Transforming Psychedelics into Mainstream Medicines | +50 articles

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Taking Psychedelics Seriously

Ira Byock, MD, FAAHPM

Recently published studies in peer-reviewed journals and high-profile articles in the New Yorker, New York Times, and Wall Street Journal, have rekindled professional and public interest in the therapeutic use of psychedelic drugs. It is easy to understand the enthusiasm. The magazine and newspaper articles include accounts of patients with profound depression, demoralization associated with terminal illness, and anxiety related to post-traumatic stress disorder (PTSD), who experienced remarkable improvements, including some who had previously considered suicide.

Nevertheless, psychiatric and palliative care clinicians who care for profoundly depressed, anxious, and seriously ill patients have every reason to be skeptical. As people become more mentally or physically ill and established treatments remain insufficiently effective, patients' susceptibility increases. Physicians play an important role in protecting vulnerable patients from spurious, nonevidence-based miracle cures, as well as from scientifically grounded, but overly zealous burdensome treatments that are certain to do more harm than good.

An abundance of caution should be accorded psychedelics, which carry real risks and are formally designated Schedule I drugs, signifying that they are dangerous, without therapeutic value, and illegal. Older clinicians remember news stories of deaths of individuals high on hallucinogens who thought they could fly, those with bad trips and flashbacks, and studies that purported to show chromosome damage associated with use of LSD.

However, given the extent of persistent emotional and existential suffering that palliative care clinicians encounter in the patients we serve, these medications deserve serious consideration by our field.

Background

Psychedelic properties of mushrooms and cactuses have been used for centuries by indigenous cultures to induce expanded states of consciousness and spiritual experiences. During the 1950s and early 1960s, research sponsored by the National Institute of Mental Health demonstrated potential for drugs of this class to markedly alleviate depression and existential suffering among people with cancer.11–13 Subsequently, non-medical use of these drugs and associated political and cultural upheavals resulted in the Schedule I classification, abruptly banning psychedelics from further clinical research and medical use. Although many of the mid-twentieth century clinical trials involved people with terminal conditions, few references to these published studies can be found in the literature of palliative medicine, a young specialty that developed after this period. Over the past 20 years, a few small clinical studies were conducted abroad, mostly in Europe and the United Kingdom. In the United States, over the past decade, with support from the Multidisciplinary Association for Psychedelic Studies and private funders, a few tenacious researchers earned governmental permission to carry out carefully designed trials of pharmaco-assisted therapy with psilocybin and MDMA.

The recently published research strengthens findings of earlier studies, showing significant efficacy and few adverse effects when these medications are administered as adjuncts to psychotherapy to carefully screened patients, under medical supervision. Three drugs, psilocybin, ketamine, and MDMA, have attracted most of the recent attention. Psilocybin, a naturally occurring drug found in psilocybe mushrooms, has strong and durable benefits for some patients with treatment-resistant depression, and for those with demoralization, anxiety, and depression associated with terminal illness. Ketamine, a Federal Drug Administration (FDA)-approved anesthetic with analgesic and psychedelic properties, has been used off-label in patients with treatment-resistant depression. In case studies and small clinical series, ketamine has shown notably positive effects. MDMA, a drug synthesized in 1912 as a potential anticoagulant, was later found to have strong psychoactive properties. In the 1970s and early 1980s, psychiatrists who administered MDMA in the context of psychotherapy observed sometimes dramatic improvements in patients suffering from severe, treatment-resistant PTSD.

In deciding how to think about these drugs, the distinction between skepticism and cynicism bears examining. Skepticism is warranted, but cynical nonscientific bias can result in therapeutic nihilism. The history of medicine is studded with occasional leaps in progress—consider small pox vaccination, penicillin, and computed tomography scans—that, shortly before they occurred, might have seemed too good to be true. When I graduated from medical school, the idea that duodenal ulcers were caused by bacteria would have been risible; stem cell transplants and gene-editing therapies were the stuff of science fiction. Surprising medical advances humbly remind us to suspend cynicism and that honest inquiry is warranted.

The need is great

While not only for people who are dying, specialty palliative care teams serve the sickest patients in our health systems and communities. It is, therefore, not surprising that we occasionally encounter incurably ill people whose suffering persists despite all available evidence-based treatments.

In treating pain and other physical distress, established treatment protocols guide escalations of doses and combinations of analgesics and co-analgesic medications. When a patient is dying and physical pain, dyspnea, seizures, or agitated delirium persists and causes intolerable suffering, as a last resort, comfort can reliably be achieved with proportionate sedation.

However, not all suffering is based solely in physical distress. Palliative care clinicians and teams also encounter patients whose misery is rooted in emotional, social, existential, or spiritual distress. Cancer, heart failure, liver failure, and amyotrophic lateral sclerosis (ALS) or motor neuron disease are among the diseases that can result in a progression of personal losses: Of feeling in control. Of taking care of one's self. Of contributing to others. Of enjoyment. Of meaning and purpose. Ultimately, some ill people say they have lost any reason to go on living.

People who are incurably ill and living with progressive disease-related disabilities can experience anxiety, depression, and demoralization. Psychotherapy alone and drug treatments for such syndromes are often insufficient. Medications for depression may take weeks to become effective or prove ineffective. Antidepressants and anxiolytics carry side effects that can include mental slowing and confusion. These adverse effects are particularly common and hazardous in patients with advanced physical illness, who are also at risk of polypharmacy, multidrug interactions, and concomitant disequilibrium and falls. When nonphysical suffering persists despite prudent approaches, published, evidence-based guidelines are limited.

Severe psychological and existential suffering can rob people of feeling that life is worth living. A sense of unending helplessness and hopelessness compels some to consider ending their lives. Suicide rates have risen 24% over the past two decades and are highest among middle-aged and elderly adults, particularly men who may suffer most from feelings of dependency. Public health data from Oregon show that since implementation of the Death with Dignity Act, the large majority of patients who received prescriptions for lethal drugs were motivated by nonphysical suffering. Current or fear of future pain contributed in just 26% of cases, while loss of autonomy, decreased ability to enjoy life, and loss of dignity most often brought these people to contemplate hastening their deaths.

Exercising an abundance of caution: screening, supervision, set and setting

Prescribed to carefully screened patients, in recommended doses, in the context of professional counseling and supervision, psilocybin and MDMA have proven to be notably safe. They have no tissue toxicity, do not interfere with liver function, have scant drug–drug interactions, and carry no long-term physical effects.

These drugs are not intoxicants in the usual sense. They do not dull the senses or induce sleepiness. On the contrary, sensory perception is intensified and attention is aroused. Although abuse syndromes have been reported, few people become habituated to these drugs.

Adverse physiological effects are few and of short duration, but can be substantial. During the onset of psychedelic experiences nausea and vomiting are not unusual. In this first hour or more, visual and spatial orientation are commonly disrupted, which can give rise to anxiety. Sympathetic nervous system arousal may occur both because of fear, and from direct effects of the drugs. Particularly during the initial phase of sessions, psychedelics dissolve barriers between physical senses resulting in synesthesia; touches, smells, and tastes can take on sounds, shapes and colors. Similarly, emotions and thoughts may evoke visual images and sounds. These phenomena explain why the term hallucinogen is often used synonymously with psychedelics to refer to this class of drugs.

Clinicians and researchers familiar with this class of pharmaceuticals emphasize the importance of screening, supervision, and “set and setting.”

Screening

Not every suffering patient is a candidate for therapy involving psychedelic drugs. As a general guideline, people who have cognitive and emotional conditions associated with disorganized or diminished ego strength are not good candidates for pharmaco-assisted therapy with psychedelics. MDMA may represent a partial exception to this exclusion, because it has fewer cognitive and sensory effects and more salutary emotional and interpersonal properties. Contraindications include people with borderline personality disorders or schizophrenic tendencies.

Supervision

Supervision is necessary for ensuring safety of psychedelic experiences. Short-term psychological effects are profound. If used in unsupervised fashion by unselected and unprepared people, these drugs can be highly dangerous and, in extreme cases, cause death. The sensory effects described above interfere with hand-eye coordination and fine motor function, making operating a vehicle or machinery or even walking in public potentially dangerous. These effects are sufficient to emphasize that professionals who are skilled in managing adverse effects must be present. Most research into pharmaco-assisted therapy with psychedelics has by protocol required subjects to remain in a single comfortable room throughout the sessions. In addition to safety, the supervising therapists are able to guide patients through their experiences to optimize the drug's beneficial potential.

Set and setting

Anthropologists studying traditional use of psychedelics by shamans and indigenous people recognized the influence of expectations and motivation on subjective experience. Since the earliest psychological research into pharmaco-assisted therapy with psychedelics, clinicians have emphasized the importance of “set and setting.”

The dissolution of assumptions and diminution of barriers caused by these drugs extend to psychological and interpersonal realms of experience. An enhanced sense of connection to others not only underpins some of the therapeutic effects, but also results in vulnerability to emotional contagion. When taken without adequate preparation and when surroundings are anxiety-provoking—either physically uncomfortable or emotionally intimidating—the psychedelic experience predictably results in fear, a prolonged sense of dread, or full panic. Conversely, in controlled settings with elements of soft light, art, and appropriate music, or nature, and gentle, compassionate people, such adverse reactions are rare.

With adequate counseling and preparation, and when psychedelic experiences unfold in calm, aesthetically pleasing environments, they prove beneficial in a high proportion of cases. In these situations, the healing motivations of both therapists and patients may contribute to therapeutic outcomes.

Therapeutic effects

Clinical case studies and research trials describe common patterns of subjective experiences that are associated with therapeutic benefits for people with severe anxiety and depression. As the initial phase of psychedelic experience wanes and people regain familiar barriers between visual, auditory, tactile, olfactory senses, people typically report heightened cognitive clarity and expanded emotional receptivity. Previously unrecognized or unquestioned assumptions related to one's place in the world and relationships to nature, one's physical and social environments become available to being considered anew.

While psychedelic experiences vary significantly from one individual to another, research subjects and people interviewed for journalistic articles commonly express attributes, which include heightened clarity and confidence about their personal values and priorities, and a renewed or enhanced recognition of intrinsic meaning and value of life. People often voice a sense of exhilaration, insight, and strengthened connection to others, as well as a richer sense of relationship with nature or God. People who take psychedelics with an intention of spiritual introspection often report that the drugs opened windows into deeper realms of existential experience. In safe and supportive environments, these effects typically induce a state of wonder, conceptual frame shift, expanded capacity for love, and an intensified sense of connection. Patients living with medical conditions that had robbed them of hope or reason to live may experience a transformative shift in perspective and experience of inherent meaning, value, and worth.

Not all psychedelics drugs are alike and subcategories have been described. Drugs, such as psilocybin and LSD, classified as entheogens, are associated with introspection and new insights, shifts of perspective, and reframing of experience and relationship to others and the world. MDMA is characterized as an empathogen, referring to prominent emotional effects of interpersonal warmth, empathy, and openness. These properties may underlie the benefits of MDMA in the context of therapy for those suffering from severe PTSD.

For most of these drugs, a single six to eight-hour session or short series of sessions suffices for therapeutic benefit. Alleviation of anxiety and depression may persist for weeks to months and, for some, proves permanent. Exceptions to this treatment pattern include protocols of daily low-dose ketamine for depression and recent nonmedical reports of daily or every third day microdosing of LSD.

Political and regulatory considerations

Psychedelic drugs were closely associated with the cultural wars of the 1960s and 1970s when strong political undercurrents contributed to this class of drugs being classified Schedule I. Similarly, MDMA became well known as Ecstasy or Molly, a popular, illicit rave and party drug. In the mid-1980s, despite evidence of MDMA's striking efficacy and relative safety when used therapeutically, the FDA declared MDMA a Schedule I agent. Court rulings challenged that classification; however, in 1998 the FDA reaffirmed and made the Schedule I classification permanent.

The process of renewing clinical research of psychedelics has been long and painstaking. Future efforts to reclassify selected psychedelics, such as psilocybin, as Schedule II drugs, enabling both research and clinical administration will likely meet predictable political resistance. There are compelling reasons, however, to address the expected concerns of opponents and proceed with efforts to reclassify these drugs.

Treatment-resistant depression and anxiety associated with PTSD causes untold suffering and contributes to thousands of deaths each year. A few population health studies suggest that rising suicide rates may in part be due to suicide becoming less shameful and more socially acceptable, lowering barriers for people who feel hopeless. A person with severe depression, who has a coexisting serious, life-threatening physical condition, may feel that his or her quality of life is not worth living and may forgo arduous, but potentially life-saving treatments. Additionally, nearly one sixth of Americans live in states where physician-hastened death is legal and those with terminal illness may choose this option in absence of alternative sources of relief.

There may be higher ground on which political conservatives and progressives—as well as those on opposing sides of the issue of legalizing physician-hastened death—might build consensus. Given the life-threatening nature of persistent, treatment-resistant depression and PTSD, including among veterans of America's wars, and the rising incidence of suicide, the reclassification of psilocybin and MDMA can be legitimately cast as a right-to-try issue. Right-to-try legislation has been used to provide terminally ill patients access to potentially life-extending medications that have been tested in Phase I trials but are of uncertain benefit. Similarly, the FDA's expanded access or compassionate use provisions may make use of drugs that have not been approved available to patients who are otherwise facing death. By diminishing a desire to die among people with severe depression, anxiety, PTSD, and those with terminal cancers, genetic and neurodegenerative diseases, psychedelics may have greater life-saving effects than other drugs that have earned right-to-try and expanded access status.

Final thoughts

Faced with novel therapies with reported clinical benefits that seem too good to be true, skepticism is warranted to protect vulnerable patients from harm. Cynicism, however, may prove more dangerous still. Unscientific bias and nihilistic assumptions can keep effective treatments from people who desperately need them.

Despite the controversial history of psychedelic medications, palliative specialists who care for patients with serious medical conditions and common, difficult-to-treat nonphysical suffering have a duty to explore these hopeful, potentially life-preserving treatments. Against the backdrop of physician-hastened death becoming legal in five states, expanded research of clinical psychedelics must proceed.

In reexamining the use of psychedelics in pharmaco-assisted therapy, we must not allow preconceptions, politics, or puritanism to prevent suffering people, who are now considered helpless and hopeless, from receiving promising, at times life-saving, treatments.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5867510/​

 

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UC Davis
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The Promise of Psychedelic Science

by David E. Olson | ACS Publications | 25 Mar 2021

The vast majority of drugs in psychiatrists’ arsenals were developed decades ago during an era when we understood very little about the pathophysiology of neuropsychiatric disorders. As a result, even our best medicines for treating illnesses like depression can offer relief to only a subset of patients, usually for a limited amount of time. (1) It is clear that if we ever hope to move beyond simply treating symptoms to actually curing mental illness, we need to embrace truly innovative therapeutic approaches. The use of psychedelics as medicines is perhaps one of the most exciting developments in neuropsychiatry given that these drugs appear to produce both rapid and sustained therapeutic effects across multiple neuropsychiatric disorders, including depression, post-traumatic stress disorder (PTSD), and substance use disorder (SUD). Understanding exactly how these powerful drugs affect brain function will require all the tools of modern science as well as the combined efforts of chemists, molecular biologists, neuroscientists, psychologists, and clinicians. In this Special Issue of ACS Pharmacology& Translational Science, we highlight the incredible breadth of research being done to elucidate how psychedelics impact brain function—studies that span the molecular, cellular, and organismal levels.

