of my “self” or “ego”’ or ‘The experience had a supernatural quality’) have been correlated with reductions in alpha power localized to anterior and posterior cingulate cortices and the parahippocampal regions under psilocybin and throughout the brain under LSD.

The concept of functional connectivity rests upon fMRI brain imaging observations that reveal temporal correlations of activity occurring in spatially remote regions of the brain which form highly structured patterns (brain networks). Imaging of brains during perceptual or cognitive task performance reveals patterns of functional connectivity known as functional networks; e.g., control network, dorsal attention network, ventral attention network, visual network, auditory network, and so on. Imaging brains in taskless resting conditions reveals resting-state functional connectivity (RSFC) and structured patterns of RSFC known as resting state networks. One particular RSN, the default mode network (DMN; Buckner increases activity in the absence of tasks and decreases activity during task performance. DMN activity is strong during internally directed cognition and a variety of other ‘metacognitive’ functions. DMN activation in normal waking states exhibits ‘inverse coupling’ or anticorrelation with the activation of task-positive functional networks, meaning that DMN and functional networks are often mutually exclusive; one deactivates as the other activates and vice versa.

In what ways does brain network connectivity change under psychedelic drugs? First, functional connectivity between key ‘hub’ areas—mPFC and PCC—is reduced. Second, the ‘strength’ or oscillatory power of the DMN is weakened and its intrinsic functional connectivity becomes disintegrated as its component nodes become decoupled under psilocybin, ayahuasca, and LSD. Third, brain networks that normally show anticorrelation become active simultaneously under psychedelic drugs. This situation, which can be described as increased between-network functional connectivity, occurs under psilocybin, ayahuasca and especially LSD. Fourth and finally, the overall repertoire of explored functional connectivity motifs is substantially expanded and its informational dynamics become more diverse and entropic compared with normal waking states. Notably, the magnitude of occurrence of the above four neurodynamical themes correlates with subjective intensity of psychedelic effects during the drug session. Furthermore, visual cortex is activated during eyes-closed psychedelic visual imagery, and under LSD “the early visual system behaves ‘as if’ it were receiving spatially localized visual information” as V1-V3 RSFC is activated in a retinotopic fashion.

Taken together, the recently discovered neurophysiological correlates of subjective psychedelic effects present an important puzzle for 21st-century neuroscience. A key clue is that 5-HT2A receptor agonism leads to desynchronization of oscillatory activity, disintegration of intrinsic integrity in the DMN and related brain networks, and an overall brain dynamic characterized by increased between-network global functional connectivity, expanded signal diversity, and a larger repertoire of structured neurophysiological activation patterns. Crucially, these characteristic traits of psychedelic brain activity have been correlated with the phenomenological dynamics and intensity of subjective psychedelic effects.​

21st-Century Theories of Psychedelic Drug Effects

How should we understand the growing body of clues emerging from investigations into the neurodynamics of psychedelic effects? What are the principles that link these thematic patterns of psychedelic brain activity (or inactivity) to their associated phenomenological effects? Recent theoretical efforts to understand psychedelic drug effects have taken advantage of existing frameworks from cognitive neuroscience designed to track the key neurodynamic principles of human perception, emotion, cognition, and consciousness. The overall picture that emerges from these efforts shares core principles with filtration and psychoanalytic accounts of the late 19th and early 20th century. Briefly, normal waking perception and cognition are hypothesized to rest upon brain mechanisms which serve to suppress entropy and uncertainty by placing various constraints on perceptual and cognitive systems. In a ‘selecting’ and ‘limiting’ fashion, neurobiological constraint mechanisms support stability and predictability in the contents of conscious awareness in the interest of adaptability, survival, and evolutionary fitness. The core hypothesis of recent cognitive neuroscience theories of psychedelic effects is that these drugs interfere with the integrity of neurobiological information-processing constraint mechanisms. The net effect of this is that the range of possibilities in perception, emotion, and cognition is dose-dependently expanded. From this core hypothesis, cognitive neuroscience frameworks are utilized to describe and operationalize the quantitative neurodynamics of key psychedelic phenomena; namely, the diversity of effects across many mental processes, the elements in common with symptoms of psychoses, and the way in which temporarily removing neurobiological constraints is therapeutically beneficial.

