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mr peabody

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Alexander Shulgin

An introduction to psychedelic neuroscience

Tanya Calvey, Fleur Margaret Howells | January 2018

This chapter is an introduction to the volume Psychedelic Neuroscience of Elsevier's Progress in Brain Research addressing the neurobiological mechanisms of psychedelic drugs, the resulting changes in brain activity and integration of traditional viewpoints. As the field is relatively new, there are discrepancies in the literature related to classification, composition and effects of the various psychedelics. Currently, psychedelics are grouped according to their neuro-receptor affinities into classic and atypical psychedelics, each with individual treatment potentials and abilities to elicit potent acute experiences and long-lasting changes in neurobiology through concurrent activation of several neuromodulatory systems. There is disparity in psychedelic brain imaging studies, delineating what is neural activity and hemodynamic needs further investigation for us to understand the brain state changes that are apparent. The psychedelic brain state is often compared to acute psychosis and we review the psychedelic animal models of psychosis and human brain imaging studies and contrast these to psychosis. The term psychedelic means mind-revealing and psychedelics have exceptional anti-amnesic effects and are able to make conscious that which was previously unconscious through changes in brain state, but also there is growing evidence which demonstrates the role of epigenetic mechanisms. This supports traditional therapeutic use of psychedelics to heal ancestral trauma. Details of these mechanisms are provided along with suggestions for further research.

WHAT ARE PSYCHEDELICS?

The field of psychedelic neuroscience has witnessed a recent renaissance following decades of restricted research due to their legal status. As this is a relatively new field, there are incongruences in the literature related to terminology, classification, content and effect of the various psychedelics.

The currently accepted classification of psychedelics includes classic psychedelics and atypical/non-traditional/non-classical psychedelics. Classic psychedelics are the phenethylamines such as mescaline, tryptamines such as 5-MeO-DMT, DMT, psilocybin, and ergolines such as LSD. Atypical psychedelics can be further divided into dissociative psychedelics, e.g., PCP, ketamine and ibogaine, as well as cannabinoid agonists (e.g. THC), muscarinic receptor antagonists (e.g., scopolamine), and entactogens (e.g., MDMA).

Problematic in the field, perhaps more so than in other fields, is the issue of conflicting results, likely due to the limited research. For example, there is conflicting evidence as to whether or not the low 5HT2A affinity of ibogaine has any functional relevance. Ly et al. found that the 5HT2A receptor antagonist, ketanserin, blocked the effect of noribogaine on structural plasticity yet both ibogaine and noribogaine failed to induce head-shake response in rats, a behavior which is seen to be comparable to hallucinations in humans and mediated by 5HT2A activation. Gonzalez et al. suggest that this result supports the subjective experiences in humans, where ibogaine does not produce the typical interferences in thinking, identity distortions, and space-time alteration, which are produced by the classic psychedelics. A second example, where there is confusion is the literature regarding 5-MeO-DMT. 5-MeO-DMT is described as being a constituent of ayahuasca, while it is evidenced that ayahuasca holds a high concentration of DMT, 5-MeO-DMT concentration is either non-existent or negligible in most brews, and the ayahuasca psychedelic experience bears little to no resemblance to an experience with 5-MeO-DMT. Then cannabis research is possibly the best example of conflicting psychedelic research. As reviewed in Colizzi and Bhattacharyya, evidence as to whether cannabis use is associated with adverse effects to mental health or cognition in humans is equivocal. There are also many divergent results in the functional human neuroimaging studies as detailed by Meuller et al. Indeed, this is a new and growing field of research and more research is required to uncover the various psychedelics drugs, their active components and neurobiological effects.

NEUROBIOLOGY OF PSYCHEDELIC THERAPY FOR DEPRESSION AND ADDICTION

Classic psychedelics and dissociative psychedelics are known to have rapid onset antidepressant and anti-addictive effects, unlike any currently available treatment. Randomized clinical control studies have confirmed antidepressant and anxiolytic effects of classic psychedelics in humans. Ketamine also has well established antidepressant and anti-addictive effects in humans mainly through its action as an NMDA antagonist. Ibogaine has demonstrated potent anti-addictive potential in pre-clinical studies and is in the early stages of clinical trials to determine efficacy in robust human studies.

Psychedelics are not only known to have rapid onset but their effects persist long after their acute effects; this includes changes in mood and brain function. These effects are suggested to result from their unique receptor affinities which affect neurotransmission via neuromodulatory systems which then serve to modulate brain activity, i.e., neuro-plasticity. These lasting effects are reported to promote cell survival, be neuroprotective, and modulate neuroimmune systems of the brain. The mechanisms which lead to these long-term neuromodulatory changes have been linked to epigenetic modifications and gene expression changes. These psychedelic drug effects, previously under-researched, may potentially provide the next-generation of neurotherapeutics, where treatment resistant diseases, e.g., depression and addiction, may become treatable with attenuated pharmacological risk profiles.

Classic psychedelics have been shown to stimulate the serotonergic system mainly via 5HT1A, 5HT2A, 5HT2C, and 5HT7 receptors, with the dopaminergic system primarily via D2 receptors, and indirectly with the glutamatergic and GABAergic systems. There is significant cross-talk between these neuromodulatory systems and classic psychedelics, and activation of 5HT1A and 5HT2A receptors modulates glutamatergic and dopaminergic neurotransmission in brain networks associated with depression and addiction. Then activation of 5HT2C receptors localized in dopaminergic and GABAergic neurons in the ventral tegmental area (VTA) regulates motivation by modulating transmissions to the nucleus accumbens (NAc) and altered balance in this 5HT2C receptor-associated network is postulated to cause reward-related disorders, such as schizophrenia, depression, and addiction. Further, it is acknowledged that classic psychedelics have an extremely low potential for abuse, and it is suggested that stimulation of 5HT2C receptors limits their potential for addiction and that their therapeutic effects are mediated by acute 5HT2C receptor stimulation followed by sustained downregulation of 5HT2A and 5HT1A receptors. Investigation into the complex mechanisms of action of classic psychedelics which lead to its anti-depressant and anti-addiction properties via the serotonergic system continues to gain momentum, e.g., minimal research has investigated the role of 5HT7 activation by psychedelics, but has been suggested to play a role in classic psychedelic anti-addiction properties, specifically 5-MeO-DMT in alcohol use disorder.

The classic psychedelics act directly via the serotonergic system whereas certain atypical psychedelics have direct affinity for numerous neuromodulatory systems. A remarkable example, ibogaine, addressed by Corkery and Barsuglia et al., demonstrates novel pharmacological mechanisms of action to be considered in the potential treatment of substance use disorders and depression through simultaneous activation of multiple neuro-transmitter systems. This alkaloid has low micromolar affinity for mu and kappa opioid receptors, SIGMA-1 and SIGMA-2 receptors, serotonin reuptake transporter (SERT) and dopamine transporter (DAT), is an antagonist to NMDA and α3β4 nicotinic acetylcholine (nAChR) receptors and a weak 5HT2A receptor agonist. Drugs with similar NMDA affinity (e.g., ketamine and memantine) or NMDA regulators have shown promise in reducing symptoms of substance use disorders and depression. The mu-opioid receptor has demonstrated a functional role in drug reward as well as craving. Further, ibogaine possesses an opiate replacement mechanism of action as reported for compounds such as methadone. However, neither ibogaine nor its principle psychoactive metabolite, noribogaine, activate G-proteins associated with morphine administration, or produce signs and symptoms of opioid intoxication in opioid naive persons; therefore, it seems that ibogaine is able to produce a neuroadaptive effect on endogenous opioid systems which reverses opi- oid tolerance and may be implicated broadly in its addiction-interrupting effects.

ADDITIONAL THERAPEUTIC MECHANISMS OF ACTION

There is strong evidence suggesting that various psychedelics influence the expres- sion and modulation of genes, which in turn, may lead to long-term neurochemical and neuroplastic changes and modification of epigenetic mechanisms. When administered chronically, LSD has been shown to have effects on dopaminergic neurotransmission at the level of gene expression by decreasing the mRNA expression of the dopamine receptor genes DRD1 and DRD2 in the medial prefrontal cortex (mPFC). Classic and dissociative psychedelics lead to structural and functional changes in cortical neurons, with plasticity-promoting properties that rival brain-derived neurotropic factor (BDNF). LSD has demonstrated to be extremely potent in this regard possibly due to slow off kinetics of the LSD-bound 5HT2B crystal structure. Although the molecular targets of classic and dissociative psychedelics differ, their plasticity promoting properties are similar and are known to activate TrkB, mTOR, and 5HT2A signaling pathways, suggesting that these key signaling hubs may serve as potential targets for the development of psychoplastogens, fast-acting antidepressants, and anxiolytics. The mTOR signaling pathways may also play a role in certain psychedelics' ability to modify epigenetic mechanisms as mTORC1 is thought to be involved in regulating gene expression through epigenetic mechanisms or by directly affecting RNA stability/degradation. Another relevant receptor involved in epigenetic modification is SIGMAR1. DMT and ibogaine both activate SIGMAR1 and recently, SIGMAR1 has been shown to modulate epigenetic processes by creating a dose-dependent interaction between emerin and histone deacetylase (HDAC)1, HDAC2 and HDAC3, affecting chromatin compaction and gene expression. At the nuclear envelope, SIGMAR1 recruits chromatin-remodeling molecules to regulate gene expression and at the synaptic level it interacts with voltage-gated ion channels, which leads to modification and reorganization of several homo- and heteroreceptor complexes which in turn modulates of neurotransmission, reviewed in Inserra.