As small molecule drugs, the functional properties of psychedelics are dictated by their chemical structures, making structure–activity relationship (SAR) studies essential for fully understanding how they affect the nervous system. Not only do these types of studies help to identify potential designer drugs of abuse, they are critical for efforts aimed at optimizing the therapeutic properties of psychedelics. Using rats trained to discriminate (−)-2,5-dimethoxy-4-methylamphetamine (DOM) from saline, Gatch and coworkers found that a variety of tryptamine analogues produced DOM-like effects. (2) The abuse potential of several of these compounds was also observed by Halberstadt and coworkers using an automated head-twitch response assay. (3) Moreover, they found that O-acetylation of 4-hydroxy-N,N-dialkyltryptamines drastically reduced potency in vitro but not in vivo, suggesting that these compounds likely serve as prodrugs for their 4-hydroxy parent compounds.

Like many tryptamines, a large number of phenethylamine-containing compounds possess psychedelic properties. Of these, phenethylamines possessing an N-methoxybenzyl group, so-called NBOMe compounds, have gained a lot of attention due to their high potencies. Stove and coworkers tested a series of 25H-NBOMe positional isomers in G protein and β-arrestin activation assays and found that they stimulate 5-HT2A receptors to varying degrees. (4) In an effort to explain the differences between these isomers, they performed modeling using the active-state cryo-EM structure of the 5-HT2A receptor recently reported by Roth and coworkers. (5) With the advent of cryo-EM and other advances in GPCR structural biology, it seems likely that in silico SAR studies will play a prominent role in psychedelic research in the not too distant future. Collectively, the SAR studies in this issue add to the large body of work by David Nichols, Richard Glennon, and others, investigating how the structures of psychedelics lead to their hallucinogenic effects.

In addition to inducing hallucinations, it is now clear that psychedelics can produce a variety of other important biological effects that may contribute to their therapeutic properties. These include the potential to promote neural plasticity (9) (i.e., psychoplastogenic effects) and the ability to dampen immune responses. (10) The first SAR study aiming to characterize the psychoplastogenic pharmacophore of psychedelics was published last year, (11) and here, Nichols and coworkers used a rodent model of allergic asthma to better define the anti-inflammatory pharmacophore. (12) Excitingly, they found that there is no correlation between anti-inflammatory and hallucinogenic effects, suggesting that psychedelics might be used as lead structures to identify nonhallucinogenic compounds capable of reducing inflammation.

Understanding the therapeutic mechanisms of psychedelics will be key for maximizing both efficacy and safety. Given that many stress-related neuropsychiatric disorders are characterized by the atrophy of neurons in the prefrontal cortex, the psychoplastogenic effects of psychedelics have received a lot of attention. (13) In this issue, our group demonstrated that the psychoplastogens ketamine and LSD only need to stimulate cortical neurons for a very short period of time to elicit sustained neuronal growth. (14) These results might explain why psychedelics can produce long-lasting behavioral effects after a single administration. (15) Additional support for the notion that LSD might promote plasticity in humans was provided by Kuypers and coworkers. They found that low doses of LSD (<20 μg) increased plasma levels of brain-derived neurotrophic factor (BDNF). (16)

The work of Kuypers and coworkers suggests that even low doses of psychedelics can increase measures of plasticity. Recently, the first nonhallucinogenic psychedelic analogue with sustained therapeutic properties was reported. (17) However, high doses of psychedelics produce profound subjective effects that are often cited as being among the most meaningful experiences in a person’s life. Together, these studies raise the question as to whether or not the subjective effects of psychedelics are necessary for their therapeutic properties. Two alternative views on this important topic are presented in this issue, (19,20) and it is clear that this debate will not be settled anytime soon.

As the field continues to move toward using psychedelics as medicines, it will be important to establish robust biomarkers for evaluating efficacy and understanding how these drugs impact brain function. Carrera, Torterolo, and coworkers used EEG to demonstrate that ibogaine produces a pattern of gamma oscillations that resembles activity observed during REM sleep. These results are intriguing given the well-known oneirogenic properties of ibogaine. In addition to its ability to induce a dream-like state and reduce drug-seeking behavior, ibogaine also binds to monoamine transporters and serves as a pharmacochaperone. (21,22) Frissmuth, Newman, and coworkers engineered ibogaine analogues with potential to correct monoamine transporter folding defects. (23) This work adds another potential medical condition that might be treated by psychedelics or related compounds.

While the beneficial effects of psychedelics on depression are well-known, (24) very little is known about their effects on suicidality. To address this gap in knowledge, Weissman and coworkers reviewed the current literature and concluded that psychedelic therapy might reduce suicidality, though it is clear that this is a nascent area of research. Ross and coworkers made an important contribution to this field by reporting that psilocybin-assisted psychotherapy reduced suicidal ideation in people with cancer. (25)

Optimizing the clinical efficacy of psychedelic treatment is an active area of research. Most people agree that “set and setting” are critical components of a psychedelic experience, but research aimed at systematically evaluating these factors is only in its infancy. (26) In this issue, Johnson and coworkers take an important step toward better understanding the influence of music genres on psychedelic therapy. They found that overtone-based music occasioned more mystical-type experiences and increased smoking abstinence compared to Western classical music. These results challenge the common practice of using Western classical music in psychedelic therapy sessions.

Identifying factors capable of predicting how patients will respond to psychedelic therapy is an important goal for maximizing therapeutic potential while minimizing risk of adverse effects. In a study on male AIDS survivors, Stauffer and coworkers determined that baseline attachment anxiety and baseline attachment avoidance correlated with mystical-type and challenging experiences, respectively. (27) Other factors with potential predictive power were identified in a systematic review of the literature by Aday and coworkers. For example, they found that patients exhibiting preoccupation, apprehension, and confusion were more likely to experience adverse effects, while those characterized by baseline openness, absorption, acceptance, and surrender were more likely to have mystical-type experiences. Importantly, they concluded that participant sex did not predict response, but other biological variables such as 5-HT2AR binding potential and rACC volume were important.

Liknaitzky and coworkers discuss another approach for optimizing psychedelic treatment involving its combination with mindfulness meditation. (29) They argue that a psychedelic experience might be useful for initiating a reorientation toward more adaptive behaviors and that mindfulness meditation might be effective at sustaining those changes.

With increased attention paid to the use of psychedelics in medicine, several important ethical concerns have emerged. In a viewpoint article, Johnson warns about the potential for clinicians/researchers to inappropriately impose their own religious/spiritual beliefs on patients. (30) He also cautions that without appropriate safeguards, such as the inclusion of multiple healthcare workers during drug and nondrug sessions, there is a real danger of clinicians acting inappropriately or abusing their positions of authority. If the field is to avoid repeating mistakes made in the 1960s, it is important to heed these warnings. Schenberg and coworkers raise another ethical concern regarding the cultural appropriation of psilocybin-related traditional medicines. (31)

We hope that this special issue of ACS Pharmacology& Translational Science underscores the breadth of research taking place in the field of psychedelic science. To fully understand how these powerful drugs impact brain function and human health, we need to embrace multiple perspectives, work across length scales, and take advantage of the latest scientific tools. Neuropsychiatry is desperate to find effective medicines for treating diseases such as depression, PTSD, and SUD, which are among the greatest contributors to disability worldwide. (32) While psychedelics have demonstrated enormous promise for combatting these illnesses, we must guard against hype, move cautiously toward therapeutic applications, and most importantly, conduct psychedelic research with the rigor demanded of modern science.
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David E. Olson
Department of Chemistry, University of California, Davis, One Shields Avenue, Davis, California 95616, United States; Department of Biochemistry & Molecular Medicine, School of Medicine, University of California, Davis, 2700 Stockton Blvd, Suite 2102, Sacramento, California 95817, United States; Center for Neuroscience, University of California, Davis.​

https://pubs.acs.org/doi/10.1021/acsptsci.1c00071

 

[mr peabody]

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The New Age of Psychedelics*

by Elaine Quilici | Pharmaceutical Executive | 8 March 2022

While the COVID-19 pandemic has contributed to a rise in mental health issues, it also has placed long-overdue attention on the mental health therapeutics space. As people struggle with a variety of illnesses, from addiction to depression to post-traumatic stress disorder (PTSD), many of the available treatments for these conditions have been around for decades without innovation.

Today, a number of biopharma companies—both big and small—are looking toward psychedelic medicine as a new way to help patients in need. Substances such as ketamine, MDMA, psilocybin, DMT, and LSD are being explored. Many companies even see the potential for these substances to move beyond the mental health space into other areas.

The need for change

There has not been any significant innovation in the treatment of mental health disorders for quite some time. Selective serotonin reuptake inhibitors (SSRIs), introduced in the 1980s, are still the standard of treatment. But these drugs are only effective in a limited number of patients—treating symptoms rather than the underlying pathology—and carry a wide range of side effects.

“The drugs available now are required to be administered continuously, so the side effects become problematic,” says Rob Barrow, CEO of MindMed, a New York-based psychedelic medicine biotech company. “It leads to less adherence, which leads to patients not wanting to take medications in the first place.”

In addition, central nervous system (CNS) and mental health have been an underinvested area for venture capitalists for years due to risk. But that doesn’t mean mental health issues are not a huge burden on society. “The mental health crisis is one of the largest unmet needs of our time, and we need better ways to address them,” says Mark Rus, CEO and director of Delix Therapeutics. “This has been a growing epidemic exacerbated by the impacts of the COVID-19 pandemic.”

An October 2021 report by The Lancet revealed the impact of the pandemic on mental health in 2020. It estimated there were an additional 53 million cases of major depressive disorder and 76 million cases of anxiety disorders due to the pandemic.

“COVID-19 has significantly increased the global prevalence and burden of many mental health problems, including but not limited to depression, anxiety, and substance abuse,” says Shaun McNulty, DPhil, chief scientific officer of Awakn Life Sciences. “The rise in alcohol abuse alone is very concerning. Therefore, novel and effective therapeutic options are urgently needed to treat unmet medical needs both for existing patients and for the growing number of mental health disorder patients emerging as a consequence of COVID-19."

Modern medicine

In 2012, FDA created new designations that allow for fast-tracking the development and review of drugs intended to treat serious conditions if there is evidence they have a clear improvement over existing therapies. This opened a door for psychedelics research—which had all but come to a halt with the Controlled Substances Act in 1970.

Today, scientists are building on first-generation psychedelics that have challenging side effects not conducive to medical treatment. Because of hallucinogenic and dissociative reactions, current psychedelics need to be administered in approved clinics that can monitor patients, and these sessions can take up to 12 hours sometimes. Biopharma’s goal is to take the original molecules and remove any negative effects while harnessing their therapeutic power.

“We think we can do better,” says Judy Blumstock, CEO of Diamond Therapeutics. “We don’t think you have to have all of that subjective experience with hallucinogenic symptoms in order to have a good drug. We’re going to need drugs that people can take at home.”

In contrast to the dulling effects often associated with antidepressants, psychedelics require just one or a few doses that can offer many months of effects. “It changes the entire game for how mental health can be treated,” says Barrow. “The beauty of this drug class is that it does the exact opposite [of antidepressants]; it effectively opens the experience and helps people lean into their experience. This can reframe and shift the trajectory of mental health conditions. These can be huge tools that could be applicable both to treatment-resistant patients but really across the entire spectrum.”

Unlike the psychedelics of the 1960s and ’70s, the next generation of drugs will be researched and manufactured to high industry standards to ensure their safety, efficacy, and consistency. Awakn is working to develop combination approaches utilizing both medicine and psychotherapy.

“Patients will be monitored carefully and supported throughout the experience to ensure a positive patient outcome,” McNulty tells Pharm Exec.

Delix is focusing on a new class of non-hallucinogenic psychoplastogens as an improvement to treating mental illness. By targeting the biology of mental illness and repairing the neurons in the brain, it hopes to restore healthy connections that promote healing.

A second-generation therapy that MindMed is developing is R(-)-MDMA to treat social anxiety and functioning in diagnoses that include autism spectrum disorder. It also has a next-generation molecule called 18-MC in trials, which is a non-hallucinogenic cousin of ibogaine, a classic psychedelic that’s been used for the treatment of opioid use disorder and opioid withdrawal.

Atai is testing several promising psychedelic or psychedelic-like compounds with the goal of finding new and improved options for patients who aren’t sufficiently helped by current therapies. “We are fully aware that one size doesn’t fit all in the treatment of mental health disorders, so we are intentionally exploring a range of pharmacologically distinct compounds, with the ultimate goal of being able to provide the right therapy for a given patient through precision psychiatry,” says Srinivas Rao, MD, PhD, co-founder and chief scientific officer of Atai. “In addition to our 11 pharmacotherapeutic programs, we are also building out our capabilities in digital therapeutics, drug discovery, and formulation technologies.”​

Digital twist​

The growth of psychedelic medicine couldn’t happen at a better time. With the worldwide embracement of technology since the pandemic, the industry now has an invaluable tool to pair with these therapeutics.

“There’s going to be substantial barriers and frictions in terms of getting psychedelics to patients at scale,” says Barrow. “Going in for a 10-hour treatment session in psychiatry is a bit more unusual than a knee replacement, so we have to think very creatively about how we can overhaul the entire delivery landscape—lean into the infrastructure that’s there, but use digital medicine tools to help patients and providers be ready to access these therapies, help providers make better decisions, help patients remain engaged, and have more precise medicine and delivery of care in psychiatry.”

As companies develop therapies, they should start looking toward the creation and/or adoption of digital tools to help improve the safety and efficacy of psychedelics. Digital devices can give providers important feedback to use in their decision-making about how to deliver the drugs. They can change the way patients are monitored during treatment sessions and can offer a way to engage with them outside of sessions. They can be especially helpful in monitoring patients who might live far from treatment centers.

“It’s time-consuming to go to sessions—it’s not just the hour that you’re in with the therapist, but getting there, getting back,” says Blumstock. “And it can be expensive. We’re all used to doing things now with our phones and watches, so I think there’s a huge opportunity. We’re actively exploring how to combine the best of both.”

Atai is integrating digital therapeutics across its drug development efforts. Such integration on a shared architecture across all compounds on the company’s platform may allow for the exploration of digital biomarkers, an important element in its precision psychiatry approach.

“There are a number of opportunities to bring digital into the world of psychedelic-assisted therapy and the development of psychedelics as a general drug class,” says Barrow. “As we go forward, we really think that digital medicine is going to be a cost of entry to get into precision psychiatric care, and one that we’re really excited to be ahead of the curve on.”

Interest grows—both big and small

There is no shortage of biotechs in the psychedelic space, but large pharma is getting involved, too. Janssen Pharmaceuticals broke the barrier in March 2019 with the first-ever approved psychedelic—Spravato (esketamine), for adults with treatment-resistant depression in combination with an oral antidepressant.