This section is organized according to the broad theoretical frameworks informing recent theoretical neuroscience of psychedelic effects: entropic brain theory, integrated information theory, and predictive processing.​

Entropic Brain Theory

Entropic Brain Theory links the phenomenology and neurophysiology of psychedelic effects by characterizing both in terms of the quantitative notions of entropy and uncertainty. Entropy is a quantitative index of a system’s (physical) disorder or randomness which can simultaneously describe its (informational) uncertainty. EBT “proposes that the quality of any conscious state depends on the system’s entropy measured via key parameters of brain function." Their hypothesis states that hallmark psychedelic effects (e.g., perceptual destabilization, cognitive flexibility, ego dissolution) can be mapped directly onto elevated levels of entropy/uncertainty measured in brain activity, e.g., widened repertoire of functional connectivity patterns, reduced anticorrelation of brain networks, and desynchronization of RSN activity. More specifically, EBT characterizes the difference between psychedelic states and normal waking states in terms of how the underlying brain dynamics are positioned on a scale between the two extremes of order and disorder—a concept known as ‘self-organized criticality’. A system with high order (low entropy) exhibits dynamics that resemble ‘petrification’ and are relatively inflexible but more stable, while a system with low order (high entropy) exhibits dynamics that resemble ‘formlessness’ and are more flexible but less stable. The notion of ‘criticality’ describes the transition zone in which the brain remains poised between order and disorder. Physical systems at criticality exhibit increased transient ‘metastable’ states, increased sensitivity to perturbation, and increased propensity for cascading ‘avalanches’ of metastable activity. Importantly, EBT points out that these characteristics are consistent with psychedelic phenomenology, e.g., hypersensitivity to external stimuli, broadened range of experiences, or rapidly shifting perceptual and mental contents. Furthermore, EBT uses the notion of criticality to characterize the difference between psychedelic states and normal waking states as it “describes cognition in adult modern humans as ‘near critical’ but ‘sub-critical’—meaning that its dynamics are poised in a position between the two extremes of formlessness and petrification where there is an optimal balance between order and flexibility. EBT hypothesizes that psychedelic drugs interfere with ‘entropy-suppression’ brain mechanisms which normally sustain sub-critical brain dynamics, thus bringing the brain “closer to criticality in the psychedelic state."

Entropic Brain Theory further characterizes psychedelic neurodynamics using a neo-psychoanalytic framework proposed in an earlier paper by Carhart-Harris and Friston where they “recast some central Freudian ideas in a mechanistic and biologically informed fashion.” Freud’s primary process (renamed “primary consciousness”) is hypothesized to be a high-entropy brain dynamic which operates at criticality, while Freud’s secondary process (renamed “secondary consciousness”) is hypothesized to involve a lower-entropy brain state which sustains a sub-critical dynamic via a key neurobiological entropy-suppression mechanism—the ego—which exerts an organizing influence in order to constrain the criticality-like dynamic of primary consciousness. EBT argues that these ego functions have a signature neural footprint; namely, the DMN’s intrinsic functional connectivity and DMN coupling of medial temporal lobes (MTLs) in particular. Furthermore, EBT argues that DMN/ego develops ontogenetically in adult humans and plays an adaptive role in which it sustains secondary consciousness and associated metacognitive abilities along with an “integrated sense of self."

Importantly, this hypothesis maps onto the subjective phenomenology of psychedelic effects, particularly ego dissolution. As psychedelics weaken the oscillatory power and intrinsic functional connectivity of the DMN, the normally constrained activity of subordinate DMN nodes—MTLs in particular—becomes “freely mobile” allowing the emergence of more uncertain (higher entropy) primary consciousness. This view, based on Freudian metapsychology, is also consistent with filtration accounts, like those of Bergson and Huxley, who hypothesized that psychedelic drug effects are the result of a pharmacological inhibition of inhibitory brain mechanisms. EBT recasts these theoretical features using the quantitative terms of physical entropy and informational uncertainty as measured via “the repertoire of functional connectivity motifs that form and fragment across time." In normal waking states, the DMN constrains the activity of its cortical and subcortical nodes and prohibits simultaneous co-activation with TPNs. By interfering with DMN integration, psychedelics permit a larger repertoire of brain activity, a wider variety of explored functional connectivity motifs, co-activation of normally mutually exclusive brain networks, increased levels of between-network functional connectivity, and an overall more diverse set of neural interactions.

Carhart-Harris et al. point out a number of implications of EBT. First, they map the feelings of ‘uncertainty’ that often accompany psychedelic effects onto the fact that a more entropic brain dynamic is the information-theoretic equivalent to a more ‘uncertain’ brain dynamic. “Thus, according to the entropic brain hypothesis, just as normally robust principles about the brain lose definition in primary states, so confidence is lost in ‘how the world is’ and ‘who one is’ as a personality."

Second, like Huxley’s cerebral reducing valve and Freud’s ego, EBT argues that the DMN’s organizational stronghold over brain activity can be both an evolutionary advantage and a source of pathology. “It is argued that this entropy-suppressing function of the human brain serves to promote realism, foresight, careful reflection and an ability to recognize and overcome wishful and paranoid fantasies. Equally however, it could be seen as exerting a limiting or narrowing influence on consciousness." Carhart-Harris et al. point out that neuroimaging studies have implicated increased DMN activity and RSFC with various aspects of depressive rumination, trait neuroticism, and depression. “The suggestion is that increased DMN activity and connectivity in mild depression promotes concerted introspection and an especially diligent style of reality-testing. However, what may be gained in mild depression (i.e., accurate reality testing) may be offset by a reciprocal decrease in flexible or divergent thinking (and positive mood)."