NEUROBIOLOGY OF THE PSYCHEDELIC EXPERIENCE

The psychedelic experience can produce eyes-closed and eyes-open imagery. The imagery can be clear and visual or it can have a dream-like quality with strong emotions and insights. There is also often heightened memory retrieval where long-forgotten memories are retrieved with exceptional clarity and detail. A common experience on ibogaine, for example, is that one's life flashes before their eyes as clear as if they were watching a movie about their life.

The neurophysiological mechanisms that facilitate the psychedelic experience are largely unknown but progress is being made in understanding how the neurochemical profile of psychedelics elicits this effect, bringing that which was previously unconscious to the conscious mind. The differences in the psychedelic state elicited by the various classic and atypical psychedelics hold promise in differentiating the exact neuroreceptor-mind interactions. Neuroreceptors are coded by individual genes and extensive genetic variation exists in the population for these neuromodulatory systems. Variation in the neuroreceptor-mind interactions, thus, holds further promise for psychiatric neurogenomics research as it will uncover how individual genetic variation in the neuromodulatory systems affects different psychedelic states and changes in neurobiology.

The serotonergic system's involvement in the psychedelic state has received the most research attention, and has provided new insights related to the neurochemical mechanisms underlying changes in brain network activity and perfusion. Serotonin is involved in many neurological (e.g., epilepsy) and psychiatric (e.g., depression) diseases. Serotonin receptors may directly or indirectly depolarize or hyperpolarize neurons by changing the ionic conductance and/or concentration within the cells and is able to change excitability within brain networks. For example, pharmacological magnetic resonance imaging (phMRI) in rats indicates that psilocin induces brain signal increases in olfactory and limbic areas and brain signal decreases in somatosensory and motor cortices. 5-MeO-DMT disrupts cortical activity and low frequency cortical oscillations in the frontal cortex of rats with alternating activity in frontal and visual areas associated with psychedelic effects.

In humans, activation of postsynaptic 5HT2A receptors in layer V of the medial prefrontal cortex mPFC is considered to be responsible for the visual hallucinations produced by classic psychedelics. Cortical 5HT2A hyper-activation affects cortico-striatal-thalamo-cortical circuit functioning and triggers a disruption in the thalamic gating of sensory and cognitive information leading to perceptual distortions.

Studies point toward not only brain network activity changes but also significant increases in hemodynamics. Increased cerebral blood flow has been reflected in temperature record of different brain areas with administration of MDMA, increased blood flow to the cortex correlated with increased neuronal activity as expected, however within the thalamus increased blood flow negatively correlated with increased neuronal activity. Then a psilocin study reported decreased local field potentials to sensory stimuli while hemodynamic response was enhanced. These data support a brain state change, but also require us to challenge our knowledge of the nature of this differential activity, neural versus hemodynamic, and their interplay which leads to the psychedelic experience.

Human brain imaging studies are limited, the neurophysiological underpinnings are largely speculative, while the findings are interesting and need to be further investigated. For example, an LSD functional MRI (fMRI) study found increased hemodynamic activity within brain areas rich in 5HT2A receptors and globally, the authors conclude that this reflected increased functional connectivity and that this increased activity led to ego dissolution. Then a psilocybin fMRI study found decreased hemodynamic activity within the thalamus and anterior and posterior cingulate cortices, where the decreased activity in the anterior cingulate correlated with the psychedelic experience. They further report a decrease in resting state connectivity between the medial prefrontal cortex and posterior cingulate cortex; the authors conclude that psilocybin reduced connectivity, and this reduction enabled the psychedelic experience. A different psilocybin resting state fMRI study reported that connectivity increased in higher brain networks such as the default mode, executive control, and dorsal attention networks. Then an arterial spin labelling study found that post MDMA, hemodynamics decreased and this was localized to right medial temporal lobe (MTL), thalamus, inferior visual cortex, and somatosensory cortex. Then a spontaneous magnetoencephalo-graphic (MEG) study investigated Lempel-Ziv (LZ) complexity, more commonly applied in EEG studies, to determine diversity of mixed-signal being recorded. Where they found three psychedelic drugs: psilocybin, LSD, and ketamine, increased signal diversity within occipital cortices, this extended over the parietal cortex with LSD, and even further with ketamine over the full cortex, excluding medial frontal brain areas, they were also able to support a reduction in alpha MEG activity for all three psychedelics tested.

The authors concluded that their findings provide confirmation that psychedelics create a higher level of consciousness which is reflected in MEG LZ complexity. A second psychedelic MEG study, which investigated psilocybin, reported reduction in spontaneous cortical activity in posterior association cortices, and in frontal association cortices. Second, they reported hugely significant reductions within the default mode network. Then a low-resolution electromagnetic tomography (LORETA) study investigated ayahuasca and found reductions in delta, theta, alpha-2, and beta-1 frequency bands, these changes were predominantly evident over the temporo-parietal-occipital junction. Overall, the brain imaging studies, which address hemodynamic activity in humans, support acute increases and decreases in several brain regions. Electro-magnetic studies report reductions in neural activity, most notably evident for alpha band frequency, and not limited to specific brain areas, but potentially reducing frontal activity and increasing parietal activity. Together these findings support the conclusion Lebedev et al. drew in relation to psilocybin; that psychedelics lead to a disintegration of functional connectivity, and this permits ego-dissolution. It is suggested that this disintegration is at least in part due to decreased connectivity between of the parahippocampal and retrosplenial cortex, as was reported in a resting state fMRI LSD study, which may serve to support the change in cortical activity.

Psychedelic electroencephalographic research supports a brain state change, with evidence of reduced neural activity frontally and support increased activity parietally. A quantitative EEG (qEEG) study, investigated the acute effects of DMT and 5-MeO-DMT, finding significant reductions in global absolute alpha activity, while moderate significant increases were seen in theta and beta. Then ayahuasca induced decreases in delta, theta, and alpha frequency activity, the power of alpha activity in parietal and occipital cortex was negatively related with the intensity of visual psychedelic experience. Acute dosing of DMT showed reduction in coherence between anterior and posterior EEG recording sites, where anterior coherence decreased, permitting parietal coherence to drive the EEG activity. Psilocybin was reported to decrease 1.5-20 Hz frequency activity, and using source density EEG the neural networks which showed this decreased connectivity were in the anterior and posterior cingulate cortices and the parahippocampal regions. The authors also report that the psychedelic experience was related to delta activity between the retrosplenial cortex, the parahippocampus, and the lateral orbitofrontal area. These data together support shifts in brain state with changes in cortical control from frontal brain areas to parietal and in part this is related to hippocampal network activity.

Further, EEG studies have investigated and contrasted MDMA, cannabis, and MDMA with cannabis use on EEG frequency where they show that MDMA with or without cannabis use increased delta band frequency, while cannabis use alone was found to increase high alpha band activity. In addition, this study found that MDMA with or without cannabis use showed increased blood flow and diastolic blood velocity. The increased alpha band activity in cannabis-alone users contradicts several papers which support attenuated alpha band activity. Then other cannabis studies report no change in alpha, and only report reductions in delta and beta activity. Cannabis has been shown to increase heart rate when alpha band activity is reduced, CB1 antagonism prevents the increase in heart rate produced by cannabis; however, this study which tested CB1 antagonism in acute cannabis use reported no change in alpha activity. Then an acute study investigated the effects of MDMA with and without ethanol or THC, and MDMA alone was found to decrease theta and alpha power, when a combination of MDMA and THC was taken together their attenuation of theta and lower-1-alpha was less than when given alone, then the combination of MDMA with THC lead to significant reduction in lower-2-alpha, but not when administered alone. Then a study in users of MDMA showed an incremental increase in alpha activity as cumulative doses of ecstasy increased, with no effect on theta activity.

There is an absence of reliable ibogaine EEG studies in humans, a single study in cynomologus monkeys reported no effect, then several rat studies. These studies report increased low-frequency, delta and theta, activity, and found ibogaine pre-treatment lowered cocaine-induced seizure threshold, reflected in alpha1-frequency band activity. These data support changes in brain network activity, but are contradictory, and further investigation is needed. There are significant changes in alpha activity, which may be related to changes in thalamocortical gating activities.

Then event-related potential (ERP) EEG studies, which are few, report some discrete neural circuitry psychedelic effects, and the little evidence which is available suggests that exposure to psychedelic drugs impacts the relevant neural circuitry needed for specific cognitive tasks.