That approval was followed by a second FDA indication for Spravato in August 2020 to treat depressive symptoms in adult patients with major depressive disorder with suicidal thoughts or actions.

Otsuka Pharmaceutical recently sealed a deal with Mindset Pharma to provide funding in early stage clinical testing of its range of psychedelic compounds. Otsuka also is collaborating with Perception Neuroscience, an Atai company, in the development and commercialization of Perception’s lead molecule, PCN-101 (R-ketamine) in Japan as a potential treatment for mood disorders and treatment-resistant depression.

The interest of large pharma can be beneficial to gaining overall momentum for the field, whether that’s from a couple players entering the space with their own programs or partnering with other companies.

“It creates a great dynamic and a great ecosystem where then others are interested,” says Barrow. “We’ve seen a lot of big pharma companies turn away from treating CNS and psychiatry, in particular, in the past. This is an opportunity for some to get back into that world more substantially. It’s an opportunity for others to consolidate and think about how they can wrap up an entirely new industry.”

Though the field is deep, the data generated by the companies will ultimately determine who will lead the march forward. For example, Janssen’s long-term studies produced more than a decade of research on Spravato, including four years of real-world data affirming its safety and efficacy.

“Spravato has brought hope to patients and their families, and we’re proud to continue paving the way in bringing innovation to underserved populations,” says Mohamed Issa, vice president of commercial at Janssen Neuroscience. “We look forward to continuing to partner with stakeholders across the industry who are committed to identifying new ways to support those living with serious mental illness.”

Broader use of psychedelics

As researchers explore next-generation compounds and employ digital tools, many life sciences organizations see the potential to expand psychedelic medicine to more common mental health issues and other therapeutic and disease areas. For example, Awakn recently published the outcomes of two clinical trials demonstrating efficacy to treat alcohol use disorder, and the nonprofit Multidisciplinary Association for Psychedelic Studies (MAPS) has published studies demonstrating positive outcomes to treat PTSD.

“In the future, it’s likely that a wide range of trauma-associated mental health problems will be well-treated effectively, for the first time, by second-generation drugs,” says McNulty. “We believe that as well as substance addictions, behavioral [non-substance] addictions will be amenable to treatment with second-generation products. This is very important, as there are no currently available pharmacological treatments for behavioral addictions, in an area that is seeing alarming rates of increase.”

Outside of mental health, Barrow believes there is potential in the analgesic effects of LSD and says MindMed has some early programs in the space. He says clinical evidence has shown that repeated and single-use administration have proven effective in treating various pain indications, and suggests additional opportunities exist in neurodegenerative disease and substance use disorder, too.

“The body of evidence outside of what we think of as psychiatric conditions is pretty substantial,” he says. “We think there’s a potential opportunity in a number of directions where there’s CNS or brain involvement and disease. We see a nice safety profile relative to a lot of the drugs that are out there and think the opportunities are quite large down the road.”

Rao likewise sees the potential for psychedelics in CNS, including Alzheimer’s disease. He also thinks the drugs might be able to treat symptoms that cross diagnostic categories, such as social isolation.

In the future, McNulty believes the use of artificial intelligence will have the potential to identify new indications for treatment. These will be areas where the use of polypharmacology to modulate brain circuits could deliver positive patient outcomes for the first time.

Moving forward

With the growing recognition that SSRIs don’t work for everyone, the example of cannabis becoming acceptable after being seen as taboo by many, a vast amount of literature supporting scientific research, and a growing presence in mainstream media, opportunities for psychedelic medicine are becoming more difficult to ignore.

“For everyone who says that psychedelics are the next greatest thing, there’s probably an equal number of people who feel hesitant, because there’s a lot of baggage with psychedelics,” says Blumstock. “The careful approach we’re taking to clinical trials—getting the evidence, making sure it’s safe, making sure it’s effective, dispelling whatever fears people may have—will pave the way forward. There’s a lot of work to be done. I think it’s fantastic that society is now embracing this idea that was very ‘contraband’ even five or 10 years ago.”

Rao agrees and encourages a dialog that lands somewhere between addressing the naysayers and overhyping the potential of psychedelics. He, too, believes that clinical evidence will be the determinant.

“Psychedelic compounds and the experience itself suffer from a degree of stigmatization because of their complicated past, and this stigmatization may impact both physician and patient attitudes toward such drugs,” says Rao. “Conversely, one could argue that these compounds have been oversold in the media recently, suggesting that they represent a cure or near cure for a range of conditions. It’s important to avoid the risk of overinflating or overly speculating on the potential of compounds. Proper research and data are critical.”

Popular therapies

Ketamine: Parke-Davis (now part of Pfizer) discovered ketamine in 1962 as a dissociative anesthetic to be used in surgery. It won FDA approval as a field drug during the Vietnam War, but by the 1970s, it began to fall out of favor. In 1999, it was classified as a Schedule III non-narcotic substance. Today, it is obtainable through ketamine clinics, retreats, and experiences, though it is not approved by FDA for depression or any mental health use.

LSD: Similarly, LSD’s roots trace back to pharma. It was accidentally discovered by a researcher at Sandoz (now part of Novartis) in 1938. Groups such as the US government, academic professors, and many artists and college students experimented with the substance throughout the ’50s and ’60s, but research virtually disappeared in 1970, when the Controlled Substances Act was enacted, making LSD a Schedule I drug.

DMT: Structurally similar to LSD, DMT occurs naturally in many plants and animals. The substance, which produces a feeling of transcendence, has been used for ages in spiritual ceremonies of indigenous cultures. It is the active ingredient in the ayahuasca plant. It was first synthesized by a chemist in 1931, and was studied throughout the ’50s and ’60s. But that ended in the ’70s when legal restrictions were enacted. Non-therapeutic research resumed in the ’90s. In 2020, Small Pharma announced it would begin the world’s first trial of the drug.

MDMA: MDMA—which boosts oxytocin to induce feelings of well-being and anti-stress—was synthesized by Merck in 1912 as the company was looking to develop a blood clotting medicine to compete with Bayer; however, it was shelved for years. Despite not having FDA approval, some psychiatrists in the ’70s and ’80s offered it to patients to enhance their sessions. By 1985, it was becoming a problem on the streets and the DEA made it a Schedule I substance. In the early ’90s, FDA-approved research began to investigate if the drug could help terminally ill patients. In 2017, MAPS received approval to study MDMA for PTSD by way of breakthrough designation. The study found that 67% of participants who received the drug no longer met the criteria of a PTSD diagnosis two months later.

Psilocybins: Psilocybin is the psychoactive and hallucinogenic agent that puts the “magic” in magic mushrooms. Compass Pathways received breakthrough designation in 2018 to study the substance to treat treatment-resistant depression. The first large-scale trial of its kind seems to be delivering on its promise, as Phase IIb topline results reported this past November proved psilocybins “highly effective.”

For more on the science of how psychedelics work, check out our recent article on industry trends.

*From the article here :

New Age of Psychedelics

A look at the renewed efforts of biopharma companies in exploring age-old substances to treat mental health conditions and more, minus the negative effects.

www.pharmexec.com

 

[mr peabody]

Psychedelics Meet Mainstream Medicine*
​

by Paul Frysh | WebMD | 4 Jan 2022

Psychedelic drugs seem to be everywhere lately. The Silicon Valley glitterati are all a-twitter about "microdosing" with LSD and magic mushrooms to improve creativity. Nicole Kidman's character in the fictional Hulu series Nine Perfect Strangers doses her guests' morning smoothies with psilocybin. And new documentary films on psychedelics seem to drop almost monthly.

In real life, much of this is of questionable scientific rigor, and ... well ... illegal.

But there is also a growing body of medical research behind this psychedelic renaissance. Psychedelic drugs, when combined with therapy, have shown great promise for treatment of a variety of mental health issues. Scientists call the new treatment "psychedelic-assisted psychotherapy."

But would the FDA really approve drugs for medical use that are mainly known as party drugs? The answer may surprise you.
​

Psychedelics meet psychotherapy

​

The word psychedelic literally means "mind revealing," which is one way to describe the powerful effects of psychedelic drugs (sometimes also called hallucinogens or entheogens). They cause a profound shift in your sense of self and consciousness.

But so do lots of other drugs, like alcohol, cocaine, and opiates. What makes psychedelics different?

It is "their capacity reliably to induce states of altered perception, thought, and feeling that are not experienced otherwise except in dreams or at times of religious exaltation," according to a definition, often cited by scientists, from Jerome Jaffe, MD, of the University of Maryland School of Medicine. These states of "religious exaltation" are not limited to traditional religious practice, but may stem from meditation, fasting, deep breathing, and other disciplines.

In fact, psychedelics have been used for thousands of years as part of religious and cultural rituals to induce mystical experience. And it is this uncanny effect that may be part of what helps with so many mental health conditions. (WebMD explores these effects in depth in How Do Psychedelic Treatments Work?)

Most of the medical research on psychedelics has examined two drugs: psilocybin, which is the active ingredient in magic mushrooms, and MDMA, which you may know better as ecstasy or molly. There's also growing research on LSD, mescaline, DMT, and other psychedelics.

A number of universities, including Johns Hopkins, NYU, the University of California San Diego, and Imperial College London in the U.K., are doing in-depth research on these medicines. And early results, while limited in size, have been impressive.

What the research shows

A 2021 study published in the journal Nature Medicinelooked at 91 people with severe, chronic PTSD. Half of them got MDMA-assisted therapy, and the rest got a placebo. Almost 90% who got MDMA had a "clinically significant" reduction in symptoms, and 67% no longer qualified for a PTSD diagnosis.

Compare that to standard talk therapies where 30% of people simply drop out of treatment and even after that, only around 40% get well enough to no longer have PTSD. Or compare it to other FDA-approved meds for PTSD, which only help lessen symptoms around 25% of the time.

Barbara Rothbaum, PhD

But it was a small 2012 study in the Journal of Psychopharmacology that first got the attention of clinician psychologist Barbara Rothbaum, PhD, a psychiatry professor at Emory University.

That study tracked the long-term effects of MDMA-assisted psychotherapy in 19 people with PTSD that were resistant to other treatments. It showed that after a single course of treatment, most of the people in the study still had clinically significant gains in symptom relief, with no harmful effects reported.

But the kicker for Rothbaum was that the effects persisted in most people even 4 years or more after treatment.

She often worked with people with PTSD and knew how important these therapies could be for people who didn't respond to approved treatments.

"Suicide rates for people with untreated PTSD are unusually high, as are risks of substance misuse, addiction, and depression," Rothbaum says. "It disrupts relationships and lowers quality of life." MDMA-assisted therapy looked like a lifeline, Rothbaum says. "And it still does."

Oncologist Manish Agrawal, MD, was equally taken with research on people with anxiety and depression due to a cancer diagnosis.

People with life-threatening disease who got psilocybin-assisted psychotherapy had "significant decreases" in anxiety and depression as long as 12 months after the treatment, according to studies published in 2011, 2014, and 2016. And as with MDMA, there were few, if any, harmful effects in people in these clinical trials.

Agrawal, now co-director of clinical research at the Aquilino Cancer Center in Rockville, MD, had long sought a more effective way to help his patients and their families deal with the mental and emotional effects of a cancer diagnosis. He would send people for therapy or group sessions or support groups. But too many people remained psychologically shattered after their diagnosis.

"This research was the first time I saw something that looked like it could really move the needle," Agrawal says.

Manish Agrawal, MD

Agrawal was so impressed that he decided to get certified in psychedelic-assisted therapies. In 2021, Agrawal and his colleagues at Aquilino finished collecting data for their own trial of psilocybin-assisted therapy for depression in people with cancer. It's the first psychedelic research in cancer patients in several years. And initial results look promising, he says.

Half of all people in the study no longer had clinical depression 8 weeks after a single dose of psilocybin and accompanying therapy, says Agrawal. "That's a very encouraging result." (Learn more about Agrawal's work and follow one man through his psychedelic trip in One Man's Psychedelic Journey to Confront His Cancer).

In November 2021, COMPASS Pathways released initial data on a study on psilocybin-assisted therapy for treatment-resistant depression. It showed that 30% of people appeared to be in complete remission from their symptoms 3 weeks after treatment.

And this is just the tip of the iceberg. There have also been excellent outcomes for obsessive-compulsive disorder (OCD), anxiety, alcohol use disorder, smoking, and more.

For two conditions -- PTSD and treatment-resistant depression -- the FDA has designated psychedelic-assisted treatments as "breakthrough therapies" that show "substantial improvement over available therapy" for a "serious condition."

Approval for the first of these, MDMA-assisted psychotherapy for PTSD, could be less than 2 years away, experts say. And an approved form of psilocybin-assisted psychotherapy for treatment-resistant depression could be as little as 4 years away, according to experts at the Johns Hopkins Center for Psychedelic & Consciousness Research.

How we got here

So where did this research suddenly come from?

"There's nothing sudden about it," says Rick Doblin, PhD, who founded the Multidisciplinary Association for Psychedelic Studies (MAPS), which is working to bring MDMA-assisted therapy to the market.

Doblin has been involved in the study of psychedelic medications for decades. Since its founding in 1986, the mission of MAPS has been to prove beneficial medical uses of psychedelics and other drugs in a therapeutic setting and get the FDA to approve them.

It has not been easy.

The excesses of the 1960s, says Doblin, did much to shut down years of fascinating and promising research on psychedelic medications.

Before that, psychologists and psychiatrists treated tens of thousands of people with "psychedelic psychotherapy" over a period of about 15 years, starting in the early

1950s. This was due in part to reports of effects of LSD in test patients, but also to positive results reported by researchers and doctors. For much of that time, these substances were perfectly legal.

But things got "complicated," says Doblin, after psychedelic drugs became integrated into '60s counterculture and the anti-war movement.

In 1967, thousands gathered in San Francisco's Golden Gate Park to hear former Harvard psychologist and professor Timothy Leary who famously told the crowd of mostly young people to "turn on, tune in, and drop out."

Leary, a larger-than-life counterculture icon, clad in flowing white robe, beaded necklaces, and flowers in his hair, was a great advocate of psychedelics. But in the midst of deep cultural and political division, many look back on Leary's famous pronouncement as the death knell for mainstream acceptance of psychedelics.

Three years later, in 1970, President Richard Nixon signed the Controlled Substances Act that made LSD and psilocybin illegal. Psychedelics were now a "Schedule I" controlled substance. Psychedelic research and mental health treatments effectively came to a standstill, not only in the U.S. but around the world.

The 'recent' renaissance?

The current boom in psychedelic research actually started in 1990. That's when the FDA allowed a single researcher to study DMT (the active ingredient in the drink ayahuasca). Then in 1992, the FDA and an FDA Advisory Committee cracked the door for some more limited research.

The success of early studies combined with a growing awareness that psychedelics were far less toxic than other Schedule I drugs like cocaine, heroin, and fentanyl also has helped clear the way for more robust research.

And even these early studies only came about because of die-hard believers like Doblin and organizations like MAPS who thought the government had thrown the baby out with the bathwater. You don't put a stop to promising research just because of a few bad actors, Doblin says. That's why, says Doblin, they never stopped trying.

"The promise was all there in the research from the '50s and '60s," he says. "All you had to do was look."