Third, consistent with both psychoanalytic and filtration theory, is the notion that psychedelic drugs’ capacity to temporarily weaken, collapse, or disintegrate the normal ego/DMN stronghold underpins their therapeutic utility. “Specifically, it is proposed that psychedelics work by dismantling reinforced patterns of negative thought and behavior by breaking down the stable spatiotemporal patterns of brain activity upon which they rest."

Fourth and finally, EBT sheds light on the shared descriptive elements between psychedelic effects and psychotic symptoms by characterizing both in terms of elevated levels of entropy and uncertainty in brain activity which lead to a “regression” into primary consciousness. The collapse of the organizing effect of DMN coupling and anticorrelation patterns, according to EBT, point to “system-level mechanics of the psychedelic state as an exemplar of a regressive style of cognition that can also be observed in REM sleep and early psychosis."

Thus, EBT formulates all four of the theoretical features identified in filtration and psychoanalytic accounts, but does so using 21st-century empirical data plugged into the quantitative concepts of entropy, uncertainty, criticality, and functional connectivity. EBT hints at possible ways to close the gaps in understanding by offering quantitative concepts that link phenomenology to brain activity and pathogenesis to therapeutic mechanisms.​

Integrated Information Theory

Integrated Information Theory (IIT) is a general theoretical framework which describes the relationship between consciousness and its physical substrates. While EBT is already loosely consistent with the core principles of IIT, Gallimore demonstrates how EBT’s hypotheses can be operationalized using the technical concepts of the IIT framework. Using EBT and recent neuroimaging data as a foundation, Gallimore develops an IIT-based model of psychedelic effects. Consistent with EBT, this IIT-based model describes the brain’s continual challenge of minimizing entropy while retaining flexibility. Gallimore formally restates this problem using IIT parameters: brains attempt to optimize the give-and-take dynamic between cause-effect information and cognitive flexibility. In IIT, a (neural) system generates cause-effect information when the mechanisms which make up its current state constrain the set of states which could casually precede or follow the current state. In other words, each mechanistic state of the brain: (1) limits the set of past states which could have causally given rise to it, and (2) limits the set of future states which can causally follow from it. Thus, each current state of the mechanisms within a neural system (or subsystem) has an associated cause-effect repertoire which specifies a certain amount of cause-effect information as a function of how stringently it constrains the unconstrained state repertoire of all possible system states. Increasing the entropy within a cause-effect repertoire will in effect constrain the system less stringently as the causal possibilities are expanded in both temporal directions as the system moves closer to its unconstrained repertoire of all possible states. Moreover, increasing the entropy within a cause-effect repertoire equivalently increases the uncertainty associated with its past (and future) causal interactions. Using this IIT-based framework, Gallimore argues that, compared with normal waking states, psychedelic brain states exhibit higher entropy, higher cognitive flexibility, but lower cause-effect information (Figure 4).

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FIGURE 4. “Increasing neural entropy elevates cognitive flexibility at the expense of a decrease in the cause-effect information specified by individual mechanisms” (Gallimore, 2015, p. 10).

Neuroimaging data suggests that human brains exhibit a larger overall repertoire of neurophysiological states under psychedelic drugs, exploring a greater diversity of states in a more random fashion. For example, in normal waking states, DMN activity ‘rules out’ the activity of TPNs, and vice versa, due to their relatively strict anticorrelation patterns. Brain network anticorrelation generates cause-effect information because it places constraints on the possible causal interactions within and between brain mechanisms; for example, DMN-TPN anticorrelation patterns ‘rule out’ the DMN activity in the presence of activated TPNs. However, psychedelic drugs ‘dissolve’ DMN-TPN (and other) network anticorrelation patterns, which permits simultaneous activation of brain networks which are normally mutually exclusive. The cause-effect repertoire of brain mechanisms thus shifts closer to the unconstrained repertoire of all possible past and future states. This has the effect of “increasing the probability of certain states from zero or, at least, from a very low probability." Therefore the subjective contents perception and cognition become more diverse, more unusual, and less predictable. This increases flexibility but decreases precision and control as the subjective boundaries which normally demarcate distinct cognitive concepts and perceptual objects dissolve. Gallimore leverages IIT in an attempt unify these phenomena under a formalized framework.

However, as Gallimore notes, “this model does not explain how neural entropy is increased by (psychedelic drugs), but predicts consequences of the entropy increase revealed by functional imaging data." How do psychedelic drugs increase neural entropy?​

Predictive Processing

The first modern brain imaging measurements in humans under psilocybin yielded somewhat unexpected results: reductions in oscillatory power (MEG) and cerebral blood flow (fMRI) correlated with the intensity of subjective psychedelic effects. In their discussion, the authors suggest that their findings, although surprising through the lens of commonly held beliefs about how brain activity maps to subjective phenomenology, may actually be consistent with a theory of brain function known as the free energy principle.