In a randomized, double-blind study, psilocybin, the preferential 5HT2A antagonist ketanserin, or psilocybin with ketanserin was administered acutely, during the completion of a facial recognition task psilocybin enhanced positive mood and attenuated recognition of negative facial expression, which was reflected in P300 wave form amplitude, positive > negative. A second study by the same group which investigated the spatiotemporal dynamics of a modal object completion task found psilocybin to attenuate the N170 amplitude, particularly apparent during the processing of incomplete objects, while slightly enhancing P100 component. The authors found the attenuated N170 over right extrastriate and posterior parietal cortices correlated with intensity of visual hallucinations. The authors suggest this reduction in N170 reflects 5HT1A and 5HT2A receptor-mediated visual hallucinations.

Then ERP cannabis studies report on occasional versus heavy cannabis users which completed a divergent attention task with acute administration of THC, occasional users showed reduced P100 amplitude; while both occasional and heavy users showed decreased P300 amplitudes, no effect on ERP waveforms were reported for their second task, the stop signal task, a task which measures activation of behavioral inhibitory circuitry. A second study, which addressed acute dose-related effects of THC on a three-stimulus oddball paradigm, found that with increasing dose of THC, P300a increased and P300b decreased, latency of P300 and wave-form of the N100 were not affected. The sparse ERP wave form findings suggest neural circuit function, versus state, is dependent on psychedelic exposure and dosing, beyond this further research needs to be conducted to gain better insight to the effects of psychedelics on neural processing during cognition.

THE MYSTERY

Wisdom requires not only the investigation of many things but contemplation of the mystery. -Jeremy Narby

Science is at the early stages of understanding psychedelic molecular mechanisms and even further from understanding the psychedelic state as any scientist who has experienced it is aware. Let us try to imagine how psychedelics are able to make conscious previously subconscious information, which forms part of traditional practitioners' imperative in administering psychedelics for therapeutic purposes over the millennia. This may provide insight to the relevant brain changes needed to promote attenuation of anxiety and promote anti-addictive brain states.

At a 2-month follow-up, approximately 70 of the participants rated the psilocybin experience as among the most personally meaningful of their lives. A subsequent study documented that administration of psilocybin led to increases in the open-ness domain of personality that was stable for at least a year. This was notable because few, if any, previous studies had demonstrated that any discrete experimental manipulation was capable of yielding long-lasting changes in personality. -Murnane

The 5-MeO-DMT state began with images of floating through the universe and being surrounded by the stars. He also described seeing a "universal cosmic matrix" that had a central column of electric light and spiritual beings merging into the light.

"It's just love. Everything. All of it. That is all that exists. Love is it. Upon debriefing from his session several hours afterwards, he believed this experience was the single-most peak transformational experience of his life. He reported he lost all sense of his body and surroundings, and was transformed on a cellular level into infinite energy and pure love, and described, all of [his] stress and difficulties throughout [his] life felt like they occurred for a meaningful purpose, and the traumas of [his] past were washed over by an infinitely loving energy." -Barsuglia et. al.

In individuals with substance use disorders, ibogaine stimulates heightened memory retrieval specifically related to drug abuse, the perception of one's own future with or without drug use, and visions which reveal powerful insights into the nature of the addiction such as personal traumas. -Barsuglia et. al.

Psychedelics are known to have exceptional anti-amnesic effects where memories are retrieved in great detail. In fact, all psychedelics have the ability to make conscious/reveal/retrieve that which was previously unconscious and the term, psychedelic, means mind-revealing.

The neurophysiological mechanisms that facilitate this anti-amnesic effect are largely unknown but progress is being made in identifying the molecular and cellular mechanisms and brain networks involved.

The anti-amnesic effect of psychedelics has also been supported in rodent studies where administration of ibogaine facilitated spatial memory retrieval, and low dose THC has been shown to improve memory in aged rodents, and to enhance synaptic marker proteins and increase hippocampal spine density. The anti-amnesic effect of ibogaine and ayahuasca is, partly, due to the SIGMAR1 affinity of both compounds. SIGMAR1 activation has been shown to reverse experimental-induced amnesia in rodents, via enhancement of the cholinergic and glutamatergic systems. Peak densities of SIGMAR1 are found in brain areas relevant to traumatic memory formation, retrieval and updating, such as the amygdala and the hippocampal formation.

Psychedelics also enhance synaptic plasticity and increase neurogenesis, processes known to be involved in memory reconsolidation and fear extinction. The fear response triggered by the memory can be reprogramed and/or extinguished through synaptic plasticity and changes in gene expression mediated by epigenetic modification via 5HT2A and SIGMAR1 activation.

Subsequently, the memory is reconsolidated and stored with updated significance via cortical mechanisms. As suggested, there is a change in cortical control from frontal brain areas to parietal brain areas and, in part, this is related to hippocampal network activity. For example, varying doses of PCP have been shown to change the functional connectivity (phMRI) between several brain areas, including the fronto-cortical and hippocampal brain regions. Atasoy et al. report that changes in brain activity occur in a frequency-specific manner with LSD and psilocybin, and that these changes in power-law components lead to an expansion of the repertoire of active brain states and the emergence of more complex brain dynamics which heightens information processing capabilities.

Perhaps a similar mechanism may be involved in ancestral communication.

Higher doses of ibogaine generate its psychoactive effects, including hallucinations and the facilitation of communion with the spirits of the ancestors in rites of passage. Ibogaine ingestion in a religious context allows a bonding across time and space between consumers and their ancestors and fellow community members through a shared common experience of a distinctive system of belief and consciousness. -Corkery

Ayahuasca and ibogaine are the psychedelics most commonly associated with ancestor communication. Ayahuasceros and Bwiti tribesman summon the ancestors during ceremony. The Basotho people of southern Africa use Boophone disticha, a psychedelic bulb for ancestor communication as well. This may be culturally-specific interpretation but an alternate hypothesis proposed here is that the same mechanisms that are involved in psychedelics' anti-amnestic properties, i.e., their ability to retrieve and reconsolidate memories via changes in gene expression and brain activity, are the same mechanisms involved in making conscious information in our DNA and inherited epigenetic information. Genetic memory is a field of psychology and epigenetic modification from ancestral experience and/or trauma is now known to be heritable and able to affect offspring for many generations afterward. More research is required but if changes to our mind, memories and personality are due to changes in gene expression and epigenetic mechanisms and if psychedelics are able to make conscious stored neural information that is coded by genes and epigenetics, then it may be possible for information stored in our DNA and in our epigenome to be made conscious and in the case of the epigenome, reconsolidated in the same way as memories are. This is not a new concept in the psychedelic community. Psychedelics are said to heal ancestral trauma. After spending many years researching ayahuasca in South America, Narby concluded that ayahuasca used by shamans in the Western Amazon affords them access to knowledge coded in DNA. As more and more research uncovers the molecular mechanisms of psychedelic neuro-science, this does not seem like an impossible idea. Early psychedelic use in South America and Africa may be the origin of modern ancestor worship.

https://www.researchgate.net/publication/328974974_An_introduction_to_psychedelic_neuroscience
 
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mr peabody

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Psychedelics found to promote structural and functional neural plasticity

Ly et al. demonstrate that psychedelic compounds such as LSD, DMT, and DOI increase dendritic arbor complexity, promote dendritic spine growth, and stimulate synapse formation. These cellular effects are similar to those produced by the fast-acting antidepressant ketamine and highlight the potential of psychedelics for treating depression and related disorders.

Highlights

- Serotonergic psychedelics increase neuritogenesis, spinogenesis, and synaptogenesis
- Psychedelics promote plasticity via an evolutionarily conserved mechanism
- TrkB, mTOR, and 5-HT2A signaling underlie psychedelic-induced plasticity
- Noribogaine, but not ibogaine, is capable of promoting structural neural plasticity

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SUMMARY

Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse number and function, as measured by fluorescence microscopy and electrophysiology. The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clinical effectiveness of these compounds. Our results underscore the therapeutic potential of psychedelics and, importantly, identify several lead scaffolds for medicinal chemistry efforts focused on developing plasticity-promoting compounds as safe, effective, and fast-acting treatments for depression and related disorders.



Neuropsychiatric diseases, including mood and anxiety disorders, are some of the leading causes of disability worldwide and place an enormous economic burden on society. Approximately one-third of patients will not respond to current antidepressant drugs, and those who do will usually require at least 2-4 weeks of treatment before they experience any beneficial effects. Depression, PTSD, and addiction share common neural circuitry and have high comorbidity. A preponderance of evidence from a combination of human imaging, postmortem studies, and animal models suggests that atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders and is precipitated and/or exacerbated by stress. These structural changes, such as the retraction of neurites, loss of dendritic spines, and elimination of synapses, can potentially be counteracted by compounds capable of promoting structural and functional neural plasticity in the PFC, providing a general solution to treating all of these related diseases. However, only a relatively small number of compounds capable of promoting plasticity in the PFC have been identified so far, each with significant drawbacks. Of these, the dissociative anesthetic ketamine has shown the most promise, revitalizing the field of molecular psychiatry in recent years.

Ketamine has demonstrated remarkable clinical potential as a fast-acting antidepressant, even exhibiting efficacy in treatment-resistant populations. Additionally, it has shown promise for treating PTSD and heroin addiction. Animal models suggest that its therapeutic effects stem from its ability to promote the growth of dendritic spines, increase the synthesis of synaptic proteins, and strengthen synaptic responses.