When scientists finally started to do just that, they could not look away. Though this early research was often less rigorous by today's standards, the possibilities for future research were clear.

Of course, it didn't hurt, says Doblin, that there was a real lack of new and effective therapies for conditions like PTSD, depression, addiction, OCD, and more. The medical community -- and the public -- were on the lookout for something new.

This time it's different

After all that time in the scientific wilderness, Doblin and others at the forefront of psychedelic-assisted therapy are doing everything they can to make sure they don't repeat the mistakes of the 1960s.

That means strict rules about how to train the doctors who prescribe these treatments and the therapists who administer them.

The MAPS trials require 6 to 8 hours of training for the doctors who prescribe the medication and 100 hours of training for the therapists who give the treatments. A prescribing doctor who also wants to administer the treatment must do both parts of the training.

"We're the sponsor. We're the pharmaceutical company," Doblin says. "If something goes wrong, the FDA will pull the drug from the market. So we want to make sure that the therapists are properly trained."

"Eventually," Doblin says, "I believe people will be trained in traditional medical and therapeutic education to do psychedelic psychotherapy."

MAPS already has a training program for therapists who hope to do MDMA-assisted therapy if the FDA approves it, which Doblin says should be sometime in 2023.

Therapy is part of the treatment

You probably don't give much thought to where you are when you take medication to ease your headache, or clear your sinuses, or lower your blood pressure. You simply check the dosage, take the pill, and get back to your daily business.

Psychedelic medications work differently. They require certain conditions, including psychotherapy before, during, and after the dosing.

This helps prepare the "set and setting" of psychedelic-assisted therapy. "Set" is your mindset going into the day of your psychedelic dosing. And "setting" describes the space and people around you when you take your dose and experience its effects.

A 2021 psilocybin trial for treatment-resistant depression required 6 to 8 hours of preparatory talk therapy about mental health issues and what to expect during the dosing session, which can be quite intense, emotional, and even scary.

The dosing session itself took about 8 hours and required two psychotherapists in a closed room with a nurturing physical environment to ensure full safety and support. Later, there were three sessions of "integration," where a therapist helped participants process their psychedelic experience in order to get the most out of it.
The MAPS trials for MDMA-assisted psychotherapy for PTSD have similar requirements, as do many other proposed psychedelic-assisted therapies.

Part of the reason for this is safety. These are powerful medications. And because of their long history of recreational use, there is some risk of misuse, or at the very least, unsafe use.

In a club where you're dancing for hours or using other drugs, a high dose of MDMA could make you overheat and pass out, or even damage parts of your brain. And for some people, the psychological effects of psychedelics can be frightening or trigger risky behavior, especially in an unstable environment without trained support. Psychedelics may also be unsafe for people with serious heart conditions or a family history of psychosis.

In a controlled clinical setting with proper screening, doctors can minimize these risks.

But it's not just about safety, says Boadie Dunlop, MD, associate professor of psychiatry and behavioral sciences and director of the Mood and Anxiety Disorders Program at Emory University.

Set and setting are actually key to the success of the treatments.

Boadie Dunlop, MD

"If psychedelic drugs worked on their own to treat mental health issues, people would already be using them," Dunlop says.

"Word of mouth would have spread about the power to treat these very common conditions and people would just take them."

Sure, Dunlop says, psychedelics can lift mood for a short time in some people. But for long-lasting effects -- what scientists call "enduring benefit" -- patients need to take them in a psychotherapy setting.

But nothing is set in stone. As research builds, the treatments will continue to evolve, Dunlop says.

"There's no doubt that we're going to have to keep fine-tuning it."

Is approval possible?

Would the federal government ever seriously consider approving such seriously mind-altering substances better known at clubs and parties than in any kind of medical setting?

"It's already happened," says John Krystal, MD, chairman of the psychiatry department at the Yale School of Medicine.

John Krystal, MD

He's talking about esketamine (Spravato), a nasal-spray form of ketamine that got the FDA's nod in 2019 for treatment-resistant depression. Ketamine is known in recreational settings as "special K."

In a clinical setting, you take esketamine at a doctor's office, and a prescription typically means you also need to be on an antidepressant medication like selective serotonin reuptake inhibitor (SSRI). Of course, unlike proposed psychedelic-assisted treatments, esketamine doesn't require psychotherapy along with it.

Still, Krystal says, esketamine takes a similar approach: It changes consciousness temporarily to treat depression over a longer term. And its approval has helped open the doors for study of psychedelic-assisted therapies.

But Krystal is wary of moving too quickly to FDA approval. He notes that many psychedelic studies have been fairly small. He wants to see bigger studies and more of them.

And there are other limitations.

The gold standard for scientific research -- the randomized, double-blind, placebo-controlled study -- requires that neither the giver nor the receiver of a medication in a study know for certain what it is. But it is very hard to hide, or "blind," psychedelic drugs because they cause such deep, distinct, and well-known effects. That makes it much harder to do these studies in an effective way.

Still, Krystal is optimistic. Psychedelic research, he says, has shed new light on the way certain mental health conditions seem to work in the brain and it offers new hope for some conditions, like treatment-resistant depression, which he calls "a devastating medical condition that shortens life span by over 5 years."

That's why he applauds psychedelic research, even when it pushes the limits with studies that might be politically unpopular or hard to administer -- just as long as there's no rush to approve.

"I am hopeful that the FDA will exert its usual cautious approach to the approval of new medications. As they used to say about wine, 'We want no drug approved before its time.'"

A tipping point
​

A quick search on ClinicalTrials.gov shows hundreds of active clinical trials on psychedelic medications. There are more than 50 studies on psilocybin alone, and similar numbers for MDMA, LSD, DMT, and other psychedelics.

"We are no longer investigating whether psychedelics can help. The evidence is pretty clear."

-- Rick Doblin, PhD

And there has been an explosion of interest in the private sector from companies that want to get approval for psychedelic treatments and bring them to market. MAPS is one such organization. But there are many others, like COMPASS Pathways, who recently secured a new U.S. patent (it already has 8 others) for a form of psilocybin to treat major depressive disorder.

B.More and Awakn are working on psychedelics to treat alcoholism and other addictions. Usona Institute, another nonprofit, is working on forms of psilocybin and DMT for other psychedelic therapies.

In August 2021, a company called Cybin became the first psychedelics company to list its stock on the New York Stock Exchange. And there are quite a number of psychedelic pharmaceutical companies (including COMPASS, listed on NASDAQ) that are traded around the world.

Rick Doblin, for one, sees this as a tipping point.

Psychedelic research today is far more advanced than at the height of the 1960s, he says, and prescription approval is well within range.

"We are no longer investigating whether psychedelics can help," says Doblin. "The evidence is pretty clear."
​

The question now, he says, is where do we go from here?

​

A Long, Strange Trip: Magic Mushrooms, MDMA, and the Promise of Psychedelic-Assisted Therapy

Find out how psychedelic drugs such as MDMA and psilocybin are being tested as treatments for a wide range of mental health conditions, including depression and PTSD.

www.webmd.com

 

[mr peabody]

Inside the brave new world of psychedelic medicine*

by Joe Castaldo | The Globe and Mail | 23 Mar 2022

Psychedelics have huge potential to treat a range of mental illnesses. Field Trip Health is one of dozens of companies to leap into a sector reminiscent of the early days of the cannabis craze. But what do investors—and patients—stand to gain?

The first time Julian Uzielli took ketamine, he did not have visions or travel to new realms of existence. But the second—and third, fourth, fifth and sixth—times he took the psychoactive drug, his consciousness seemed to spring loose from his body. But in the moment, he says, every revelation felt profound. More important, the experience helped relieve his suicidal thoughts—and that’s where ketamine’s promise lies.

The drug is an anaesthetic whose psychedelic properties made it popular on the party circuit, where it’s better known as Special K. More recently, it’s been touted as the future of mental health medicine, applicable to a whole range of illnesses. Janssen Pharmaceuticals has already won approval in both Canada and the United States for a ketamine-based nasal spray called Spravato for patients with treatment-resistant depression. And dozens of start-ups are now hoping to push psychedelics further into the mainstream, both among consumers and investors.

The potential is massive. One in four Americans experience a mental illness in any given year, and the market for antidepressants in the U.S. alone could be worth US$98 billion by 2025. Even if psychedelics capture a small slice of that, it could be significant.

The research is moving beyond the mental health realm, too. A report from the global investment bank Stifel estimates psychedelics like ketamine, psilocybin and MDMA could help more than three billion people and potentially treat 20-plus conditions, including chronic pain and obesity. Not surprisingly, money is starting to flood the sector: In 2019 psychedelics start-ups received roughly US$60 million in investment, according to research firm LEK Consulting. Last year, investors poured in an estimated US$2 billion.

Field Trip Health Ltd., a small publicly traded start-up in Toronto, provides a glimpse of what a psychedelic future could look like. Uzielli’s ketamine trips were part of a highly curated program offered at Field Trip’s 11 clinics across North America (plus one in Amsterdam that administers psilocybin, the active ingredient in magic mushrooms). A full three-week round, which includes six ketamine dosings and three appointments with a psychotherapist, costs roughly $5,000. (Group sessions bring that down to about $2,875.) According to Stifel analyst Andrew Partheniou, the clinical business in the U.S. alone could be worth US$10 billion—though so far, Field Trip has generated just $3.1 million in revenue in its latest three quarters. It also has an R&D division dedicated to developing psychedelic medications.

To be clear, the industry is nascent. “There’s way more enthusiasm than data,” says Dr. Susan Abbey, director of the Nikean Psychedelic Psychotherapy Research Centre in Toronto, which launched within the University Health Network last October. For instance, there’s limited research on whether the kind of treatment Field Trip offers—a combination of ketamine and talk therapy—is any more effective than ketamine on its own. And while Field Trip’s slick branding leans heavily on the psychedelic experience—in fact, it wants people to have the most intense trip possible—it’s not clear whether that’s necessary. Some people who’ve received ketamine for depression see symptoms improve without entering an altered state of consciousness at all.

Today’s market is reminiscent of the early years of the cannabis craze: bold claims, huge uncertainties and a swath of money-losing companies angling to lead the way. In fact, Field Trip’s executive chair and chief ambassador, Ronan Levy, once ran a chain of medical cannabis clinics and has the sort of vibe you’d expect from an affluent business guy who’s gotten very into mindfulness. His head is shaved, and he wears a stubbly goatee and beaded necklace. He meditates. “I come across as pretty easygoing,” says Levy, one of five co-founders, “and a lot of people have said that’s what the psychedelic industry needs.”

It’ll take more than a chill vibe to ensure Field Trip prevails—like a deft strategy, medical and scientific rigour, and buckets of capital. (Just ask any of the dozens of cannabis growers and retailers floundering today.) And those are the factors within Field Trip’s control; it can’t do much about the glacial pace of research and regulation.

None of that dampens Levy’s fervour. He sees a much bigger market ahead, with Field Trip treating a wide array of conditions with a variety of psychedelic drugs. “I have always had this archetype of a 28-year-old bro dude in Pittsburgh who would probably rather be dead than caught in a therapist’s office,” he says. “We can’t reach those people with conversations about therapy and meditation. But can I get that guy to try mushrooms once? Yeah, probably.”

Co-founder Ronan Levy says Field Trip's Insta-chic clinics, complete with zero-gravity chairs in the dosing rooms, are designed to sooth patients and ensure no one has a bad tripHandout

When Uzielli walked into the upscale lobby of Field Trip’s Toronto clinic—with a moss wall behind reception, and trendy furniture dotted with fiddle-leaf figs and succulents—he wondered what he’d gotten himself into. For him, ketamine-assisted psychotherapy straddled the line between “real” and alternative medicine, and the essential-oil diffuser in particular added a whiff of pseudoscience. On arrival, he was handed a Field Trip tote bag containing a journal, a reishi mushroom tincture and a copy of Michael Pollan’s book How to Change Your Mind, an exploration of the benefits of psychedelics.

The 30-year-old radio producer had a long history of depression. In 2020, he found he could barely get out of bed, let alone do his job. During video calls, he could see his resistance exercise bands dangling from the ceiling behind him; in his mind, they looked like a noose hanging over his head. He took two leaves of absence, overcome with intense suicidal thoughts. By the time he came across Field Trip—whose patients must be referred by a doctor for treatment-resistant depression, a label that applies to roughly 30% of cases—he was ready to try anything.

He was led to one of six dosing rooms (with names like Sea, Sunset and Mountain), where a nurse and a respiratory therapist tucked him under a weighted blanket on a zero-gravity chair meant to mimic weightlessness. The nurse gave him a lozenge packed with about 200 milligrams of ketamine that slowly dissolved in his mouth. Feeling woozy, he put on a sleep mask and headphones, where music curated for tripping flowed into his ears. (Franklin Chavez, a soft-spoken nurse practitioner and the clinic’s manager, says Field Trip has assembled several playlists of largely ambient music. “If the client’s intention is to feel love,” he says, “our therapists have put together playlists specifically for that.”)

Uzielli’s first trip didn’t yield much in the way of revelations, but his mood improved, and he returned for five more sessions. Each ketamine journey lasted 45 minutes to an hour. As the ketamine wore off, he debriefed with a Field Trip therapist and had separate weekly sessions. The drug left him emotionally vulnerable, making it easier to open up.

Until then, Uzielli was convinced he’d always be depressed. But after three weeks, he simply wasn’t anymore. He felt exuberant. The feeling faded after a couple of months, and a year later, Uzielli is still on antidepressants. But he says he is nevertheless transformed. Most days are good, and his suicidal thoughts have disappeared. “I feel like it gave me my life back,” he says.

Field Trip Health is one of dozens of companies to leap into a sector reminiscent of the early days of the cannabis craze.Romain Lasser/The Globe and Mail

Ketamine was first synthesized as a painkiller some 60 years ago. At low doses, it induces dissociative psychoactive effects and was later co-opted as a recreational drug. Clinicians kept experimenting, though. Research into ketamine’s effect on depression began in the 1990s at Yale University, and it was found to relieve symptoms within hours, though only briefly.

A wide body of research has since shown it can alleviate symptoms of depression for which other interventions have failed, with up to 65% of users receiving at least some benefit. Between 20% and 30% of those treated with ketamine go into remission. Exactly why isn’t completely understood, but the drug seems to regulate glutamate, a neurotransmitter that helps facilitate the brain’s ability to change and form new connections.

Today, ketamine can be prescribed off-label in Canada and the U.S. And it’s not the only psychoactive drug being studied in labs worldwide, following a long government clamp-down after the 1960s that has since eased. Since August 2020, Health Canada has allowed psilocybin, which can help reduce depression and anxiety, to be administered to nearly 80 people with terminal illnesses. In January, the department further modified regulations to allow doctors to request access to psychedelics for patients with serious or life-threatening conditions for whom other options had failed. Field Trip immediately announced it would apply to Health Canada for permission to administer psilocybin and MDMA, which research has shown to be effective in treating PTSD.

Field Trip opened its first clinic in Toronto in March 2020 (just as the pandemic sent rates of depression and anxiety soaring). Outlets in New York, Los Angeles, Vancouver and Fredericton soon followed. By 2024, it plans to have 75 branches worldwide. “I genuinely believe it’ll be a drop in the bucket relative to anticipated demand,” says Levy.