In one model of global brain function based on the free-energy principle, activity in deep-layer projection neurons encodes top-down inferences about the world. Speculatively, if deep-layer pyramidal cells were to become hyperexcitable during the psychedelic state, information processing would be biased in the direction of inference—such that implicit models of the world become spontaneously manifest—intruding into consciousness without prior invitation from sensory data. This could explain many of the subjective effects of psychedelics.

What is FEP? “In this view, the brain is an inference machine that actively predicts and explains its sensations. Central to this hypothesis is a probabilistic model that can generate predictions, against which sensory samples are tested to update beliefs about their causes." FEP is a formulation of a broader conceptual framework emerging in cognitive neuroscience known as predictive processing. PP has links to bayesian brain hypothesis, predictive coding, and earlier theories of perception and cognition dating back to Helmholtz. At the turn of the 21st century, the ideas of Helmholtz catalyzed innovations in machine learning, new understandings of cortical organization, and theories of how perception works.

PP subsumes key elements from these efforts to describe a universal principle of brain function captured by the idea of prediction error minimization. What does it mean to say that the brain works to minimize its own prediction error? Higher-level areas of the nervous system (i.e., higher-order cortical structures) generate top-down synaptic ‘predictions’ aimed at matching the expected bottom-up synaptic activity at lower-level areas, all the way down to ‘input’ activity at sense organs. Top-down signals encode a kind of ‘best guess’ about the most likely (hidden) causes of bodily sensations. In this multi-level hierarchical cascade of neural activity, high-level areas attempt to ‘explain’ the states of levels below via synaptic attempts to inhibit lower-level activity—“high-level areas tell lower levels to ‘shut up”’. But lower levels will not ‘shut up’ until they receive top-down feedback (inference) signals that adequately fit (explain) the bottom-up (evidence) signals. Mismatches between synaptic ‘expectation’ and synaptic ‘evidence’ generate prediction error signals which ‘carry the news’ by propagating the ‘surprise’ upward to be ‘explained away’ by yet higher levels of hierarchical cortical processing anatomy. This recurrent neural processing scheme approximates (empirical) Bayesian inference as the brain continually maps measured bodily effects to different sets of possible causes and attempts to select the set of possible causes that can best ‘explain away’ the measured bodily effects. Crucially, the sets of possible causes must be narrowed in order for the system to settle on an explanation. Prior constraints which allow the system to narrow the hypothesis space are known as ‘inductive biases’ or priors. Efforts in Bayesian statistics and machine learning have demonstrated that improvements in inductive capabilities occur when priors are linked in a multi-level hierarchy, with “not just a single level of hypotheses to explain the data but multiple levels: hypothesis spaces of hypothesis spaces, with priors on priors." Certain priors in the hierarchy, known as ‘hyperpriors’ or ‘overhypotheses’, are more abstract and allow the system to ‘rule out’ large swaths of possibilities, drastically narrowing the hypothesis space, making explanation more tractable. For example, the brute constraints of space and time act as hyperpriors; e.g., prior knowledge “that there is only one object (one cause of sensory input) in one place, at a given scale, at a given moment,” or the fact that “we can only perform one action at a time, choosing the left turn or the right but never both at once."

Thus, PP states that brains are neural generative models built from linked hierarchies of priors where higher levels continuously attempt to ‘guess’ and explain activity at lower levels. The entire process can be characterized as the agent’s attempt to optimize its own internal model of the sensorium (and the world) over multiple spatial and temporal scales.

Interestingly, PP holds that our perceptions of external objects recruit the same synaptic pathways that enable our capacity for mental imagery, dreaming, and hallucination. The brain’s ability to ‘simulate’ its own ‘virtual reality’ using internal (generative) models of the world’s causal structure is thus crucial to its ability to perceive the external world. “A fruitful way of looking at the human brain, therefore, is as a system which, even in ordinary waking states, constantly hallucinates at the world, as a system that constantly lets its internal autonomous simulational dynamics collide with the ongoing flow of sensory input, vigorously dreaming at the world and thereby generating the content of phenomenal experience."

How do psychedelic molecules perturb predictive processing? If normal perception is a kind of ‘controlled hallucination’ where top-down simulation is constrained by bottom-up sensory input colliding with priors upon priors, then, as the above quotation from Muthukumaraswamy et al. suggests, psychedelic drugs essentially cause perception to be less controlled hallucination. The idea is that psychedelic drugs perturb the (learned and innate) prior constraints on internal generative models. Via their 5-HT2A agonism, psychedelic drugs cause hyperexcitation in layer V pyramidal neurons, which might cause endogenous simulations to ‘run wild’ so that awareness becomes more imaginative, dreamlike, and hallucinatory. This hypothesis could in principle still be consistent with observed reductions in brain activity under psychedelics; recall from above that, in PP schemes, the higher-level areas ‘explain away’ lower-level excitation by suppressing it with top-down inhibitory signals. “Here, explaining away just means countering excitatory bottom-up inputs to a prediction error neuron with inhibitory synaptic inputs that are driven by top-down predictions."