Like ketamine, serotonergic psychedelics and entactogens have demonstrated rapid and long-lasting antidepressant and anxiolytic effects in the clinic after a single dose, including in treatment-resistant populations. In fact, there have been numerous clinical trials in the past 30 years examining the therapeutic effects of these drugs, with MDMA recently receiving the breakthrough therapy designation by the Food and Drug Administration for treating PTSD. Furthermore, classical psychedelics and entactogens produce antidepressant and anxiolytic responses in rodent behavioral tests, such as the forced swim test and fear extinction learning, paradigms for which ketamine has also been shown to be effective. Despite the promising antidepressant, anxiolytic, and anti-addictive properties of serotonergic psychedelics, their therapeutic mechanism of action remains poorly understood, and concerns about safety have severely limited their clinical usefulness.

Because of the similarities between classical serotonergic psychedelics and ketamine in both preclinical models and clinical studies, we reasoned that their therapeutic effects might result from a shared ability to promote structural and functional neural plasticity in cortical neurons. Here, we report that serotonergic psychedelics and entactogens from a variety of chemical classes (e.g., amphetamine, tryptamine, and ergoline) display plasticity-promoting properties comparable to or greater than ketamine. Like ketamine, these compounds stimulate structural plasticity by activating the mammalian target of rapamycin (mTOR). To classify the growing number of compounds capable of rapidly promoting induced plasticity, we introduce the term psychoplastogen, from the Greek roots psych- (mind), -plast (molded), and -gen (producing). Our work strengthens the growing body of literature indicating that psychoplastogens capable of promoting plasticity in the PFC might have value as fast-acting antidepressants and anxiolytics with efficacy in treatment-resistant populations and suggests that it may be possible to use classical psychedelics as lead structures for identifying safer alternatives.

Psychedelics promote neuritogenesis

Because atrophy of cortical neurons is believed to be a contributing factor to the development of mood and anxiety disorders, we first treated cultured cortical neurons with psychedelics from a variety of structural classes and measured the resulting changes in various morphological features. Using Sholl analysis, we observed that several psychedelics increased dendritic arbor complexity comparably to ketamine, as measured by the area under the curve of the Sholl plots as well as the maximum number of crossings. This increase in arbor complexity appeared to result from large changes in both the number of dendritic branches and the total length of the arbors. Psychedelics had a limited effect on the number of primary dendrites and did not alter the length of the longest dendrite.

Nearly all psychedelic compounds tested were capable of robustly promoting neuritogenesis, with comparable effects being produced by tryptamines, amphetamines, and ergolines. As a positive control, we treated cells with DHF, a psychoplastogen structurally dissimilar to classical psychedelics, and found that it also increased dendritic arbor complexity. This neurite outgrowth structural phenotype seems to only be induced by select compounds because serotonin and D-amphetamine, molecules that are chemically related to classical psychedelics and entactogens, exerted minimal to no effects on neuritogenesis.

To establish the relative potencies and efficacies of hallucinogens and entactogens for promoting neurite outgrowth, we conducted 8-point dose-response studies. We defined 100% and 0% efficacy as the maximum number of crossings induced by ketamine (10 nM) and vehicle (0.1% DMSO), respectively. We chose the 10 nM concentration of ketamine as the upper limit because this concentration of ketamine is reached in the brain following intra-peritoneal administration of an antidepressant dose in rats. For consistency, we used this same concentration when testing the effects of psychedelics and entactogens, with DMT being the only exception. We used a maximum 90 nM concentration of DMT in our studies to more closely mimic the brain concentration of DMT in rats treated with an antidepressant dose. In this neuritogenesis assay, ketamines half maximal effective concentration (EC50) value was 132 nM. Surprisingly, the majority of the psychedelics and entactogens we tested exhibited significantly greater potency than ketamine, with LSD being particularly potent. In fact, LSD exhibited activity across 8 orders of magnitude into the low picomolar range.

Notably, the anti-addictive alkaloid ibogaine was the only psychedelic tested that had absolutely no effect. This was a surprising result because we hypothesized that ibogaines long-lasting anti-addictive properties might result from its psychoplastogenic properties. Previous work by He et al. clearly demonstrated that ibogaine increases the expression of glial cell line-derived neurotrophic factor (GDNF) and that this plasticity-promoting protein is critical to ibogaines anti-addictive mechanism of action. Because several reports have suggested that noribogaine, a metabolite of ibogaine, might actually be the active compound in vivo, we decided to test its ability to promote neuritogenesis in cultured cortical neurons. Gratifyingly, noribogaine robustly increased dendritic arbor complexity with an EC50 value comparable to ketamine, providing additional evidence suggesting that it may be the active compound in vivo.

To assess the in vivo effects of classical psychedelics on neuritogenesis, we started treating Drosophila larvae during the first instar with LSD and DOI. As observed in rodent cortical cultures, both LSD and DOI significantly increased dendritic branching of class I sensory neurons; however, they did not increase the total length of the dendritic arbors. Because of the striking effects of psychedelics on the structures of immature neurons, we hypothesized that they might influence neuro-development. To test this, we chronically treated zebrafish embryos with compounds for 6 days immediately following dechorionation and assessed gross morphological changes and behavior. We did not observe any differences in head sizes between the treatment groups, nor did we detect any statistically significant differences in activity levels.

Next we assessed the ability of psychedelics to promote neuritogenesis in more mature neurons by starting to treat Drosophila larvae during the late second instar. Again, psychedelics increased the branching of class I neurons, although the effect was less dramatic than that observed when treatment was started during the first instar. Although different developmental stages might be more or less susceptible to the effects of psychedelics, it is also possible that the smaller effect size observed after administering compounds starting at the later time point was simply the result of treating the larvae for a shorter period of time. Regardless, it was quite surprising to observe compound-induced changes in neuronal structure after initiating treatment during the late second instar because class I neurons are stereotyped and typically possess relatively few higher-order branches. Moreover, our results demonstrate that psychedelics can promote changes in neuronal structure across vertebrate (rats) and invertebrate (Drosophila) species, suggesting that they act through an evolutionarily conserved mechanism.

Psychedelics promote spinogenesis and synaptogenesis

In addition to dendritic atrophy, loss of dendritic spines is a hallmark of depression and other neuropsychiatric disorders, so we next assessed the effects of psychedelics on spinogenesis. We treated mature rat cortical cultures for 24 hr with DOI, DMT, and LSD as representative compounds from the amphetamine, tryptamine, and ergoline classes of psychedelics, respectively. All three compounds increased the number of dendritic spines per unit length, as measured by super-resolution structured illumination microscopy (SIM), with LSD nearly doubling the number of spines. Additionally, treatment caused a shift in spine morphology, favoring immature over more mature (mushroom) spine types. Co-localization of pre- and post-synaptic markers following treatment demonstrated that psychedelics promoted synaptogenesis by increasing the density, but not the size of synapses. This increase in synapse density was accompanied by an increase in the density of VGLUT1 puncta, but not PSD-95 puncta, following compound administration.

Encouraged by our in vitro results, we next assessed the effects of a single intraperitoneal dose of DMT on spinogenesis in the PFC of adult rats using Golgi-Cox staining. We chose to administer a 10 mg/kg dose of DMT for three reasons. First, all available data suggested that this dose would produce hallucinogenic effects in rats with minimal safety risks. Second, we have previously shown that a 10 mg/kg dose of DMT produces positive effects in rat behavioral tests relevant to depression and PTSD. Finally, we wanted to directly compare the effects of DMT with ketamine, and seminal studies conducted by Li et al. had previously demonstrated that a 10 mg/kg dose of ketamine produced a robust increase in dendritic spine density in the PFC of rats. We observed a significant increase in the density of dendritic spines on cortical pyramidal neurons 24 hr after dosing with DMT. This effect was comparable with that produced by ketamine at the same dose. Importantly, this DMT-induced increase in dendritic spine density was accompanied by functional effects. Ex vivo slice recordings revealed that both the frequency and amplitude of spontaneous excitatory postsynaptic currents (EPSCs) were increased following DMT treatment. Interestingly, 10 mg/kg and 1 mg/kg doses produced similar responses despite the fact that they are predicted to be hallucinogenic and sub-psychedelic, respectively.

Because the half-life of DMT is exceedingly short (15 min), these results confirm that structural and functional changes induced by DMT persist for hours after the compound has been cleared from the body. Moreover, they demonstrate that DMT produces functional effects on pyramidal neurons of the PFC that mirror those produced by ketamine. Because the PFC is a key brain region involved in extinction learning, and both ketamine and DMT have been shown to facilitate fear extinction, our results suggest a link between the plasticity-promoting and behavioral effects of these drugs. Because fear extinction can be enhanced by increasing levels of brain-derived neurotrophic factor (BDNF) in the PFC, and ketamines behavioral effects have been shown to be BDNF-dependent, we next sought to determine the role of BDNF signaling in the plasticity-promoting effects of classical psychedelics.