He’s a relative newcomer to the psychedelics field, a corporate lawyer who left Big Law behind and co-founded a cash-for-gold business before finding his way to medical cannabis in 2014. He and his partners (including Joseph del Moral, now Field Trip’s chief executive) started a chain of clinics called CanvasRX Holdings. “We got into the cannabis industry as entrepreneurs, certainly not as advocates,” says Levy. “As soon as we saw the work our clinics were doing on a humanitarian basis, we were really moved.” They sold CanvasRX to Aurora Cannabis in 2016, in a deal valued at $10.3 million (with further payments contingent on hitting performance goals), and left two years later, just as interest in psychedelics was building.

To get a feel for the field, Levy and a few associates procured some mushrooms, holed up in a rented office and tripped. As Levy and his partners honed their business plan, experts suggested there was a need for new clinics. Most medical centres and doctors’ offices, they were told, didn’t have the proper staff or accommodations for patients to trip and come back to Earth, which can take a few hours. The partners also knew from their cannabis days that producers stood to make far more money than medical clinics. So they created Field Trip Discovery to develop psychedelic medications. Its lead candidate is a synthetic molecule called FT-104 that has a potency similar to psilocybin and binds with the serotonin receptor in the brain believed to be responsible for psychedelic experiences. So far, Field Trip has only tested the molecule in animals, but Phase I trials in humans are set to begin this year in either the Netherlands or Australia.

Field Trip is bullish on FT-104 because of its relatively short trip time. A psilocybin experience can last for hours, which isn’t practical in a medical context. FT-104, however, has a trip time of two to three hours. Field Trip believes it could be used to address treatment-resistant depression, a US$21-billion market in the U.S., as well as postpartum depression. The company expects to gain approval for the drug sometime between 2026 and 2028.

Field Trip's 5 co-founders, left to right: COO Mujeeb Jafferi, president Hannan Fleiman,
chief clinical officer Dr. Ryan Yermus, CEO Joseph del Moral and executive chair Ronan Levy

Developing drugs is highly capital-intensive, of course, with different funding needs from the retail operation. In the first three quarters of their latest fiscal year, Field Trip lost $40.5 million, in part from building new clinics, but also due to its drug research. Levy says Field Trip is reviewing whether to separate the two units. In the meantime, the clinics remain its primary money-maker—and things can get a little weird.

Field Trip describes itself first and foremost as a wellness company, one that offers a “deeply human experience” that combines modern medicine with the “wisdom of the psychedelic approach.” It has imbued ketamine with an almost spiritual aura. One client told me that during a group session, participants were asked to place a personal object on an altar to help focus their intentions. The session, she said, felt like a religious retreat.

Indeed, a recent article in Wired criticized Field Trip and some of its peers for blurring the line between “medical treatment and spiritual healing.” Michael Pollan himself—the revered author whose psychedelics book has its own neon-lit shrine at Field Trip’s Toronto clinic—tweeted the article and described it as “a warning against the Gooping of psychedelics,” a reference to actor Gwyneth Paltrow’s lifestyle brand, notorious for its dubious health advice.

Levy contends the high-end aesthetic serves a purpose: to ensure clients can relax and avoid a bad trip. (After all, ketamine has been known to send recreational users into an unresponsive state known as a K-hole.) When Kristine Iglesias began researching ketamine facilities, she found them to be overtly medical. “I would feel like I was in a treatment centre for psychiatric help,” says the 49-year-old from Connecticut. Iglesias had been suffering from depression and suicidal thoughts. After a three-week cycle at Field Trip’s Manhattan clinic last year, she no longer felt suicidal. She has since returned for a group session and a booster dose. “That process changed the way my mind works.”

Field Trip’s approach is at odds with competitors like Braxia Scientific, which opened Canada’s first private clinic offering ketamine for depression in Mississauga in 2018. It now has four. “We are not a spa,” says Braxia’s CEO, Dr. Roger McIntyre. “We’re a medical company that treats a very, very, very serious medical problem.” His strategy is informed by his background: Dr. McIntyre is a professor of psychiatry and pharmacology at the University of Toronto and heads up a mood disorder research unit at UHN.

Braxia doesn’t offer therapy in conjunction with ketamine, either. “The scientific question is, if you combine the two together, do you get an additive effect?” That, he says, is a work in progress, and he’s conducting a study into whether intravenous ketamine followed by cognitive behavioural therapy (CBT) is more effective at reducing suicidality than either treatment alone.

Indeed, most of the research on ketamine examines the effect of the drug itself, not when it’s administered alongside therapy. “It’s very new,” says Dr. Yuliya Knyahnytska with Toronto’s Centre for Addiction and Mental Health (CAMH), who is conducting her own ketamine research. “All the trials available are very small.” Another complication: There’s no consensus on what ketamine-assisted psychotherapy actually is and how it’s delivered. Field Trip, for example, says its sessions can involve a number of techniques, including CBT and motivational interviewing. “If we have an unstandardized treatment,” says Dr. Knyahnytska, “we cannot evaluate it, and we cannot measure it.”

Field Trip’s own data is limited. It encourages clients to fill out a questionnaire before and after each visit to gauge effectiveness. Dr. Michael Verbora, Field Trip’s medical director for Canada, says patients report a 50% reduction in the severity of depression, anxiety and trauma after a three-week cycle. Three to six months later, their self-reported depression scores are roughly the same. “They’re massively decreased compared to when they first came to see us,” says Dr. Verbora, who also serves as chief medical officer of cannabis firm Aleafia Health. The data is based on roughly 100 patients, and collecting it is tricky since there’s no incentive for clients to respond. “The data set is not as ideal as we’d love it to be,” he says.

There’s not even consensus on the importance of the trip itself, which is key to Field Trip’s pitch. In Dr. Knyahnytska’s own clinical experience with ketamine, she has seen patients for whom an altered state is integral to healing and others who improved with no trip at all. For her, it points to the need for further research. Dr. McIntyre, meanwhile, says not only is a psychedelic trip not necessary, but “we see it as an aspect of the treatment we wish to avoid.”

The gulf between the enthusiasm for psychedelics and that data gap is challenging. “As an academic, I like data. And I also really feel very compassionately for the suffering of people with major mental illness,” says the Nikean Centre’s Susan Abbey. “It just speaks to how desperately people want these treatments.”

In a sign of just how volatile the psychedelic sector is, even some pretty good news can send stocks plunging. In November, Compass Pathways, one of the more prominent players in the space, released the results of the largest ever randomized controlled trial on psilocybin.

The results showed patients who received a high dose reported a significant decrease in depression. But investors sold shares across the board. Stifel’s Partheniou wrote at the time that investors were concerned some patients may require additional dosing; given a psilocybin trip can last from four to eight hours, the results raised questions about its clinical practicality.

Field Trip’s own stock is down by 70% in the past year, leaving it with a valuation of roughly $105 million. Its plans to boost revenue by opening more and more clinics won’t be straightforward, either. There are capacity constraints, for one. Each clinic has just a handful of dosing rooms, and the process takes hours, limiting the number of clients it can treat. And Levy admits finding trained therapists who have psychedelic experience will be tough.

The cost could also be prohibitive. While some insurers might cover the therapy component of Field Trip’s program, at least some would have to pay out of pocket. And the benefits don’t last forever. Studies have shown that people who receive ketamine intravenously relapse within one to three months, although their depression may not be as severe. That means clients might have to come back for top-ups—if they can afford it in the first place.

Such limitations provide an incentive to expand the range of conditions Field Trip can treat. Levy points out there’s promising research showing ketamine is effective for alcohol use disorder, which will afflict roughly one-fifth of Canadians throughout their lifetime, according to Statistics Canada. “There are natural struggles in life that don’t fit into this very rigid box we call the DSM 5,” says Levy. “Our physicians are becoming progressively more open—not being flagrant about it, but satisfying themselves that maybe you don’t have major depression, but you still have some sort of condition that can justify treatment.” The U.S. is considerably looser in that regard; patients don’t need a referral or pre-existing diagnosis.

Field Trip’s branding is certainly designed for mass appeal. The company sells clothes featuring its undulating rainbow logo, and it has a meditation app for “consciousness expansion.” It’s similar to the approach taken by Tweed, the cannabis company co-founded by Bruce Linton in 2013. Tweed, which became Canopy Growth Corp., built a consumer brand long before the recreational market was established, helping it cement an early lead.

Levy goes so far as to say Field Trip is, at its core, a lifestyle company. Lately, he’s been devoting thought to what a “psychedelic-informed” life can look like. “When you support people who are leaning into changing their lifestyle, tapping into meditation, eating healthier, exercising, being more empathetic,” he says, “that’s how you’re going to change the world.”

Patients like Janine, meanwhile, just want relief. After surviving a suicide attempt a few years ago, the 34-year-old Torontonian began taking antidepressants. Two years later, she hit a low. In June, she had her first session with Field Trip. Afterward, she looked in the mirror and told herself she was beautiful. “That was the first time I actually believed it,” Janine says. “After that first week, it sort of ripped out the skeleton of how I treated myself.” By the end of the three weeks, she felt reborn.

When she noticed her old thought patterns returning, she booked another treatment in July, attended a group session in October and recently had another maintenance dose. Janine, who works in web development, likens it to updating computer software: It can be buggy, and sometimes legacy programming can gum up the works. “Each subsequent session has helped to remove more of that old programming,” she says. “I’ve rewired so much of what I used to be. I’m okay for a while now.”

*From the article here :

This is your brain on ketamine: Inside the brave new world of psychedelic medicine

Psychedelics have huge potential to treat a range of mental illnesses. Field Trip Health is one of dozens of companies to leap into a sector reminiscent of the early days of the cannabis craze. But what do investors—and patients—stand to gain?

www.theglobeandmail.com

 

[mr peabody]

Momentum grows for the use of psychedelics as part of mainstream therapy*

by Gary Enos | Oct 4 2019

MAPS founder, Rick Doblin, recently updated attendees of Psych Congress 2019 on a Phase 3 research program that could result in FDA approval of MDMA-assisted psychotherapy for PTSD by the end of 2021.

MDMA was seen as therapeutic before it was declared illegal in the mid-1980s, but now Dr. Doblin says research evidence is demonstrating that the drug can help individuals process traumatic memories. MDMA-assisted psychotherapy participants feel that “when they are no longer scared of these memories, they can work with them on their own,” he said.

More than two-thirds of patients receiving 3 sessions of MDMA-assisted psychotherapy no longer met criteria for PTSD in Phase 2 research that compared their outcomes to those of patients receiving therapy without MDMA.

The FDA has granted Breakthrough Therapy status to MDMA-assisted psychotherapy for PTSD, a treatment that Dr. Doblin envisions as being delivered by a pair of trained therapists in individual therapy sessions. He emphasized that the medication is not the treatment, and that a variety of potential therapeutic methods can be employed depending on what emerges from the patient in the sessions in which MDMA is administered.

If MDMA-assisted psychotherapy were to receive FDA approval for PTSD, the approval would be accompanied by a Risk Evaluation and Management Strategy (REMS) ensuring that only those trained in the MDMA-assisted psychotherapy could prescribe it, with delivery only under direct supervision in clinical settings. MDMA would not be a take-home treatment for PTSD.

More from Dr. Doblin: MDMA Moving Closer to Therapeutic Use

Dr. Doblin emphasized the enormous impact this tool ultimately could have on US military veterans, just over 1 million of whom were receiving disability payments based on PTSD as of September 2018. "The Department of Veterans Affairs (VA) has contributed nothing financially to the drug development process, for political reasons, but that has not stopped some in the research community from continuing to try to convince VA leaders that this could represent a therapeutic breakthrough for a crippling and costly illness," he said.

A parallel drug development process that is taking place in Europe has had a focus on using MDMA-assisted psychotherapy to reach the continent's burgeoning populations of refugees.

Taking profit out of the equation

Dr. Doblin, who says his own interest in mysticism and psychedelics emerged out of childhood trauma around historic events such as the Holocaust and the Cuban Missile Crisis, founded MAPS in 1986 to bring MDMA back into the mainstream. The nonprofit now invests in an associated for-profit public benefit corporation that is conducting the research and will be the entity selling the drug if it is approved.

Suddenly pharmaceutical companies have started to express interest in being involved, but MAPS has declined their overtures. “When we really needed you, you were nowhere,” has been Dr. Doblin's message, referring to the lack of industry interest at the time when MDMA was seen as a dangerous party drug.

The script has decidedly flipped since then, as evidenced by developments such as the FDA's recent indication that it will draft a guidance document for psychedelic research.

“We have tried not to optimize it financially,” Dr. Doblin said. He characterized many of the MAPS research team as “refugees from Big Pharma.”

The focus instead has been on training therapists in how to follow a regimen comprising three 8-hour sessions with overnight stays at the research facility followed by sessions the day after. “It's how it's integrated that's essential,” Dr. Doblin said.

"MAPS' provider training offers therapists the option of being administered MDMA themselves, in order to understand better what the patient experiences in therapy. Eighty therapists have accepted that option so far," Dr. Doblin said.

*From the article here :

Momentum Grows for Psychedelics as Part of Mainstream Therapy

SAN DIEGO—With much of the historical fear around psychedelics having dissipated, the founder of the Multidisciplinary Association for Psychedelic Studies (MAPS) sees current research as leading the field to the emergence of a new branch of psychotherapy.

www.psychcongress.com

 

[mr peabody]

The real promise of LSD, MDMA and Psychedelic Mushrooms for Medical Science*

by Erika Dyck | The Conversation

Psychedelic science is making a comeback.

Scientific publications, therapeutic breakthroughs and cultural endorsements suggest that the historical reputation of psychedelics — such as lysergic acid diethylamide (LSD), mescaline (from the peyote cactus) and psilocybin (mushrooms) — as dangerous or inherently risky have unfairly overshadowed a more optimistic interpretation.

Recent publications, like Michael Pollan’s How to Change your Mind, showcase the creative and potentially therapeutic benefits that psychedelics have to offer — for mental health challenges like depression and addiction, in palliative care settings and for personal development.
​

Major scientific journals have published articles showing evidence-based reasons for supporting research in psychedelic studies. These include evidence that pscilocybin significantly reduces anxiety in patients with life-threatening illnesses like cancer, that MDMA improves outcomes for people suffering from PTSD and that psychedelics can produce sustained feelings of openness that are both therapeutic and personally enriching.

Other researchers are investigating the traditional uses of plant medicines, such as ayahuasca, and exploring the neurological and psychotherapeutic benefits of combining Indigenous knowledge with modern medicine.

I am a medical historian, exploring why we now think that psychedelics may have a valuable role to play in human psychology, and why over 50 years ago, during the heyday of psychedelic research, we rejected that hypothesis. What has changed? What did we miss before? Is this merely a flashback?

Healing trauma, anxiety, depression

In 1957, the word psychedelic officially entered the English lexicon, introduced by British-trained and Canadian-based psychiatrist Humphry Osmond.