How does PP tie into filtration theories and psychoanalytic accounts? Carhart-Harris et al. link Huxley with Friston to interpret their initially surprising fMRI scans of humans under psilocybin. One objection to this linkage might be that Huxley often describes psychedelic opening of the cerebral reducing valve as revealing more of the world. At first glance this seems at odds with the above PP account of psychedelic effects, which describes psychedelic drugs causing rampant internal simulations of reality, not revealing more of the external world. However, this apparent tension might be resolved in light of active inference, a key principle of FEP. Active inference shows how internal models do not merely generate top-down (inference) signals but also shape the sampling and accumulation of bottom-up sensory (evidence) signals. “In short, the agent will selectively sample the sensory inputs that it expects. This is known as active inference. An intuitive example of this process (when it is raised into consciousness) would be feeling our way in darkness: we anticipate what we might touch next and then try to confirm those expectations." The principle of active inference hints at a resolution to the apparent tensions between Osmond’s ‘mind-manifesting’ model and Huxley’s ‘world-manifesting’ model. Psychedelics manifest mind by perturbing prior constraints on internal generative models, thereby expanding the possibilities in our inner world of feelings, thoughts, and mental imagery. Importantly, this could also manifest normally ignored aspects of world by altering active inference, which would in effect expand the sampling of sensory data to include samples that are normally routinely ‘explained away.’ Potentially, this understanding goes some way in explaining the perception-hallucination continuum of psychedelic drug effects (reviewed above) as it shows how perceptual intensifications, on the one hand, and distortions and hallucinations, on the other hand, could both be caused by a synaptic disruption of hierarchically linked priors in internal generative models.

The brief speculative remark by Muthukumaraswamy et al. is not the only PP-based account of psychedelic drug effects. The PP framework describes a recurrent back-and-forth give-and-take between colliding top-down and bottom-up signals, where internal models serve to shape experience and experience serves to build internal models, so this leaves room for rival PP-based accounts that diverge regarding where exactly the psychedelic drug perturbs the system. For example, increased top-down activity could be the result of pharmacological hyperactivation of top-down synaptic transmission; yet equally plausible is the hypothesis that increased top-down activity is a compensatory response to pharmacological attenuations or distortions of bottom-up signal.

For example, Corlett et al. hypothesize that LSD hallucinations result from “noisy, unpredictable bottom-up signaling in the context of preserved and perhaps enhanced top-down processing.” In contrast to the PP-based account outlined above, which focuses on changes to top-down signals, the strategy of Corlett et al. is to map various psychedelic effects to disturbances of top-down and/or bottom-up signals. The issue of what is primary and what is compensatory illustrates the vast possibilities in the hypothesis space of PP-based accounts.

While most PP-based accounts point to changes in top-down signaling, even within this hypothesis space there are contrasting conceptions of exactly how psychedelic molecules perturb top-down processing. Briefly, these differing hypotheses include: (1) hyperactivation or heavier weighting of top-down signaling; described above), (2) reduced influence of signals from higher cortical areas, (3) interference with multisensory integration processes and PP-based binding of sensory signals, and (4) changes in the composition and level of detail specified by top-down signals.

Carhart-Harris and Friston argue that the Freudian conception of ego, with its organizing influence over the primary process, is consistent with PP descriptions of higher-level cortical structures predicting and suppressing the excitation in lower levels in the hierarchy (i.e., limbic regions). Freud hypothesized that the secondary process binds, integrates, and organizes the ‘lower’ and more chaotic neural activity of the primary process into the broader and more cohesive composite structure of the ego. Carhart-Harris and Friston argue that when large-scale intrinsic networks become dis-integrated, the activity at lower levels can no longer be ‘explained away’ (suppressed) by certain higher-level systems, causing conscious awareness to take on hallmark characteristics of the primary process. In normal adult waking states, networks based in higher-level areas can successfully predict and explain (suppress and control) the activity of lower level areas. “In non-ordinary states, this function may be perturbed (e.g., in the case of hallucinogenic drugs, through actions at modulatory post-synaptic receptors), compromising the hierarchical organization and suppressive capacity of the intrinsic networks."