Psychedelics promote plasticity through a TrkB- and mTOR-dependent mechanism

The role of BDNF in both neuritogenesis and spinogenesis is well known, and several reports suggest that psychedelics are capable of increasing levels of neurotrophic factors. Therefore, we treated cortical neurons with BDNF, DOI, and a combination of the two to see whether they had any additive or synergistic effects. Dose-response studies using recombinant BDNF revealed that a 50 ng/mL treatment increased neuritogenesis to a comparable extent as DOI. Moreover, a combination of the two did not confer any added benefit, suggesting that they operate through a related mechanism. Next, we treated cortical neurons with DOI, DMT, and LSD for 24 hr before measuring BDNF gene and protein expression using droplet digital PCR and ELISA, respectively. Although psychedelics did not increase the expression of BDNF transcript, they did result in a 2-fold increase in BDNF protein levels, although this effect was not statistically significant. When cortical cultures were co-treated with ANA-12, a selective antagonist of BDNFs high-affinity receptor TrkB, the ability of psychedelics or BDNF to stimulate neuritogenesis and spinogenesis was completely blocked.

Activation of TrkB is known to promote signaling through mTOR, which plays a key role in structural plasticity, the production of proteins necessary for synaptogenesis, and the effects of ketamine. Treatment with rapamycin, an mTOR inhibitor, completely blocked psychedelic-induced neuritogenesis, thus confirming that mTOR activation plays a role in the plasticity-promoting effects of classical serotonergic psychedelics.



The 5-HT2A receptor mediates the effects of psychedelics on structural plasticity

Finally, we sought to determine whether the 5-HT2A receptor played any role in the plasticity-promoting effects of DOI, DMT, and LSD because this receptor is known to be primarily responsible for the hallucinogenic effects of classical psychedelics. Furthermore, the psychoplastogenic potencies of these and related compounds correlate well with their 5-HT2A receptor affinities. Control experiments demonstrated that 5-HT2A receptors were expressed on cultured rat cortical neurons at both 6 days in vitro and DIV19. Next we found that co-treatment with ketanserin, a selective 5-HT2A antagonist, completely abrogated the ability of DMT, LSD, and DOI to promote both neuritogenesis and spinogenesis. Ketanserin was also able to block the effects of psilocin as well as the non-classical psychedelic noribogaine and enactogen MDMA.

These initial experiments were performed using doses of psychoplastogens that produced maximal effects on structural plasticity in combination with a 10-fold excess of ketanserin. At these concentrations, we could not rule out the possibility of other receptors contributing to the antagonistic effects of ketanserin. Therefore, we treated cultured cortical neurons with a significantly lower dose of LSD and attempted to block its ability to promote neurite outgrowth using increasing doses of ketanserin. We found that ketanserin blocks the psychoplastogenic effects of LSD by ~50% when treated at 10 nM. This is consistent with the fact that the binding affinities of ketanserin and LSD for the 5-HT2A receptor are roughly equivalent. Increasing the concentration of ketanserin to 100 nM, 10-fold higher than the concentration of LSD used in this experiment, completely prevented LSD-induced neuritogenesis. At 100 nM, ketanserin is relatively selective for the 5-HT2A receptor, although, at this concentration, we cannot rule out the possible involvement of 5-HT2C, adrenergic, or histamine receptors.

As a final note, the concentration responses of most psychoplastogens had Hill slopes that deviated from 1.0, implying polypharmacology. Because psychedelics have relatively high affinities for 5-HT2A receptors, it is likely that the effects of psychedelics are mediated primarily through 5-HT2A receptors at low concentrations and modulated by other targets at high concentrations. Interestingly, the concentration response of DMT was the only one to exhibit a Hill slope greater than 1.0, indicating some form of cooperativity.

Discussion

Classical serotonergic psychedelics are known to cause changes in mood and brain function that persist long after the acute effects of the drugs have subsided. Moreover, several psychedelics elevate glutamate levels in the cortex and increase gene expression in vivo of the neurotrophin BDNF as well as immediate-early genes associated with plasticity. This indirect evidence has led to the reasonable hypothesis that psychedelics promote structural and functional neural plasticity, although this assumption had never been rigorously tested. The data presented here provide direct evidence for this hypothesis, demonstrating that psychedelics cause both structural and functional changes in cortical neurons.

Prior to this study, two reports suggested that psychedelics might be able to produce changes in neuronal structure. Jones et al. demonstrated that DOI was capable of transiently increasing the size of dendritic spines on cortical neurons, but no change in spine density was observed. The second study showed that DOI promoted neurite extension in a cell line of neuronal lineage. Both of these reports utilized DOI, a psychedelic of the amphetamine class. Here we demonstrate that the ability to change neuronal structure is not a unique property of amphetamines like DOI because psychedelics from the ergoline, tryptamine, and iboga classes of compounds also promote structural plasticity. Additionally, D-amphetamine does not increase the complexity of cortical dendritic arbors in culture, and therefore, these morphological changes cannot be simply attributed to an increase in monoamine neurotransmission.

The identification of psychoplastogens belonging to distinct chemical families is an important aspect of this work because it suggests that ketamine is not unique in its ability to promote structural and functional plasticity. In addition to ketamine, the prototypical psychoplastogen, only a relatively small number of plasticity-promoting small molecules have been identified previously. Importantly, the psychoplastogenic effects of psychedelics in cortical cultures were also observed in vivo using both vertebrate and invertebrate models, demonstrating that they act through an evolutionarily conserved mechanism. Furthermore, the concentrations of psychedelics utilized in our in vitro cell culture assays were consistent with those reached in the brain following systemic administration of therapeutic doses in rodents. This suggests that neuritogenesis, spinogenesis, and/or synaptogenesis assays performed using cortical cultures might have value for identifying psychoplastogens and fast-acting antidepressants. It should be noted that our structural plasticity studies performed in vitro utilized neurons exposed to psychedelics for extended periods of time. Because brain exposure to these compounds is often of short duration due to rapid metabolism, it will be interesting to assess the kinetics of psychedelic-induced plasticity.

A key question in the field of psychedelic medicine has been whether or not psychedelics promote changes in the density of dendritic spines. Using super-resolution SIM, we clearly demonstrate that psychedelics do, in fact, increase the density of dendritic spines on cortical neurons, an effect that is not restricted to a particular structural class of compounds. Using DMT, we verified that cortical neuron spine density increases in vivo and that these changes in structural plasticity are accompanied by functional effects such as increased amplitude and frequency of spontaneous EPSCs. We specifically designed these experiments to mimic previous studies of ketamine so that we might directly compare these two compounds, and, to a first approximation, they appear to be remarkably similar. Not only do they both increase spine density and neuronal excitability in the cortex, they seem to have similar behavioral effects. We have shown previously that, like ketamine, DMT promotes fear extinction learning and has antidepressant effects in the forced swim test. These results, coupled with the fact that ayahuasca, a DMT-containing concoction, has potent antidepressant effects in humans, suggests that classical psychedelics and ketamine might share a related therapeutic mechanism.

Although the molecular targets of ketamine and psychedelics are different, they appear to cause similar downstream effects on structural plasticity by activating mTOR. This finding is significant because ketamine is known to be addictive whereas many classical psychedelics are not. The exact mechanisms by which these compounds stimulate mTOR is still not entirely understood, but our data suggest that, at least for classical psychedelics, TrkB and 5-HT2A receptors are involved. Although most classical psychedelics are not considered to be addictive, there are still significant safety concerns with their use in medicine because they cause profound perceptual disturbances and still have the potential to be abused. Therefore, the identification of non-hallucinogenic analogs capable of promoting plasticity in the PFC could facilitate a paradigm shift in our approach to treating neuropsychiatric diseases. Moreover, such compounds could be critical to resolving the long-standing debate in the field concerning whether the subjective effects of psychedelics are necessary for their therapeutic effects. Although our group is actively investigating the psychoplastogenic properties of non-hallucinogenic analogs of psychedelics, others have reported the therapeutic potential of safer structural and functional analogs of ketamine.

Our data demonstrate that classical psychedelics from several distinct chemical classes are capable of robustly promoting the growth of both neurites and dendritic spines in vitro, in vivo, and across species. Importantly, our studies highlight the similarities between the effects of ketamine and those of classical serotonergic psychedelics, supporting the hypothesis that the clinical antidepressant and anxiolytic effects of these molecules might result from their ability to promote structural and functional plasticity in prefrontal cortical neurons. We have demonstrated that the plasticity-promoting properties of psychedelics require TrkB, mTOR, and 5-HT2A signaling, suggesting that these key signaling hubs may serve as potential targets for the development of psychoplastogens, fast-acting antidepressants, and anxiolytics. Taken together, our results suggest that psychedelics may be used as lead structures to identify next-generation neurotherapeutics with improved efficacy and safety profiles.

https://www.cell.com/cell-reports/pdf/S2211-1247(130755-1.pdf
 

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Ketamine may relieve depression by repairing damaged brain circuits

by Jon Hamilton | NPR | April 11, 2019

The anesthetic ketamine can relieve depression in hours and keep it at bay for a week or more. Now scientists have found hints about how ketamine works in the brain.