Osmond studied mescaline from the peyote cactus, synthesized by German scientists in the 1930s, and LSD, a laboratory-produced substance created by Albert Hofmann at Sandoz in Switzerland. During the 1950s and into the 1960s, more than 1,000 scientific articles appeared as researchers around the world interrogated the potential of these psychedelics for healing addictions and trauma.

But, by the end of the 1960s, most legitimate psychedelic research ground to a halt. Some of the research had been deemed unethical, namely mind-control experiments conducted under the auspices of the CIA. Other researchers had been discredited for either unethical or self-aggrandizing use of psychedelics, or both.

Timothy Leary was perhaps the most notorious character in that regard. Having been dismissed from Harvard University, he launched a recreational career as a self-appointed apostle of psychedelic living.

Drug regulators struggled to balance a desire for scientific research with a growing appetite for recreational use, and some argued abuse, of psychedelics.

In the popular media, these drugs came to symbolize hedonism and violence. In the United States, the government sponsored films aimed at scaring viewers about the long-term and even deadly consequences of taking LSD. Scientists were hard-pressed to maintain their credibility as popular attitudes began to shift.

Now that interpretation is beginning to change.

A psychedelics revival

In 2009, Britain’s chief drug adviser, David Nutt, reported that psychedelic drugs had been unfairly prohibited. He argued that substances such as alcohol and tobacco were in fact much more dangerous to consumers than drugs like LSD, ecstasy (MDMA) and mushrooms (psilocybin).

He was fired from his advisory position as a result, but his published claims helped to reopen debates on the use and abuse of psychedelics, both in scientific and policy circles.

And Nutt was not alone. Several well-established researchers began joining the chorus of support for new regulations allowing researchers to explore and reinterpret the neuroscience behind psychedelics. Studies ranged from those looking at the mechanisms of drug reactions to those revisiting the role of psychedelics in psychotherapy.

In 2017, Oakland, Calif., hosted the largest gathering to date of psychedelic scientists and researchers. Boasting attendance of more than 3,000 participants, Psychedelic Science 2017 brought together researchers and practitioners with a diverse set of interests in reviving psychedelics — from filmmakers to neuroscientists, journalists, psychiatrists, artists, policy advisers, comedians, historians, anthropologists, Indigenous healers and patients.

The conference was co-hosted by the leading organizations dedicated to psychedelics — including the Multidisciplinary Association for Psychedelic Studies (MAPS) and The Beckley Foundation — and participants were exposed to cutting-edge research.

Measuring reaction, not experience

As a historian, however, I am trained to be cynical about trends that claim to be new or innovative. We learn that often we culturally tend to forget the past, or ignore the parts of the past that seem beyond our borders.

For that reason, I am particularly interested in understanding the so-called psychedelic renaissance and what makes it different from the psychedelic heyday of the 1950s and 1960s.

The historic trials were conducted at the very early stages of the pharmacological revolution, which ushered in new methods for evaluating efficacy and safety, culminating in the randomized controlled trial (RCT). Prior to standardizing that approach, however, most pharmacological experiments relied on case reports and data accumulation that did not necessarily involve blinded or comparative techniques.

Historically, scientists were keen to separate pharmacological substances from their organic cultural, spiritual and healing contexts — the RCT is a classic representation of our attempts to measure reaction rather than to interpret experience. Isolating the drug from an associated ritual might have more readily conveyed an image of progress, or a more genuine scientific approach.

Today, however, psychedelic investigators are beginning to question the decision to excise the drug from its Indigenous or ritualized practices.

Over the past 60 years, we have invested more in psychopharmacological research than ever before. American economists estimate the amount of money spent on psychopharmacology research to be in the billions annually.

Rethinking the scientific method

Modern science has focused attention on data accrual — measuring reactions, identifying neural networks and discovering neuro-chemical pathways. It has moved decidedly away from larger philosophical questions of how we think, or what is human consciousness or how human thoughts are evolving.

Some of those questions inspired the earlier generation of researchers to embark on psychedelic studies in the first place.

We may now have more sophisticated tools for advancing the science of psychedelics. But psychedelics have always inspired harmony between brain and behaviour, individuals and their environments, and an appreciation for western and non-western traditions mutually informing the human experience.

In other words, scientific pursuits need to be coupled with a humanist tradition — to highlight not just how psychedelics work, but why that matters.

*From the article here :

The real promise of LSD, MDMA and mushrooms for medical science

Once associated with mind-control experiments and counter-cultural defiance, psychedelics now show great promise for mental health treatments and may prompt a re-evaluation of the scientific method.

theconversation.com

 

[AbbeyLee]

My good friend is a pharmacist in London. He's told me they are waiting on psychedelics.. So it's happening!! I personally think this is so exciting and could be a turning point for humanity.

He just sent me this article:

Psilocybin for depression could help brain break out of a rut, scientists say

Research shows effects of compound found in magic mushrooms can be seen weeks after treatment

www.theguardian.com

​

 

[mr peabody]

​

The future of Psychedelic Science

by Ryan O'Hare | Imperial College London | 17 May 2021

From treating depression to understanding consciousness, the promise of psychedelics is shifting their study from fringe to frontier neuroscience.

In 2019 a small group of researchers at Imperial established the world’s first dedicated centre for research into the action and clinical use of psychedelic compounds.

Two years on, the Centre for Psychedelic Research has completed landmark studies into the therapeutic potential of magic mushroom compound psilocybin for depression, exploring the ‘waking dream state’ linked to ayahuasca, and digging deeper into the science of micro-dosing with LSD.

Ryan O’Hare spoke to Dr Robin Carhart-Harris, the head of the Centre, to discuss what’s in store for the future. Listen to the full interview below.
Here are five of the big questions the work of the Centre for Psychedelic Research hopes to answer in the future.



How do psychedelics change our brain?

Work from the Centre has shown that psilocybin may help to ‘reset’ the brain and break out of long-entrenched patterns of activity seen in depression.

Early, unpublished follow up work from the team shows that when people are shown emotionally charged faces, SSRI antidepressants (drugs like fluoxetine and escitalopram) blunt the response to all faces, but psilocybin may only dampen the negatively charged faces.

Dr Carhart-Harris explains: “With the Prozac-like antidepressant…we see a dampening or muffling of the brain’s responsiveness to emotional stimuli relative to the psilocybin. That makes sense because the psilocybin is more like an emotional recalibration or reset, whereas the SSRI [antidepressant] is more like taking the edge off emotional intensity which helps with stress management.”

Delving into this further, the Centre plans to study how psychedelics change the activity of our brains. Studies are due to begin analysing brain waves and MRI data in volunteers given psilocybin and DMT (the active compound found in the psychedelic Amazonian brew ayahuasca) to compare their brain activity before and after their experience.

How are people using psychedelics and can we reduce potential harms?

ver the last two years, the team has been gathering real-world data on how people are using psychedelic drugs, gaining valuable insights.

Through the ongoing Psychedelic Survey and the imminent launch of the MyDelica app, the team hopes to use a data-driven approach to help inform people intent on taking psychedelics of the importance of the setting, wider context and psychological state on outcomes.

One of the aims is to educate people and provide advice, which may help to reduce harms and ultimately improve psychological outcomes.

“We’ve actually seen, looking at some recent data, that use of psychedelics over the last 10 years has increased exponentially,” explains Dr Carhart-Harris.

“With the online sampling and the app we’re developing, the intention is to de-risk some of that and provide harm reduction, psycho-education advice to try and keep people safe, essentially.”

The researchers warn that people should not attempt to self-medicate or replicate findings from clinical trials with psychedelics, as the team provided a special therapeutic context for the drug experience and things may go awry if the extensive psychological component of the treatment is neglected.

Could psilocybin help to treat anorexia?

Following positive initial results in a small trial of psilocybin assisted therapy for depression, the Centre is set to look at whether the same approach could help with anorexia nervosa.

Building on evidence from a small number of historical case studies of using psychedelics in eating disorders, the team will trial psilocybin-assisted therapy in young adults with anorexia to see if the treatment is feasible and effective.

According to the Centre: “Anorexia nervosa is the most fatal of all psychiatric conditions. With the current paucity of effective pharmacological and psychological treatments, and fewer than half of those diagnosed making a full recovery, there is a great need for new treatment avenues to be explored.”

A small study is due to begin in the coming months.

Can psychedelics offer relief from chronic pain?

Despite numerous advances in pain relief, effective and non-addictive treatments for long-term chronic pain – such as lower back pain – remain elusive.

There is mounting evidence that in those with chronic pain conditions, the brain connections which relay and processes pain signals can become reinforced and strengthened over time, as part of a feedback loop which sensitises them even more to feeling pain and associated negative emotional response.

Psychedelics could offer an opportunity to ‘reset’ these neural pathways. The hope is that by disrupting this entrenched pain circuitry, psychedelics might offer a way to reduce the brain’s over-sensitivity to pain signals.

According to Dr Carhart-Harris, the Centre hopes to begin a study later this year.

What is consciousness?

One of the more fundamental areas researchers are hoping to advance with psychedelics is our understanding of human consciousness.

By analysing brain activity before, during and after psychedelic experiences, the team hopes they can shine more light on brain states linked with the so called ‘mystical experience’ associated with psychedelics.

The team has already laid some of the groundwork, with its previous DMT research into the ‘waking dream state’ linked to ayahuasca. It is thought that a better understanding of how different patterns of brain activity give rise to hallucinations and waking consciousness could enable us to nudge the brain when it’s stuck in certain negative patterns.

Psychedelics could potentially ‘reset’ brain activity and enable people to break out of entrenched, negative behaviour patterns – linked to addiction, depression or pain, for example – which have been reinforced and strengthened over a person’s lifetime.

“DMT is a particularly intriguing psychedelic," Dr Carhart-Harris commented previously. "The visual vividness and depth of immersion produced by high-doses of the substance seems to be on a scale above what is reported with more widely studied psychedelics such as psilocybin or ‘magic mushrooms’," he explained.

“Our sense it that research with DMT may yield important insights into the relationship between brain activity and consciousness, and [our previous work] is a first step along that road.”

The future of psychedelic science | Imperial News | Imperial College London

From treating depression to understanding consciousness, the promise of psychedelics is shifting their study from fringe to frontier neuroscience.

www.imperial.ac.uk

 

[mr peabody]

​

Why psychedelics are seeing a surge in medical interest, in treatments for depression, addiction and more*

by Richard James Havis | South China Morning Post | 5 May 2022

Medical treatments using psychedelic drugs such as psilocybin – derived from certain mushrooms – and LSD (lysergic acid diethylamide) faded out in the 1960s when such drugs were made illegal in the United States. The last decade, however, has seen a resurgence of research into their medical properties. Read on to learn the history of their development, what they do to the brain and why they are once more being studied.

Psychedelics are illegal in most countries. LSD, for instance, was designated a Schedule 1 drug in 1968 in the US, which makes it illegal. The designation also states that the drug has no medical value, which meant research into its medical properties, and those of other psychedelic drugs, petered out by the early 1970s.

Research started to creep back during the early 2000s. Today’s researchers generally use psilocybin, the psychedelic element in “magic mushrooms”, which are grown in small quantities for research purposes.

In 2018, the US Food and Drug Administration designated some psychedelic treatments as “breakthrough therapy”, which means they have significant therapeutic potential.

The following year, Imperial College London in the United Kingdom opened the world’s first Centre for Psychedelic Research. At the time, Dr Robin Carhart-Harris, its head, said: “Psychedelic therapy holds a great deal of promise for treating some very serious mental health conditions and may one day offer new hope to vulnerable people with limited treatment options.”

The same year, private donors gave US$17 million to start the Center for Psychedelic and Consciousness Research at Johns Hopkins Medicine, part of Johns Hopkins University in Baltimore, Maryland, in the United States.

In 2021, the US National Institutes of Health gave Johns Hopkins a US$4 million grant for research into the use of psilocybin as an assisted therapy for tobacco addiction – the first US government grant for psychedelic research in 50 years.
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LSD was first synthesised by Swiss chemist Albert Hofmann in 1938 as part of a medical research programme. Hofmann did not discover its psychedelic properties until 1943, when he accidentally ingested some.

He wrote the story of LSD in the book, LSD: My Problem Child. Interviewed just before his 100th birthday in 2006, Hofmann called LSD “medicine for the soul” and was frustrated by the worldwide prohibition of it.

In a speech on his 100th birthday, Hofmann said: “[LSD] gave me an inner joy, an open-mindedness, a gratefulness, open eyes and an internal sensitivity for the miracles of creation.”

He died in April 2008, aged 102, having regularly digested microdoses of LSD after he’d first tried it.

LSD was used as a psychiatric medicine from 1947, and researchers also started to investigate the use of psilocybin, which has similar psychedelic properties.

What are today’s doctors hoping to treat with psychedelics?

Psilocybin has been tested, in conjunction with supportive psychotherapy, to combat severe depression and depression that is not improving with other treatments.

A clinical trial is under way at the University of Washington School of Medicine to test whether psilocybin-assisted psychotherapy can help front-line doctors and nurses who developed depression and anxiety amid the Covid-19 pandemic.

Research has shown psilocybin to be at least as effective as common antidepressant drugs in such treatments, and its side effects may be less. Psilocybin may also be effective in combating tobacco addiction.

Palliative care is another research area for psilocybin; it has been administered to terminal cancer patients who said that the psychedelic experience helped them face the prospect of death.

Researchers are exploring the potential of MDMA (Ecstasy) to treat sufferers of post-traumatic stress disorder (PTSD), and its efficacy in treating alcoholism.

Few tests have been run using LSD, although one test showed that microdoses – which don’t induce psychedelic experiences – may relieve pain.

Isn’t this stuff addictive? Is it safe to take it?

Scientists say that psychedelic drugs like LSD and psilocybin are not physically addictive. But due to the nature of the psychedelic experience, accidents can occur, which is why treatments take place in regulated and secure medical environments.

Recreational users of psychedelics sometimes find the experience so pleasant they want to repeat it, but there is no research into how this relates to those taking it in a medical setting.

The physical environment is also important for a successful experience.

“[While taking psilocybin] you are very vulnerable to outside stimuli which can change your brain,” said Bruna Giribaldi, lead clinical trial manager and pharmacologist at Imperial College London’s Centre for Psychedelic Research. “It could be a very good direction of change, but if you are in a bad context, you could be traumatised. That is why context is important. We have safe environments and trained people to make sure that it is safe.”

Do psychedelics give you a spiritual experience?

They might, but that’s not something that scientists can tell you, as scientific methods cannot validate spiritual or mystical experiences. However, feelings of euphoria and oneness with the universe do occur during the treatments and are central to psilocybin’s use in palliative care.

Drug-induced spiritual experiences may be an illusion, but medical practitioners say that a lack of veracity does not invalidate the treatment.

“Most people in the medical profession say that knowledge of the veracity of the patient’s psychedelic experiences is beyond their pay grade – no one knows if they are real or illusory,” said Michael Pollan, author of How to Change Your Mind, a book about psychedelics. “But they don’t care if the experience is real or not, as long as it helps the patients.”

What does treatment with psychedelics involve?

Psilocybin is administered in measured doses, while carefully selected music is sometimes played through headphones to enhance the experience.