Similar PP-based theories of psychedelic ego dissolution have been proposed without invoking Freud. PP posits that the brain explains self-generated stimuli by attributing its causes to a coherent and persisting entity (i.e., the self), much like how it predicts and explains external stimuli by attributing their causes to coherent and persisting external objects use the PP framework to recast the psychoanalysis-based theories of LSD ego effects proposed by Savage and Klee described in Section “Psychoanalytic Theory.” The core idea is that psychedelic drugs interfere with processes that bind and integrate stimuli according to probabilistic estimates of how relevant the stimuli are to the organism’s (self) goals. Letheby and Gerrans point out that ego dissolution under psychedelic drugs is correlated with the desynchronization (reductions in intrinsic functional connectivity) of brain networks implicated in “one aspect or another of self-representation”—specifically the salience network (SLN) and the DMN. This causes an ‘unbinding’ of stimuli that are normally processed according to self-binding multisensory integration mechanisms. “Attention is no longer guided exclusively by adaptive and egocentric goals and agendas; salience attribution is no longer bound to personal concern." This description echoes Huxley’s cerebral reducing valve “in which the brain with its associated normal self, acts as a utilitarian device for limiting, and making selections from, the enormous possible world of consciousness, and for canalizing experience into biologically profitable channels." Letheby and Gerrans’ PP-based account elucidates how psychedelic drugs could perturb the brain’s “associated normal self” preventing the usual self-binding of internal and external stimuli.

Pink-Hashkes et al. argue that under psychedelic drugs “top-down predictions in affected brain areas break up and decompose into many more overly detailed predictions due to hyper activation of 5-HT2A receptors in layer V pyramidal neurons.” Pink-Hashkes et al. state that when internal generative models are described as categorical probability distributions rather than Gaussian densities, “the state space granularity (how detailed are the generative models and the predictions that follow from them) is crucial." Categorical predictions that are less detailed will ‘explain’ more bottom-up data (because they cover more ground) and thus produce less prediction error. Categorical predictions that are more detailed, by contrast, will carry less precision and thus potentially generate more prediction error. Pink-Hashkes et al. propose that psychedelic drugs cause brain structures at certain levels of the cortical hierarchy to issue more detailed (less abstract) ‘decomposed’ predictions that “fit less data than the ‘usual’ broad prediction.” They argue that many psychedelic effects stem from the brain’s attempts to compensate for these decomposed top-down predictions as it responds to the increase in prediction errors that result from overly detailed predictions.

In summary, the current state of PP-based theories of psychedelic effects reveals a divergent mix of heterogeneous ideas and conflicting hypotheses. Do psychedelic molecules perturb top-down (feedback) signaling, or bottom-up (feedforward) signaling, or both? Do the subjective phenomenological effects result from direct neuropharmacological changes or compensatory mechanisms responding to pharmacological perturbations? Yet there seems to be a core intuition that transcends the conceptual variance here: psychedelic drugs (somehow) interfere with established priors that normally constrain the brain’s internal generative models.

Predictive processing-based accounts, consistent with EBT and IIT (and filtration and psychoanalytic accounts), propose that psychedelic drugs disrupt neural mechanisms (priors on internal generative models) which normally constrain perception and cognition. Perturbing priors causes subjective phenomenology to present a wider range of experiences with increased risk of perceptual instability and excessive cognitive flexibility. As prior constraints on self and world are loosened, the likelihood of psychosis-like phenomena increases. At the same time, novel thinking is increased and the brain becomes more malleable and conducive to therapeutic cognitive and behavioral change.​

Conclusion

The four key features identified in filtration and psychoanalytic accounts from the late 19th and early 20th century continue to operate in 21st-century cognitive neuroscience: (1) psychedelic drugs produce their characteristic diversity of effects because they perturb adaptive mechanisms which normally constrain perception, emotion, cognition, and self-reference, (2) these adaptive mechanisms can develop pathologies rooted in either too much or too little constraint (3) psychedelic effects appear to share elements with psychotic symptoms because both involve weakened constraints (4) psychedelic drugs are therapeutically useful precisely because they offer a way to temporarily inhibit these adaptive constraints. It is on these four points that EBT, IIT, and PP seem consistent with each other and with earlier filtration and psychoanalytic accounts. EBT and IIT describe psychedelic brain dynamics and link them to phenomenological dynamics, while PP describes informational principles and plausible neural information exchanges which might underlie the larger-scale dynamics described by EBT and IIT. Certain descriptions of neural entropy-suppression mechanisms (EBT), cause-effect information constraints (IIT), or prediction-error minimization strategies (PP, FEP) are loosely consistent with Freud’s ego and Huxley’s cerebral reducing valve.

In surveying the literature for this review I can confidently conclude that 21st-century psychedelic science has yet to approach a unifying theory linking the diverse range of phenomenological effects with pharmacology and neurophysiology while tying these to clinical efficacy. However, the historically necessary ingredients for successful theory unification—formalized frameworks and unifying principles—seem to be taking shape. Formal models are an integral part of 21st-century neuroscience where they help to describe natural principles in the brain and aid explanation and understanding. Here I have reviewed a handful of formalized frameworks—EBT, IIT, PP—which are just beginning to be used to account for psychedelic effects. I have also highlighted the fact that all of the accounts reviewed here, from the 19th-century to the 21st-century, propose that psychedelic drugs inhibit neurophysiological constraints in order to produce their diverse phenomenological, psychotomimetic, and therapeutic effects.