In mice, the drug appears to quickly improve the functioning of certain brain circuits involved in mood. Then, hours later, it begins to restore faulty connections between cells in these circuits.

The finding comes after the Food and Drug Administration in March approved Spravato, a nasal spray that is the first antidepressant based on ketamine.

The anesthetic version of ketamine has already been used to treat thousands of people with depression. But scientists have known relatively little about how ketamine and similar drugs affect brain circuits.

The study offers "a substantial breakthrough" in scientists' understanding, says Anna Beyeler, a neuroscientist at INSERM, the French equivalent of the National Institutes of Health, who wasn't involved in the research. But there are still many remaining questions, she says.

Research has found evidence that ketamine was creating new synapses, the connections between brain cells. But the new study appears to add important details about how and when these new synapses affect brain circuits, says Ronald Duman, a professor of psychiatry and neuroscience at Yale University.

Studying ketamine's antidepressant effects in mice presented a challenge. "There's probably no such thing as a depressed mouse," says Dr. Conor Liston, a neuroscientist and psychiatrist at Weill Cornell Medicine in New York and an author of the Science paper.

Liston and his team of scientists gave mice a stress hormone that caused them to act depressed. For example, the animals lost interest in favorite activities like eating sugar and exploring a maze.

Then the team used a special laser microscope to study the animals' brains. The researchers were looking for changes to synapses.

"Stress is associated with a loss of synapses in this region of the brain that we think is important in depression," Liston says. "And sure enough, the stressed-out mice lost a lot of synapses."

Next, the scientists gave the animals a dose of ketamine. And Liston says that's when they noticed something surprising. "Ketamine was actually restoring many of the exact same synapses in their exact same configuration that existed before the animal was exposed to chronic stress," he says.

In other words, the drug seemed to be repairing brain circuits that had been damaged by stress.

That finding suggested one way that ketamine could be relieving depression in people. But it didn't explain how ketamine could work so quickly.

Was the drug really creating all these new synapses in just a couple of hours?

To find out, the team used a technology that makes living brain cells glow under a microscope. "You can kind of imagine Van Gogh's Starry Night," Liston says. "The brain cells light up when they become active and become dimmer when they become inactive."

That allowed the team to identify brain circuits by looking for groups of brain cells that lit up together.

And that's when the scientists got another surprise.

After the mice got ketamine, it took less than six hours for the brain circuits damaged by stress to begin working better. The mice also stopped acting depressed in this time period.

But both of these changes took place long before the drug was able to restore many synapses.

"It wasn't until 12 hours after ketamine treatment that we really saw a big increase in the formation of new connections between neurons," Liston says.

The research suggests that ketamine triggers a two-step process that relieves depression.

First, the drug somehow coaxes faulty brain circuits to function better temporarily. Then it provides a longer-term fix by restoring the synaptic connections between cells in a circuit.

"One possibility is that the synapses are restored spontaneously once the cells in a circuit begin firing in a synchronized fashion," says INSERM'S Beyeler, who wrote a commentary accompanying the study.

"The new study suggests not only how ketamine works but also why its effects typically wear off after a few days or weeks", she says. "What we can imagine is that ketamine always has this short-term antidepressant effect, but then if the synaptic changes are not maintained, you will have relapse, and if that's true," she says, "scientists' next challenge is to find a way to maintain the brain circuits that ketamine has restored."

 
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Ayahuasca stimulates the birth of new brain cells

Beckley Foundation

For a long time, scientists believed that no new neurons are born in the brains of adults. However, it was later discovered that neurogenesis – meaning the creation of new neurons – does in fact in occur in the hippocampus, a brain region associated with memory. Unfortunately, the rate of neurogenesis is not always sufficient to replace all of our damaged neurons as we age, which is why many people suffer from dementia and other age-related cognitive deficiencies. Fortunately, a study conducted by the Beckley/Sant Pau Research Programme, and published in the journal Scientific Reports, reveals that certain compounds present in the psychedelic Amazonian brew ayahuasca actually stimulate the birth of new neurons.

Researchers placed harmine and tetrahydroharmine – the most prevalent alkaloids in ayahuasca – in a petri dish with hippocampal stem cells, and found that this greatly increased the rate at which these cells developed into fully mature neurons. The results of this study were first presented at the Interdisciplinary Conference on Psychedelics Research in 2016, and represent the first evidence that components of ayahuasca have neurogenic properties, thereby opening up a wealth of possibilities for future research.

We are currently conducting additional experiments to discern the magnitude of the observed effects. The replication of the present findings in vivo would represent a major breakthrough in mental healthcare, with potential applications ranging from treating neurodegenerative and psychiatric disorders to redressing brain damage associated with stroke or trauma. Jordi Riba of the Beckley/Sant Pau Research Programme explains the latest findings, illustrating them with the beautiful images below

What you are seeing is a “static picture” taken after several days of treatment of the stem cells with the different compounds. No neurons were present prior to the three different treatments: a) saline (water+salt); b) harmine; and c) tetrahydroharmine



The first image (above) is the control, when only salty water (saline) was added to the cell cultures. The nuclei of the stem cells can be seen in blue. These stem cells have been treated with saline for several days and only a few have developed into young neurons (the few green sports in the image).



The second image (above) shows the results after several days of treatment with harmine: blue is still present because it’s a marker of cell nuclei, and all cells have nuclei (stem cells and neurons). The green spots are the young neurons marked using Tuj1 staining (this staining is specific for “neuron-specific class III beta-tubulin) present in recently created neurons. The red spots show more mature neurons. The staining marks the “microtubule-associated protein 2 (MAP-2). Its presence increases during neuron development.



The third image (above) shows the results obtained after several days of treatment with tetrahydroharmine. The meaning of the colors is the same.

http://beckleyfoundation.org/ayahuasca-stimulates-the-birth-of-new-brain-cells/
 
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How psilocybin works on the brain

Frederick Barrett, Samuel Krimmel, Roland Griffiths, David Seminowicz, Brian Mathur | Johns Hopkins Medicine | 5 Jun 2020

To see how psychedelics impact the claustrum, a mysterious region of the brain believed to control the ego, researchers compared the brain scans of people after they took psilocybin with their scans after taking a placebo.

Perhaps no region of the brain is more fittingly named than the claustrum, taken from the Latin word for "hidden or shut away." The claustrum is an extremely thin sheet of neurons deep within the cortex, yet it reaches out to every other region of the brain. Its true purpose remains "hidden away" as well, with researchers speculating about many functions. For example, Francis Crick of DNA-discovery fame believed that the claustrum is the seat of consciousness, responsible for awareness and sense of self.

What is known is that this region contains a large number of receptors targeted by psychedelic drugs such as LSD or psilocybin ¾ the hallucinogenic chemical found in certain mushrooms. To see what happens in the claustrum when people are on psychedelics, Johns Hopkins Medicine researchers compared the brain scans of people after they took psilocybin with their scans after taking a placebo.

Their findings were published online on May 23, 2020, in the journal NeuroImage.

The scans after psilocybin use showed that the claustrum was less active, meaning the area of the brain believed responsible for setting attention and switching tasks is turned down when on the drug. The researchers say that this ties in with what people report as typical effects of psychedelic drugs, including feelings of being connected to everything and reduced senses of self or ego.

"Our findings move us one step closer to understanding mechanisms underlying how psilocybin works in the brain," says Frederick Barrett, Ph.D., assistant professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine and a member of the school's Center for Psychedelic and Consciousness Research.

"This will hopefully enable us to better understand why it's an effective therapy for certain psychiatric disorders, which might help us tailor therapies to help people more."
Because of its deep-rooted location in the brain, the claustrum has been difficult to access and study. Last year, Barrett and his colleagues at the University of Maryland, Baltimore, developed a method to detect brain activity in the claustrum using functional magnetic resonance imaging (fMRI).

For this new study, the researchers used fMRI with 15 people and observed the claustrum brain region after the participants took either psilocybin or a placebo. They found that psilocybin reduced neural activity in the claustrum by 15% to 30%. This lowered activity also appeared to be associated with stronger subjective effects of the drug, such as emotional and mystical experiences. The researchers also found that psilocybin changed the way that the claustrum communicated with brain regions involved in hearing, attention, decision-making and remembering.

With the highly detailed imaging of the claustrum provided by fMRI, the researchers next hope to look at the mysterious brain region in people with certain psychiatric disorders such as depression and substance use disorder. The goal of these experiments will be to see what roles, if any, the claustrum plays in these conditions. The researchers also plan to observe the claustrum's activity when under the influence of other psychedelics, such as salvinorin A, a psychedelic derived from a Mexican plant.​

 
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Psychedelic drugs push the brain to a state never seen before

by Andy Coghlan | New Scientist | 19 April 2017

Measuring neuron activity has revealed that psychedelic drugs really do alter the state of the brain, creating a different kind of consciousness.

“We see an increase in the diversity of signals from the brain,” says Anil Seth, at the University of Sussex, UK. “The brain is more complex in its activity.”