Patients lie blindfolded on a sofa and monitors are present to offer guidance throughout. Patients are briefed about what to expect before the experience, and debriefed after it.

The treatment takes place within the wider context of psychiatric therapy, and is not a stand-alone treatment.

So what’s going on in my head when I take the treatment?

Psilocybin affects the way serotonin, a neurotransmitter, sends messages around the brain. Essentially, the chemistry of psilocybin temporarily rewires the patient’s brain, allowing connections to be made that don’t usually exist. For instance, the part that is responsible for colour vision may connect to the part that is responsible for hearing sound, so the patient “hears” colours.

How does that cure me?

Psychedelic drugs can change your view of the world, researchers say, and that can give addicts the desire to break their addiction, and terminal patients the strength to face death.

According to Pollan, being an alcoholic or a depressive is, among many other things, about perspective. "You are looking at the world from a destructive perspective, and the drugs foster a shift in that perspective. You see your life and its problems differently. Seeing things from a different point of view can be constructive," he said.

Giribaldi said that the theory behind psychedelics is that they relax the strong beliefs people have about the world. “By relaxing your beliefs, you are able to see things in a different way. This is useful in mental illness, because the one thing that unites mental illnesses like depression and addiction is a strong and rigid way of thinking, or a strong set of ideas about what is happening in the world.”

*From the article here :

Explainer | How psychedelics like magic mushrooms could treat depression and addiction

Illegal since the 1960s, psychedelics including psilocybin and LSD are now under the microscope again as researchers see if they can help treat a range of medical conditions.

www.scmp.com

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[mr peabody]

Psilocybin edges toward mainstream therapy*

by Dennis Thompson | HealthDay | 6 Dec 2021

Tony Head was depressed and fearing death from stage 4 prostate cancer when, as part of a supervised scientific trial, he took a large dose of the psychedelic agent in "magic mushrooms," psilocybin.

Head donned a mask and headphones to shut out the world around him, and had an experience that changed the course of his life.

"At some point in that time I felt like a higher power or something -- I didn't see anything, I didn't see any type of image -- I felt like something connected and touched me and as soon as it did, I just started crying," Head, an award-nominated actor who lives in New York City, said in an interview with HealthDay Now.

He said the one-time therapy helped relieve much of the anxiety surrounding his prognosis.

"I think it taught me how to live better and not worry about dying," he added.

"I was blown away by what had just happened. It's an unimaginable experience, at least it was for me," Head added. "It's something that can't be explained, but I can tell you it is probably one of the most important things that ever happened to me."

Psychedelic therapy focused on psilocybin has garnered much new interest lately as a potential treatment against anxiety, depression and other mental ills.

In fact, the drug is now legal for mental health treatment in Oregon, a result of a ballot initiative. The recent release of Hulu's miniseries "Nine Perfect Strangers" has also focused fresh attention to the concept of microdosing psilocybin as a means of therapy.

Long history

"It's a field that foundered in the 1960s as psychedelic drugs became associated with the left-wing counterculture," explained Dr. Charles Grob, a professor of clinical psychiatry and biobehavioral sciences with the UCLA School of Medicine.

However, prior to that, psychedelics like psilocybin had shown "great promise" in mental health research, Grob told HealthDay Now.

"In the '50s and '60s, there was a period of time when psychedelics were really considered the cutting edge of psychiatric research, and there was tremendous enthusiasm," Grob said. "There were reports of patient populations who did not respond well to conventional treatments that did very well."

Even Hollywood leading man Cary Grant turned to psychedelics during that early period. The actor took LSD as many as 100 times under the care of a Beverly Hills doctor, according to the documentary "Becoming Cary Grant."

"After weeks of treatment came a day when I saw the light," Grant said in the film. "When I broke through, I felt an immeasurably beneficial cleansing of so many needless fears and guilts. I lost all the tension that I'd been crippling myself with."

Now, a new generation of researchers are exploring the possibilities of these drugs to help people in crisis.

Head, 69, took his psilocybin trip as part of a research effort at Johns Hopkins University in Baltimore, after doctors had told him he probably had three to five years to live. Head has appeared in the HBO dramas "The Wire" and "The Deuce," and had a small role in the 2019 movie "Joker."

His psilocybin experience lasted for about seven hours, and during it he felt as though he had come into contact with a "higher power" existing in a place beyond death.

"The biggest thing I got out of this was it taught me how not to fear dying. I don't fear death. I don't want to suffer for years like that, but I don't fear death at all," Head said. "I think wherever death is or leads to, it's going to be a good place."

"I think it taught me how to live better and not worry about dying," he added.

Head says he also got everything he needed from psilocybin during his single high-dose trip.

"I have no wish to do it again. I don't need to do it again," he said.

Recalibrating the mind

Just how do psychedelics work their magic on the brain? According to Grob, psilocybin and its pharmaceutical cousins "profoundly alter our state of consciousness" by acting on certain receptors in the brain.

"We also know the circuitry of the brain is briefly modified and in a sense, goes offline and creates more of a resting state," Grob said. "It's almost as if the brain for a period of time goes offline and then recalibrates in an enhanced state."

"It's an alteration of what's called the default mode network, where regions of the brain that normally are very much in communication basically briefly disconnect and create a greater sense of calm and less internal chatter, and perhaps more opportunity to perceive beyond what is normally within our field of awareness," Grob continued.

Research from the 1950s and '60s, as well as more recent studies, have shown psilocybin's promise in helping people like Head who are suffering an existential crisis, Grob said.

"Psychedelics have also shown potential in people dealing with alcoholism and addiction," he added.

"Investigators observed dating back to the '50s that individuals with one powerful experience of a psychedelic, with one powerful altered state, appeared to have lost their craving and are able to establish and maintain sobriety," Grob said.

When use turns to abuse

"The drug's promise does need to be weighed against its potential for abuse, however," Grob said.

"Going back to the '60s, there's no lack of examples of individuals who misused and abused the drug and got themselves into some serious situations which no one would want to replicate," Grob said. "There are inherent risks when this drug is ingested in uncontrolled settings, without proper facilitation by an experienced psychotherapist who is trained in administering this model."

Grob also noted that psilocybin and other psychedelics still require more research to fully understand their risks and benefits, given that academic study into the drugs fizzled out after the 1960s.

"We have today the opportunity to take a fresh look at these compounds, utilizing optimal conditions," Grob said. "We have the support of many high-level officials within academia. The regulatory agencies are far more receptive."

"For example, there needs to be rigorously controlled studies to test the potential benefits of microdosing, the psychedelic treatment highlighted by 'Nine Perfect Strangers,' Grob said.

"It's still more in the realm of conjecture, and the positive reports we're hearing are essentially anecdotal case reports," Grob said. "These individuals do report on occasion a very remarkable transformation, remarkable therapeutic outcome, but we really don't know for sure whether this is a real phenomenon or a placebo effect."

More study needed

"Psilocybin has garnered more interest in modern research and therapy than LSD because it has a few advantages over the more powerful psychedelic," Grob said.

"A psilocybin trip tends to be much shorter than with LSD, although it can extend to as long as six or seven hours. The trip also tends to be easier to guide, more visionary, and less likely to create anxiety or paranoia in the patient," Grob said.

"People running these studies will need to seriously consider the patient's mindset and expectations and place them in a positive, carefully controlled setting," Grob said.

"You take all those factors into account, there's a good likelihood you can guide someone through this altered terrain in a safe manner and allow them to have the kind of experience that might endow them with the kind of insight and the kind of positive transformative experience that leads to therapeutic change," Grob said.

Head said that he can definitely see the potential of psilocybin to help treat people with addiction and other mental health issues, if it's used in a supervised way.

"This drug opens a door to put you in another place that you wouldn't normally be able to get to in your brain," Head said. "It has that kind of effect on you."

*From the article here :

'Magic Mushroom' Drug Edges Toward Mainstream Therapy

MONDAY, Dec. 6, 2021 (HealthDay News) -- Tony Head was depressed and fearing death from stage 4 prostate cancer when, as part of a supervised scientific trial, he took a large dose of the psychedelic agent in "magic mushrooms," psilocybin.Head donned a mask and headphones to shut out the world...

consumer.healthday.com

 

[mr peabody]

​

On the Rehabilitation of Psychedelics as Medicines*

by Patricia Kubala | Society for Cultural Anthropology

“Here, read this!” J says, handing me a copy of Jim DeKorne’s (1994) cult classic, Psychedelic Shamanism. J is a fellow student in a mindfulness-centered, somatic psychotherapy course, and he is studying this method of psychotherapy as part of his training in “medicine work.” I take the book and read the passage he is pointing out to me:
​

The draconian laws against psychedelic drugs, including the prohibition of legitimate research into their effects upon human consciousness are ultimately based upon our culture’s fear of the new model of reality that they imply. To put it bluntly, if we took the psychedelic paradigm seriously, we would be forced to change our lives completely. It is hard to imagine anything more revolutionary, and hence (from the conventional point of view), more dangerous and worthy of repression. (DeKorne 1994, iii)​

“This is what we’re trying to do,” J explains. “We’re healing the whole culture, one person at a time.”

Twenty-five years after the publication of Jim DeKorne’s (1994) Psychedelic Shamanism, there has been a revival of interest in the United States and around the world in the therapeutic potential of psychedelics. In my research, I study the shifting status of psychedelics in American society by exploring their use among San Francisco Bay Area healers, therapists, patients, and consciousness explorers who incorporate what they call “medicine”—MDMA, psychoactive mushrooms, ketamine, and other psychoactive substances—into their practices of psychotherapy and self-cultivation. In the course of my fieldwork, I have frequently come across the claim that “medicine work” is not simply about relieving symptoms, but rather is a transformational and even transgressive kind of healing with the capacity to resolve deep-rooted traumas of the past and open human consciousness to a new reality and way of life. As J put it in the ethnographic scene above: “We’re healing the whole culture, one person at a time.”

This return of psychedelics, rehabilitated as medicines, was not a given and might surprise someone teleported from the late 1960s when psychedelics were scheduled during the Nixon administration. Hundreds of studies researching the potential therapeutic effects of psychedelics were undertaken in the 1940s–1960s, but Leary’s famous phrase “turn on, tune in, drop out” did not invoke an idiom of healing, and María Sabina, the Mexican curandera through whom magic mushrooms became known outside their Oaxacan context at the end of the 1950s, famously contrasted the traditional use of mushrooms for healing in her village with that of R. Gordon Wasson and the hippies who later came to her in search of God.

Something has happened in the past fifty years, and the psychedelics of today are not quite the same objects as they were during the counterculture. While I have not been able to trace the origin of referring to psychedelics as “medicines,” the current prevalence of the term indexes the paths they have traversed and nooks and crevices within which they have rooted and flourished in the five decades since the ban. These spaces include retreat centers for spiritual and medical tourism in Central and South America, underground psychotherapy sessions shaped by indigenous and neo-shamanic practices, and, in the last decade, clinical trials and laboratory research experiments. The legalization and rehabilitation of cannabis as “medical marijuana” is part of this story too, and it is now common to hear cannabis spoken of as a “medicine” alongside psilocybin mushrooms, salvia divinorum, ayahuasca, 5-Me-O-DMT, ketamine, ibogaine, MDMA, and LSD.

In short, what has emerged is a new category, one that brings together plants, fungi, and other “naturally” derived psychoactive entities with chemically synthesized ones. There is a shift in emphasis here away from “mind-manifesting” (the meaning of psychedelics, a term coined by Humphry Osmond in an exchange with Aldous Huxley in 1956) toward healing, well-being, and reckoning with traumatic histories. “Medicine” is a capacious term with the generative capacity to signify indigenous-inspired rituals for psycho-spiritual cultivation, the medicalization of psychedelics in clinical settings, as well as the notion of psychedelics as agents for civilizational healing. Medicine is for patients seeking relief from symptoms recognized by the DSM; for formally colonized and former colonizers yearning for healing from collective trauma; for consciousness explorers and those who wish to deepen their connection with nature or the divine. It carries within it the hope for redress of painful things, of stuck and knotted things that other treatments, healers, or political movements have not been able to resolve. It is an active agent and a relational one: one can pray to it, submit to it, express gratitude to it, and consult it as a wise teacher.

I conclude with another moment from my fieldwork. It was the evening of September 20; among psychedelic advocates 9/20 has become a “global mushroom day” devoted to raising awareness about and celebrating psilocybin and other “plant medicines.” I was in attendance at an event held at a community space affiliated with the Decriminalize movement, and our host welcomed us to an evening dedicated to “honoring the diverse community of Oakland that has healed from plant medicine” and “giving voice to ancestors who gave us these traditions.” Throughout the evening there were testimonies of healing from addiction, sexual abuse, and other traumas with the help of mushrooms, iboga, and other medicines; there was a display of psychoactive medicinal plants and a brief lecture about their healing properties. The evening was dedicated to the memory of Harriet Tubman; an altar had been built for her that included plants, herbs, and images of her and other important figures on the Underground Railroad. Among the floral offerings, at the center of the altar, rested dried “High John the Conqueror” root and flowers of the morning glory plant. Harriet was remembered as a medicine woman who knew the land and its healing plants and herbs; she used the root for protection on her journeys. For this is the work that psychedelics-as-medicines do: in the service of collective betterment and liberation, they bring together, under one roof, the ancestral with the present, the human with psychoactive allies, and the sick and suffering with healing agents of hope and restitution.

*From the article (including references) here :

On the Rehabilitation of Psychedelics as “Medicines”

“Here, read this!” J says, handing me a copy of Jim DeKorne’s (1994) cult classic, Psychedelic Shamanism. J is a fellow student in a mindfulness-...

culanth.org

 

[mr peabody]

Berra Yazar-Klosinski

Inside the race to make psychedelics Mainstream Medicines

NXT Psychedelics | 29 Mar 2022

When Berra Yazar-Klosinski was wrapping up her PhD in molecular cell and developmental biology at UC Santa Cruz, there was an unassuming little office right down the road, hidden inside a bungalow-style house with a postage-square lawn.

Tucked away on a busy street, the building didn’t strike Yazar-Klosinski as the type of place where scientific research would occur. But inside, she would learn, was the Multidisciplinary Association for Psychedelic Studies (MAPS), a nonprofit working on turning psychedelics into medicines for a host of mental illnesses.

Yazar-Klosinski knew nothing about them — or about the psychedelics field, for that matter. She focused on neurobiology in her undergrad days at Stanford and had a gig helping Millennium Pharmaceuticals with Phase I trials for acute myeloid leukemia. But she knew she wanted to land at a nonprofit after grad school. So when she spotted a data entry opening at MAPS on Craigslist, she threw her hat in the ring.

Then she saw the data.

One of Yazar-Klosinski’s first projects was studying the difference between MDMA and placebo in treating patients with post-traumatic stress disorder. And though it was a small trial, researchers found that MDMA was significantly better at reducing PTSD symptoms on a commonly used symptom scale, with results that were durable over an average of three and a half years.

“I have a very quantitative mind, I would say, and so just seeing the numbers, it was amazing, even in the very early studies,” she said. “People would go from a PTSD severity score of like 80 down to zero, on occasion. It was rare, but sometimes you could see it.”