Why should we pursue a unified theory of psychedelic drug effects at all? To date, theories of brain function and mind in general have resisted the kind of unification that has occurred in other areas of science. Because the human brain has evolved disparate and complex layers under diverse environmental circumstances, many doubt the possibility of and debate the merits of seeking ‘grand unified theories’ (GUTs) of brain function. “There is every reason to think that there can be no grand unified theory of brain function because there is every reason to think that an organ as complex as the brain functions according to diverse principles." Indeed, Anderson and Chemero caution that “we should be skeptical of any GUT of brain function” and charge that PP in particular, when taken as a unified theory as outlined by Clark “threatens metaphysical disaster.”

Given these understandable critical reservations about seeking after GUTs of brain function (and therefore any truly unifying theory of psychedelic drug effects), it is perhaps safer to aspire for theories that feature “broad explanatory frameworks” and offer “conceptual breadth” allowing us to “paint the big picture." PP and FEP, at the very least, offer a broad explanatory framework that emcompasses a large swath of perceptual and cognitive phenomena. Psychedelic drugs offer a unique way to iteratively develop and test such big-picture explanatory frameworks: these molecules can be used to probe the links between neurochemistry and neural computation across multiple layers of neuroanatomy and phenomenology. Meeting the challenge of predicting and explaining psychedelic drug effects is the ultimate acid test for any unified theory of brain function.

 
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Cellular receptors and their role in the psychedelic effect

by Barbara Bauer, MS | Psychedelic Science Review | 23 Mar 2020

Research is revealing that the psychedelic effect is due to much more than 5-HT2A activation.
Corpora non agunt nisi fixate. (Substances do not act unless bound.) –Paul Ehrlich

Anyone who reads about how psychedelic drugs work comes across discussions about receptors. The serotonin receptors, particularly 5-HT2A, get a lot of attention. This is because many psychedelic drugs are derivatives or analogs of the endogenous neurotransmitter serotonin, which uses those receptors. But, there’s much more to know about receptors. Here’s a brief overview of how they work, the effects they have, and which ones experts currently think are involved in the effects of psychedelics.

What are receptors?

One definition of a receptor is...​
A cellular macromolecule, or an assembly of macromolecules, that is concerned directly and specifically in chemical signaling between and within cells.

To put it another way, receptors are cellular proteins that mediate the activity of molecules. They are found inside cells and spanning the cell membrane. The different types of receptors include membrane receptors like G protein-coupled receptors (GPCRs), ion channels, and receptors that activate enzymes.

How do receptors work?

Although receptors are present at a high density on cells, they occupy only a tiny fraction of the cell’s surface area.4 Because of this, signals from receptors must be amplified to a sufficient intensity to elicit the effect. A signaling cascade is a series of events that amplify the signal and disseminates it quickly throughout the cell. This mechanism is also known as signal transduction.

Understanding how receptors work requires another definition. Substances that bind to receptors are called ligands. Simply stated, a ligand is a molecule that binds to a receptor and causes a biological response.

Now back to the signaling cascade. The cascade initiates when a ligand binds to a binding site (aka the recognition site) on the receptor. The binding triggers the activation of enzymes (often protein kinases). These enzymes, in turn, can have a variety of actions, including stimulating the creation of activators for other enzymes, changing protein configuration, and opening and closing ion channels. The cascade reaction happens until it is modulated or deactivated, often through feedback loops. As a result, the binding of a single ligand is translated into tens, possibly millions of activations that amplify the signal.

Modes of receptor interaction

Ligands can interact with receptors in several ways. Characterization of receptor/ligand interactions include aspects such as the strength of the attraction between the ligand and receptor (affinity), the relationship between the dose of the ligand and the magnitude of the effect (potency), and the degree of the response (efficacy). Here is an overview of a few types of receptor interactions.

Agonists

An agonist is...​
A ligand that binds to a receptor and alters the receptor state resulting in a biological response.

An agonist binds to a receptor like the endogenous compound does, but the effects may be quite different. For example, psilocin binding to the 5-HT2A receptor causes different effects than when serotonin binds to it. Partial agonists, as the name implies, have partial efficacy at a given receptor. Inverse agonists can be thought of as modified antagonists (see below). They block the receptor but also produce a negative response.

Antagonists

An antagonist is a compound that reduces the effects of an agonist by blocking the recognition site. It does not cause a conformational change in the protein as the ligand would. The chemical ketanserin is an example of an antagonist of the 5-HT2A receptor. It is a cardiovascular drug and is also used in receptor binding assays to study how the receptor works.

Allosteric modulators

These compounds increase or decrease the action of an agonist or antagonist. They accomplish this by binding to an area other than where an endogenous agonist binds. Allosteric ligands are particularly useful for designing drugs that target GPCRs.5 Several serotonin receptor subtypes, including 5-HT2A, belong to the GPCR family.