Seth and his team discovered this by re-analysing data previously collected by researchers at Imperial College London. Robin Carhart-Harris and his colleagues had monitored brain activity in 19 volunteers who had taken ketamine, 15 who had had LSD, and 14 who were under the influence of psilocybin, the psychedelic compound in magic mushrooms. Carhart-Harris’s team used sets of sensors attached to the skull to measure the magnetic fields produced by these volunteers’ neurons, and compared these to when each person took a placebo.
"We took the activity data, cleaned it up then chopped it into 2-second chunks,” says Seth, whose team worked with Carhart-Harris on the re-analysis. “For each chunk, we could calculate a measure of diversity.”

Higher state

Previous work had shown that people in a state of wakefulness have more diverse patterns of brain activity than people who are asleep. Seth’s team has found that people who have taken psychedelic drugs show even more diversity – the highest level ever measured.

These patterns of very high diversity coincided with the volunteers reporting “ego-dissolution” – a feeling that the boundaries between oneself and the world have been blurred. The degree of diversity was also linked to more vivid experiences.

There’s mounting evidence that psychedelic drugs may help people with depression in ways that other treatments can’t. Some benefits have already been seen with LSD, ketamine, psilocybin, and ayahuasca, a potion used in South America during religious rites.

“I think there’s an awful lot of potential here,” says Seth. “If you suddenly see things in a different way, it could give your outlook a jolt that existing antidepressants can’t because they work on the routine, wakeful state.”

https://www.newscientist.com/articl...n-to-a-state-never-seen-before/#ixzz6jxBhBvA5
 
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DMT: Biochemical swiss army knife in neuroinflammation and neuroprotection?

Attila Szabo, Ede Frecska

The inflammatory theory of many neuropsychiatric illnesses has become an emerging trend in modern medicine. Various immune mechanisms – mainly via the activity of microglia – may contribute to the etiology and symptomatology of diseases, such as schizophrenia, bipolar disorder, depression, or Alzheimer's disease. Unwanted and excess inflammation is most typically the result of dysregulated innate immune responses. Recognition of self-derived damage-associated molecular patterns (DAMPs) or pathogen-associated molecular pattern molecules (PAMPs) is usually leading to the activation of tissue resident immune cells including macrophages (microglia) and dendritic cells. They act as ‘gatekeepers’ continuously monitoring the tissue microenvironment for potential ‘danger signals’ by means of their pattern recognition receptors, such as Toll-like receptors or RIG-I-like receptors.

Once a DAMP or PAMP has been recognized by a pattern recognition receptor various downstream signaling pathways are initiated, which eventually leads to the secretion of inflammatory cytokines and many other soluble factors important in the elimination of invading microbes. Pattern recognition receptors couple to nuclear factor kappaB (NF-kB), the master transcription regulator of inflammatory cytokines and chemokines. Macrophages and dendritic cells are also capable of antigen-presentation so they can initiate adaptive immune responses by priming naive T-cells. During inflammation of the central nervous system, polarization towards the T helper 1 and 17 subsets is especially important as these T cells play a major role in the development of chronic inflammation and brain tissue damage in infectious diseases and autoimmunity.

It has been known for decades that immunomodulation through serotonin/5-hydroxytryptamine receptors (5-HTRs) has the potential to regulate inflammation and prevent damage of the nervous tissue. Recently another receptor has been added to the greater picture: the orphan receptor sigma-1 (Sig-1R). 5-HTRs and Sig-1R have been shown to be expressed ubiquitously in higher vertebrate tissues and mediate various processes, including the regulation of cognition and behavior, body temperature, as well as immune functions. Both 5-HTRs and the Sig-1R use G protein-coupled (GPCR) pathways thereby modulating a plethora of cellular functions, such as cytokine/neurotransmitter release, proliferation, differentiation, and apoptosis.

The molecular chaperone Sig-1R is located at the endoplasmic reticulum-mitochondrion interface and has an important role in the fine-tuning of cellular metabolism and energetics under stressful conditions. At the MAM, Sig-1Rs are involved in the regulation and mobilization of calcium from endoplasmic reticulum stores. Neuroprotection by Sig-1R activation can be attained by preventing elevations of intracellular calcium-mediated cell death signaling. Based on its central localization and function, pivotal physiological activities of the Sig-1R have been described such as indispensable role in neuronal differentiation, neuronal signaling, cellular survival in hypoxia, resistance against oxidative stress, and mitigating unfolded protein response.

Tryptaminergic trace amines (e.g. DMT) as well as neurosteroids are endogenous ligands of the Sig-1R. Tryptamines are naturally occurring monoamine alkaloids sharing a common biochemical – tryptamine – backbone. DMT was shown to be endogenously present in the human brain and in other tissues of the body, however the exact physiological role of this tryptamine has not been identified yet. It has been shown that, besides its affinity for the Sig-1R, DMT also acts as an agonist at numerous serotonin receptors, such as 5-HT1A, 5-HT2A, and 5-HT2C. This wide-spectrum agonist activity may allow DMT to modulate several physiological processes and regulate inflammation through the Sig-1R and 5-HTRs.

Indeed, DMT has been found to modulate immune responses through the Sig-1R under various conditions. These include the suppression of inflammation by blocking inflammatory cytokine and chemokine release of dendritic cells, as well as inhibiting the activation of Th1 and Th17 subsets. The biochemical background of this extensive ability lies in the possible cross-talk of the GPCR-coupled downstream signaling of 5-HTRs/Sig-1R and other inflammatory pathways in immune cells, as well as the fine-tuning of cytokine feedback loops in peripheral tissues. Thus, in neuroinflammation, two major scenarios are possible:

i) The modulation of cytokine production by brain resident microglia that implies a negative feedback regulation of inflammation via the induction of the release of anti-inflammatory IL-10 and TGFB occurring subsequent of both 5-HTR and Sig-1R activation;

ii) The direct/indirect control of NF-kB signaling and possibly other pathways involved in inflammation through intracellular kinases, adaptor proteins, etc. This way, the activation of 5-HTRs and Sig-1R may also interfere with the chemokine, inflammatory cytokine signaling of immune cells through intracellular mechanisms.

Most of the receptors that are involved in psychedelic effects belong to the GPCR family or interact with GPCRs. The role of 5-HTR/Sig-1R GPCR-coupled signals in the intracellular regulation and orchestration of NF-kB and MAPK pathways may be of particular importance regarding the complex neuroimmunological effects of DMT.

The above outlined picture suggests a direct control of NF-kB transcriptional regulation of chemokines, pro-inflammatory and anti-inflammatory cytokines, which may render DMT as a potentially useful therapeutic tool in a broad range of chronic inflammatory and autoimmune diseases, and pathological conditions connected to increased unfolded protein responseincluding but not restricted torheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis (ALS), Alzheimer's and Parkinson's disease, etc. However, the powerful sychedelic property of DMT poses an important problem that must be addressed in future drug design.

Protective and neuroregenerative effects of Sig-1R agonists have been reported in several in vitro and in vivo studies. The selective Sig-1R agonists 2-1 phenylcyclohexanecarboxylate and cutamesine have been shown to strongly promote neuroprotective mechanisms and significantly increase neuronal cell survival and regeneration under various conditions, such as traumas, autoimmunity, and neurodegenerative disorders. Specific Sig-1R stimulation has also been found to greatly increase the levels of the glial cell-derived neurotrophic factor GDNF that promotes neuronal cell survival and differentiation.

The neuroregenerative potential of DMT through the Sig-1R has been suggested earlier as multiple biochemical and physiological mechanisms exist, which facilitate the transportation and binding of DMT to the Sig-1R in the mammalian brain. Thus DMT, as a natural, endogenous agonist at both the Sig-1R and 5-HTRs, is hypothesized to be an unique, many-faced pharmacological entity, which has many important roles in the immunoregulatory processes of peripheral and brain tissues, as well as involved in the promotion and induction of neuroregeneration in the mammalian nervous system.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4828992/
 
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'Mystical' psychedelic compound found in the normal brain

Medical Xpress | 27 June 2019

Drinkers of Ayahuasca experience short-term psychedelic episodes many describe as life-changing.

The active ingredient responsible for these psychedelic visions is a molecule called dimethyltryptamine (DMT). For the first time, a team led by Michigan Medicine has discovered the widespread presence of naturally-occurring DMT in the mammalian brain. The finding is the first step toward studying DMT— and figuring out its role—within the brains of humans.

"DMT is not just in plants, but also can be detected in mammals," says Jimo Borjigin, Ph.D., of the Department of Molecular and Integrative Physiology. Her interest in DMT came about accidentally. Before studying the psychedelic, her research focused on melatonin production in the pineal gland.

In the seventeenth century, the philosopher Rene Descartes claimed that the pineal gland, a small pinecone-shaped organ located deep in the center of the brain, was the seat of the soul. Since its discovery, the pineal gland, known by some as the third eye, has been shrouded in mystery. Scientists now know it controls the production of melatonin, playing an important role in modulating circadian rhythms, or the body's internal clock. However, an online search for notes to include in a course she was teaching opened Borjigin's eyes to a thriving community still convinced of the pineal gland's mystical power.