Recent human data have revived a once-forgotten field looking to use modified psychedelics to rewire the brain in search of new and better therapies for mental health. In what was once a marginalized — and in some cases criminalized — research space, new companies are luring investors and inspiring a new way of thought around mental health treatment.

J&J helped drive that work a few years ago with a pioneering and highly controversial approval for esketamine in treatment-resistant depression. And though investors were slow at first to hop on board, psychedelics companies have rolled in an increasingly large amount of VC cash over the last couple of years.

Chris Dokomajilar at DealForma has tracked $538 million in venture investments into companies focused on psychedelics since 2017, with a majority coming in 2020 and 2021. And that doesn’t count another $672 million in public offerings.

While President Richard Nixon’s “War on Drugs” essentially ground psychedelic research to a halt in the 1970s, some say a “renaissance” is underway. The first batches of in-human data suggest the drug class is effective, with Jefferies analysts speculating back in September that the therapies have a “fair chance of producing profound/differentiated effects vs existing therapies.”

There’s just one question that remains, a big one when thinking about drugs that are administered and bring side effects like no other FDA-approved medicines in history: How do you make them practical?

How a Sandoz chemist became the ‘father of LSD’

Although most psychedelic biotechs are less than a decade old, the modern history of these hallucinogens has been closely tied with pharma.

A Sandoz chemist named Albert Hofmann first extracted LSD from a fungus that grows in rye kernels back in 1938, and the Swiss pharma soon produced it for psychiatric research. They added psilocybin in 1960 after Hofmann extracted it from magic mushrooms in 1958, the same year psychiatrist Humphry Osmond coined the term “psychedelic” from the Greek words psyche (mind or soul) and deloun (show).

Although Hofmann started by accidentally — and then very intentionally — dosing himself, psychiatrists were soon testing psychedelics widely for a suite of mental illnesses. Tens of thousands of patients are estimated to have been treated with psychedelic psychotherapy over roughly 15 years.

Ekaterina Malievskaia

In those early days, when the current regulatory approval system had not yet been adopted, the rules around testing new drugs were significantly more lenient, said Ekaterina Malievskaia, chief innovation officer and co-founder of Compass Pathways, which started developing psilocybin again in the 2010s.

“The pharmaceutical company was just able to send it to clinicians and say, ‘Hey, we have an interesting drug. Why don’t you try it on your patients and let us know what happens?’” she said. “So that’s where a lot of anecdotal evidence was created.”

However, that anecdotal evidence never amounted to an approval — and after an explosion of scientific study (and recreational use) in the 1950s and 1960s, research slowed to a near stop when Nixon declared the national “War on Drugs.” The president signed the Controlled Substances Act in 1970, putting most psychedelics under Schedule 1 and prohibiting their use.

New research began to surface again in the early- to mid-1990s, according to Matthew Johnson, a Johns Hopkins professor who’s been studying psychedelics since 2004. And by the 2010s, a so-called “psychedelic renaissance” began to form, driven by studies from a handful of academics and decades of work from MAPS. Companies such as Compass were suddenly able to raise millions in venture capital and a couple of states began decriminalizing — or even legalizing — psychedelic-assisted therapy.

In tandem, the number of clinical trials involving psychedelics skyrocketed. According to a report in Nature, there were 17 trials involving psychedelics in 2020 — a majority of them around psilocybin — compared to just three in 2010.

The FDA has shown it’s open to considering the benefits of psychedelic therapies, granting multiple breakthrough designations to psilocybin-based treatments, including Compass’ back in 2018. And in 2019 it approved J&J’s Spravato, or esketamine, for treatment-resistant depression, later expanding the label to major depressive disorder in adults with acute suicidal ideation or behavior.

Spravato is not a traditional psychedelic because it doesn’t act on the same serotonin receptors as LSD or psilocybin, but it can have dissociative effects such as hallucination. And its rocky rollout pointed to some of the hurdles any of the classic psychedelics will have to clear if the FDA approved.

How practical are they?

Spravato quickly found itself at the center of controversy. Part of the debate centered over its efficacy: J&J said the drug helped 41% and 43% of patients achieve clinical remission of depression, with some experiencing symptom reduction within 24 hours — a critical benefit proponents pointed to.

Theresa Nguyen

“Traditional oral antidepressants need weeks or more to take effect,” Theresa Nguyen, chief program officer at Mental Health America, said at the time, making Spravato “life-changing.”

Others, including former FDA reviewer Erick Turner, noted the drug failed in patients 65 and older, a crucial depression demographic, among a long list of questions.

But the simple fact was that, regardless of its exact efficacy, many of the patients in most need were not getting it. Although former President Donald Trump publicly promoted the drug and officials reportedly pushed the VA to buy “truckloads,” the VA only gave it to around 15 veterans in the first 10 months post-approval.

The reason? The same hallucinogenic effects that might drive the drug’s efficacy. The agency limited its use to VA clinics that had experience with ketamine, the recreational drug that had already been used off-label for depression for years, and thus “existing facility expertise.” Patients had to be given the drug under a physician’s supervision and monitored for at least two hours, “because of the risk of sedation and dissociation,” as the FDA explained.

Classic psychedelics, like psilocybin, can trigger longer trips, and thus pose greater challenges. Compass is one of the oldest players in the field, with a psilocybin treatment that recently completed a Phase IIb study for treatment-resistant depression that showed positive results, albeit with some caveats. But for Malievskaia, one of the main challenges left unsolved is how best to support patients while they are experiencing a trip.

“The challenge I see is not so much in the drug, but in how to support patients in this experience,” she said.

Inside the psych experience

Across the field, the psychedelic therapy process typically goes something like this: After in-depth screening, patients arrive at a hospital or care center for treatment, where they’re given the drug along with some eyeshades, and in some cases a specially designed soundtrack. A therapist or counselor is there for support during the experience if need be, but in most cases, minimal intervention is needed.

Robert Barrow

The eyeshades and music help encourage introspection, according to Johnson. Counselors want patients to focus within, rather than, for example, the enhanced colors they might see on the wall. "Some patients report feeling a sense of 'oneness with the universe,'” he explained, while others might think about their past or tie the experience to religion. They can also experience anxiety ranging “from mild to, like, terrifying,” he added — but that’s what the counselor is there for.

While the experience can be challenging for patients, as it is akin to an intensive psychotherapy, there are always protocols in place in the event that someone has an acute or severe anxiety reaction, said Robert Barrow, CEO of MindMed. His New York-based psychedelics company was the second to ever go public on an American exchange, behind Compass.

The procedure doesn’t require an overnight stay, though patients typically stay for hours while they are receiving the therapy. For psilocybin, it’s usually about six hours, including five hours in which they’re experiencing the drug’s effect, Johnson said.

Then they return afterward to discuss their experience and insights they may have gained. It all amounts to a far more intensive, expensive and time-consuming process than any company developing a new anti-depressant pill — or any patient being prescribed one — will have to consider.

“It is not just the drug the patients come and take and have a good time. It is a therapeutic process,” Malievskaia said, adding that patients also meet with a therapist a couple of times before the session.

As it pushes psilocybin into a final Phase III trial for depression and mid-stage trials for other conditions, Compass is also investing in refining the therapeutic experience, should they get approval. Malievskaia envisions a data-driven approach that might include, for example, prompts for therapists to refer to.

“We’re using natural language processing, we’re using machine learning to understand human experience and to understand what works, what doesn’t in therapy,” she added.

Don’t change the facility, change the trip

Other companies are trying to make psychedelics easier to scale by changing — or even doing away with — the trip.

There’s an ongoing debate on just how long a trip should last. Is a shorter, more intense experience better than a prolonged but less intense one? The folks at Eleusis are strong believers in the former, and they’re heading into Phase I to prove it. Rather than hanging around a treatment site for six hours, Eleusis thinks patients taking its so-called ELE-Psilo treatment could potentially be in and out of the treatment center in two hours.

Shlomi Raz

“This needs to be more like a dentist appointment than a surgery, right?” CEO Shlomi Raz said. “That’s the fundamental kind of cost effectiveness threshold that I think that clinicians, patients, payers, investors, everyone’s looking for.”

Raz left a career at Goldman Sachs back in 2008 to pursue a lifelong interest in psychology. It was upon enrolling at New York University that he stumbled upon a paper out of Johns Hopkins about the therapeutic use of psilocybin. It inspired him to launch Eleusis in 2013 with the goal of “transform[ing] psychedelics into mainstream medicines.”

The company recruited Eli Lilly neuroscience veteran Rob Conley as VP of R&D, and quickly promoted him to senior VP before announcing plans back in January to go public in a SPAC merger. It conducted two LSD trials in 2015 and 2016, and now has a psilocybin candidate in Phase I for major depressive disorder.

“The depression indication is an important and a good one, but it really is a tip of the iceberg,” Conley said. “There’s other psychiatric modalities, and potentially even medical things, inflammatory conditions, neurodegeneration, where this stuff might be important.”

Rob Conley

What sets ELE-Psilo apart from the pack? It’s formulated for IV delivery, as opposed to rivals going for oral or intranasal delivery. Delivering orally, he says, prolongs the drug effect. But with IV delivery, you get more consistent absorption levels, enabling control over intensity and duration.

“That’s really our approach to addressing what we think is one of the greatest challenges here, making this drug therapy practical,” Raz said.

Johnson, on the other hand, thinks there may not be just one answer to the short versus long debate. Or the IV versus oral debate. And he won’t be satisfied until he sees more data.

“That answer could be different not only across different disorders, but different individuals,” he said. “We need data on all of this, but it should all be explored.”

Johnson recently published a paper examining the effects of two different soundtracks played during therapeutic sessions, one with classical music, and another with alternative music. And while durability appears to vary from person to person, more data will be required to determine the best dosing methods, he added.

“For some people, one session, it really seems like, ‘Wow!’ That helps with their depression or their addiction, and that’s kind of all they needed, and that’s great,” he said. "But others might benefit from multiple doses, or booster doses, and that will all play out in the next batches of data."

Other scientists are looking to curb hallucinogenic effects altogether — including the team at Delix, which raked in a $70 million Series A round in September to fuel their search for therapeutic “psychoplastogens,” or small molecules that produce rapid and long-lasting psychedelic- and ketamine-like effects on neuronal structure.

The science stems from David Olson’s lab at UC Davis. These non-hallucinogenic molecules produced “sustained therapeutic effects” in preclinical models, according to Delix, and their first two candidates are likely to enter the clinic in the second half of this year.

Kurt Rasmussen

“Basically what we’re doing is taking compounds that are psychedelics and modifying them, so that we believe they retain the efficacy that is the beneficial effects like antidepressant effects and anti-anxiety effects, but no longer produce the hallucinations,” CSO Kurt Rasmussen explained.

These companies represent just a handful of the players in the race to bring psychedelic medicines to the FDA. DealForma notes 39 active companies in the space, not including another five that were recently acquired.

“We’re still scratching the surface, by the way, about what’s underneath the scientific benefits of psychedelics across the board with psilocybin, MDMA, LSD, mescaline, and Ibogaine,” said Bob Dagher, CMO of Naples, FL-based Enveric Biosciences, which is developing a “psybrary,” a library of hundreds of psychedelic-inspired molecules.

If companies can figure out a scalable method, patients will come, Barrow said. The enthusiasm they saw for clinical trials showed that.

“There are not challenges in the interest and availability of patients,” he said. “You have a lot of folks who are proactively reaching out trying to get in studies, but they’ll have conditions that make them not appropriate for the study or they’ll be excluded from the study.”

Battling a stigma

For psychedelics to enter widespread use, researchers and companies will also have to change a larger public narrative. Despite the current boom, Florian Brand, CEO of Peter Thiel-backed atai, says it was initially hard to raise money because of the stigma that exists around psychedelics.

Florian Brand

“We did have to educate a lot of people,” he said. “Mental health in itself is stigmatized. Psychedelics as a potential catalyst for innovation for mental health disorders is also stigmatized.”

Some critics argue that the class of drugs carries the potential for abuse. And while Spravato’s label does include a boxed warning for abuse and misuse, Malievskaia says there is no evidence that psilocybin causes physical dependence.

“That said, anything can be abused, obviously. Anything legal or illegal can be misused or abused. So there’s always a potential, but it doesn’t lead to physical dependency in the way opioids, for example, do,” she said.

LSD is also not considered an addictive drug. In fact, some scientists believe that psychedelics like psilocybin could be used to treat other addictions, such as smoking or alcoholism. Johns Hopkins released a study back in 2014 showing that 15 longtime smokers who took psilocybin achieved an 80% abstinence rate over six months, compared to a 35% rate seen in patients taking the widely used smoking cessation drug varenicline.

Canadian biotech Entheon Biomedical is in the midst of a Phase I/IIa trial testing DMT, a hallucinogenic drug with a much shorter effect, for nicotine addiction. Unlike psilocybin, DMT’s effect lasts no more than a few minutes, allowing for a 30- to 60-minute procedure. And atai subsidiary DemeRx is studying the use of ibogaine, another Schedule I psychedelic, for the treatment of opioid use disorder.

“I wish these things weren’t even called psychedelics,” Conley, the Eleusis exec, said. “I mean, I recognize they are. But you know, I think a lot of times in medicine, we tend to forget that there have been a natural basis and a human use of a lot of agents we use before we did them.”

What comes next?

There are still much more data to be seen — on durability, dosing size and even best counseling strategies — before the FDA is likely to make any decisions in this space.

“I think it’s premature, personally, to really get all hyped up about it. We really need FDA to make the determination about safety and efficacy, which has not been done yet,” said Yazar-Klosinski, who’s now CSO of the MAPS Public Benefit Corporation. “We hope to have that kind of news in the next year or two.”

Some have falsely compared the field to the “next cannabis,” Brand said, dispelling the connection: “It’s really not. It’s really a biotech approach.”

Looking ahead, Yazar-Klosinski said the field could benefit from more collaboration, as many players are working on different variations of the same drug. To help boost progress, MAPS posts resources on its website like its MDMA investigators’ brochure, which covers clinical, nonclinical and manufacturing research updates from its own MAPS-sponsored programs.

“I think that other companies could do the same,” she said. “That will make it a little bit easier to figure out what’s going to happen with all of these multiple people working on the same drug.”

Above all, Barrow of MindMed emphasized, the field needs to avoid another freeze-out period like the 1970s when research ground to a halt for more than a decade.

More data will likely help with that, even if it won’t answer every lingering question overnight. MAPS read out promising Phase III results for its MDMA-assisted therapy in 90 PTSD patients back in May, and it’s also studying the effects of MDMA in other conditions like eating disorders and social anxiety in autistic adults. The organization has since moved from the bungalow-style house to a strip mall in San Jose.

“I think it’s critically important that we remember that history and don’t repeat it,” Barrow said. “I firmly believe we’d have a lot better mental health outcomes and a lot better substance abuse statistics if we had these treatments available for the last five decades.”

Inside the race to make psychedelics ‘mainstream medicines’

When Berra Yazar-Klosinski was wrapping up her PhD in molecular cell and developmental biology at UC Santa Cruz, there was an unassuming little office...

www.nxtpsychedelics.com