Receptors involved in the psychedelic effect

In terms of the serotonin receptors, studies have shown that activation of the 5-HT2A receptor by an agonist or partial agonist causes the psychedelic effect. Psychedelics researcher Dr. David Nichols theorizes that the 5-HT2C receptor may also have a role. In his landmark 2016 paper titled Psychedelics, he says...​
All known psychedelics are agonists at both the 5HT2A and 5-HT2C receptors…higher doses of particular psychedelics may lead to activation of the 5-HT2C receptor, which often functionally opposes the effects of 5-HT2A receptor activation.

In addition to 5-HT2A, the psychedelic compounds psilocin and 5-MeO-DMT have a high affinity for 5-HT1A. LSD activates the dopamine D2 receptor11 but is also a full agonist at 5-HT1A.

David Nichols wrote in his 2004 paper titled Hallucinogens...​
Although the widespread consensus is that the activation of the 5-HT2A receptor is the essential pharmacological component in the actions of hallucinogens, it is still possible that interactions with other CNS receptors may modulate the overall psychopharmacology.

Study examining several psychedelic compounds at receptors

A 2010 paper published in PloS ONE analyzed the binding affinity data for 35 psychedelic drugs (primarily phenylalkylamines) at 51 receptors, transporters, and ion channels. The compounds included ones that are naturally occurring as well as synthetics.

The main observation from the data was that psychedelic drugs are not as selective as may be generally believed in the scientific community. The author Ray stated...​
…psychedelics interact with a large number of receptors (forty-two out of the forty-nine sites at which most of the drugs were assayed).

In addition, the data indicated that psychedelics...​
…exhibit diverse patterns of receptor interaction. Different drugs emphasize different classes of serotonin receptors.

For example, the author made these observations from the data (note: “hit” means inducing >50% inhibition in binding assays):​
  • “5-HT2B is the best hit for thirteen drugs.”​
  • “5-HT1A is the best hit for nine drugs.”​
  • “Five of the top six psychedelic receptors are 5-HT1 and 5-HT2”​
The author summed up the findings in the study by saying...​
This diversity of receptor interaction may underlie the qualitative diversity of these drugs. It should be possible to use this diverse set of drugs as probes into the roles played by the various receptor systems in the human mind.

Continuing research on psychedelic receptors

Scientific research is slowly revealing the complex interplay between psychedelic compounds and receptors. Indeed, the work by Ray casts a wide net and provides some intriguing observations. His work serves as a springboard for studies to understand more about the pharmacology of psychedelics at a variety of receptors. Also, consider that multiple active compounds from naturally occurring sources set the stage for the entourage effect playing a critical role in making formulations.

 
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Psychedelic chemistry guides antidepressant drug discovery*

X-ray crystal structures of psychoactive compounds bound to a key serotonin receptor suggest design strategies for non-hallucinogenic therapeutics

by Bethany Halford | C&EN | 27 Jan 2022

Scientists have long sought the secrets of the 5-HT2A serotonin receptor—a central nervous system receptor that binds hallucinogenic compounds, including LSD and psilocybin. Many hope to figure out why these molecules cause hallucinations when they bind to 5-HT2A while other compounds that bind, including serotonin, do not. LSD and psilocybin have been shown treat mood disorders, such as depression, and scientists wonder if they can design molecules that maintain that mood-altering ability without causing hallucinations.

Researchers now report a structural biology-guided strategy for making such molecules. A team led by Sheng Wang of the Chinese Academy of Sciences and Jianjun Cheng of ShanghaiTech University determined the crystal structures of the 5-HT2A receptor bound to LSD, psilocin (the active form of psilocybin), serotonin, and lisuride, a non-hallucinogenic treatment for Parkinson’s disease. By visualizing the differences in how those molecules bind, the researchers then designed several compounds that they hypothesized would interact with 5-HT2A without inducing hallucinations (Science 2022, DOI: 10.1126/science.abl8615).

The team’s strategy was to design rigid molecules that would reach into a pocket of the 5-HT2A receptor and mimic one of two poses that serotonin and psilocin strike in the receptor. The researchers also wanted their molecules to avoid binding within a hydrophobic pocket because that interaction might spur hallucinations. Tests in mice showed that two compounds, called IHCH-7079 and IHCH-7086, had antidepressant activity: mice given those compounds continued to struggle when suspended by their tails and swim when forced, unlike control mice that gave up and exhibited depression-like behavior. IHCH-7079 and IHCH-7086 also didn’t appear to make the mice twitch their heads—behavior that’s observed when the rodents take LSD or psilocybin.

David E. Olson, a professor at the University of California, Davis, who is also working on making non-hallucinogenic psychoactive compounds, says this work adds to the growing evidence that analogs of psychedelics may be effective antidepressants. “The 5-HT2A receptor is one of the most important targets in neuropsychiatry."

This additional structural data will aid efforts to design new antidepressants as well as antipsychotics,” he says in an email.

Wang says that their compounds still need to be optimized, noting that their required effective dose in mice is high. Nevertheless, he says, “we definitely want to prove our concept in a clinical trial.”

*From the article here :​
 
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