The core idea seems to come from a documentary featuring the work of researcher Rick Strassman, Ph.D. with the University of New Mexico School of Medicine. In the mid-1990s, he conducted an experiment in which human subjects were given DMT by IV injection and interviewed after its effects wore off. In a documentary about the experiment, Strassman claims that he believed the pineal gland makes and secretes DMT.

I said to myself, 'wait, I've worked on the pineal gland for years and have never heard of this,'" she said. She contacted Strassman, requesting the source of his statement. When Strassman admitted that it was just a hypothesis, Borjigin suggested they work together to test it. "I thought if DMT is an endogenous monoamine, it should be very easy to detect using a fluorescence detector."

Using a process in which microdialysis tubing is inserted into a rat brain through the pineal gland, the researchers collected a sample that was analyzed for—and confirmed—the presence of DMT. That experiment resulted in a paper published in 2013.

However, Borjigin was not satisfied. Next, she sought to discover how and where DMT was synthesized. Her graduate student, Jon Dean, lead author of the paper, set up an experiment using a process called in situ hybridization, which uses a labeled complementary strand of DNA to localize a specific RNA sequence in a tissue section.

"With this technique, we found brain neurons with the two enzymes required to make DMT," says Borjigin. "And they were not just in the pineal gland."

"They are also found in other parts of the brain, including the neocortex and hippocampus that are important for higher-order brain functions including learning and memory."


The results are published in the journal Scientific Reports.

Her team's work has also revealed that the levels of DMT increase in some rats experiencing cardiac arrest. A paper published in 2018 by researchers in the U.K. purported that DMT simulates the near death experience, wherein people report the sensation of transcending their bodies and entering another realm. Borjigin hopes to probe further to discover the function of naturally occurring levels of DMT in the brain—and what if any role it plays in normal brain functions.

"We don't know what it's doing in the brain. All we're saying is we discovered the neurons that make this chemical in the brain, and they do so at levels similar to other monoamine neurotransmitters."

 
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This figure shows the effects of three psychedelics, DMT, LSD, amphetamines (DOI) and one control
(VEH) on neurons in the prefrontal cortex (Ly et al)


LSD and magic mushrooms could heal brain cells damaged by depression, study shows

by Alex Matthews-King | The Independent | 12 June 2018

Psychedelics could be 'next generation' of safer treatments for mental health.

Psychedelic drugs like LSD and ecstasy ingredient MDMA have been shown to stimulate the growth of new branches and connections between brain cells which could help address conditions like depression and addiction.

Researchers in California have demonstrated these substances, banned as illicit drugs in many countries, are capable of rewiring parts of the brain in a way that lasts well beyond the drugs' effects.

This means psychedelics could be the "next generation" of treatments for mental health disorders which could be more effective and safer than existing options, the study's authors from the University of California.

In previous studies by the same team, a single dose of DMT, the key ingredient in ayahuasca medicinal brews of Amazonian tribes, has been shown to help rats overcome a fear of electric shock meant to emulate post-traumatic stress disorder (PTSD).

Now they have shown this dose increases the number of branch-like dendrites sprouting from nerve cells in the rat's brain.

These dendrites end at synapses where their electrical impulses are passed on to other nerve cells and underpin all brain activity. But they can atrophy and draw back in people with mental health conditions.

“One of the hallmarks of depression is that the neurites in the prefrontal cortex – a key brain region that regulates emotion, mood, and anxiety – those neurites tend to shrivel up,” says Dr David Olson, who lead the research team.

These brain changes also appear in cases of anxiety, addiction, and post-traumatic stress disorder and stimulating them to reconnect could help to address this.

The research, published in the journal Cell Reports today, looked at drugs in several classes including tryptamines, DMT and magic mushrooms; amphetamines, including MDMA; and ergolines, like LSD.

In tests on human brain cells in the lab, flies and rats, it found these substances consistently boosted brain connections.

Dr Olson compared the effects to ketamine, another illicit drug which represents one of the most important new treatments for depression in a generation, and found many psychedelics have equal or greater effects.

A ketamine nasal spray is being fast-tracked through clinical trials after it was shown to rapidly relieve major depression and suicidal thoughts in people who cannot be helped by other treatments.

However its use has to be weighed against its potential for abuse, and its ability to cause a form of drug-induced psychosis.

“The rapid effects of ketamine on mood and plasticity are truly astounding,” said Dr Olson. “The big question we were trying to answer was whether or not other compounds are capable of doing what ketamine does.”

“People have long assumed that psychedelics are capable of altering neuronal structure, but this is the first study that clearly and unambiguously supports that hypothesis."


The fact that many of these drugs seem to mimic the groundbreaking benefits of ketamine opens up an array of new treatment options, which may be less open to abuse, if these drugs can make it to clinical trials.

Dr Olson said: “Ketamine is no longer our only option. Our work demonstrates that there are a number of distinct chemical scaffolds capable of promoting plasticity like ketamine, providing additional opportunities for medicinal chemists to develop safer and more effective alternatives.”

The news that yet more banned substances could help tackle serious and debilitating disease comes as the UK Home Office is embroiled in a row over medicinal cannabis in treating epilepsy.

After months seizure-free, 12-year-old Billy Caldwell had a seizure last night after airport customs officials confiscated his prescription from Canada.

Billy had previously had the UK’s only NHS medical cannabis prescription, for an oil which banished seizures that used to strike 100 times a day, but the Home Office intervened to block his GP from prescribing it.

 
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Homological scaffolds of the brain's functional networks

Petri, Expert, Turkheimer, Carhart-Harris, Nutt, Hellyer, Vaccarino

Networks, as efficient representations of complex systems, have appealed to scientists for a long time and now permeate many areas of science, including neuroimaging. Traditionally, the structure of complex networks has been studied through their statistical properties and metrics concerned with node and link properties, e.g. degree-distribution, node centrality and modularity. Here, we study the characteristics of functional brain networks at the mesoscopic level from a novel perspective that highlights the role of inhomogeneities in the fabric of functional connections. This can be done by focusing on the features of a set of topological objects—homological cycles—associated with the weighted functional network. We leverage the detected topological information to define the homological scaffolds, a new set of objects designed to represent compactly the homological features of the correlation network and simultaneously make their homological properties amenable to networks theoretical methods. As a proof of principle, we apply these tools to compare resting-state functional brain activity in 15 healthy volunteers after intravenous infusion of placebo and psilocybin—the main psychoactive component of magic mushrooms. The results show that the homological structure of the brain's functional patterns undergoes a dramatic change post-psilocybin, characterized by the appearance of many transient structures of low stability and of a small number of persistent ones that are not observed in the case of placebo.

Motivation

The understanding of global brain organization and its large-scale integration remains a challenge for modern neurosciences. Network theory is an elegant framework to approach these questions, thanks to its simplicity and versatility. Indeed, in recent years, networks have become a prominent tool to analyse and understand neuroimaging data coming from very diverse sources, such as functional magnetic resonance imaging (fMRI), electroencephalography and magnetoencephalography, also showing potential for clinical applications.

A natural way of approaching these datasets is to devise a measure of dynamical similarity between the microscopic constituents and interpret it as the strength of the link between those elements. In the case of brain functional activity, this often implies the use of similarity measures such as (partial) correlations or coherence, which generally yield fully connected, weighted and possibly signed adjacency matrices. Despite the fact that most network metrics can be extended to the weighted case, the combined effect of complete connectedness and edge weights makes the interpretation of functional networks significantly harder and motivates the widespread use of ad hoc thresholding methods. However, neglecting weak links incurs the dangers of a trade-off between information completeness and clarity. In fact, it risks overlooking the role that weak links might have, as shown for example in the cases of resting-state dynamics, cognitive control and correlated network states.

In order to overcome these limits, Rubinov & Sporn recently introduced a set of generalized network and community metrics for functional networks that among others were used to uncover the contrasting dynamics underlying recollection and the physiology of functional hubs.

In this paper, we present an alternative route to the analysis of brain functional networks. We focus on the combined structure of connections and weights as captured by the homology of the network.

Discussion

In this paper, we first described a variation of persistent homology that allows us to deal with weighted and signed networks. We then introduced two new objects, the homological scaffolds, to go beyond the picture given by persistent homology to represent and summarize information about individual links. The homological scaffolds represent a new measure of topological importance of edges in the original system in terms of how frequently they are part of the generators of the persistent homology groups and how persistent are the generators to which they belong to. We applied this method to an fMRI dataset comprising a group of subjects injected with a placebo and another injected with psilocybin.

By focusing on the second homology group H1, we found that the stability of mesoscopic association cycles is reduced by the action of psilocybin, as shown by the difference in the probability density function of the generators of H1.

It is here that the importance of the insight given by the homological scaffolds in the persistent homology procedure becomes apparent. A simple reading of this result would be that the effect of psilocybin is to relax the constraints on brain function, ascribing cognition a more flexible quality, but when looking at the edge level, the picture becomes more complex. The analysis of the homological scaffolds reveals the existence of a set of edges that are predominant in terms of their persistence although they are statistically part of the same number of cycles in the two conditions. In other words, these functional connections support cycles that are especially stable and are only present in the psychedelic state. This further implies that the brain does not simply become a random system after psilocybin injection, but instead retains some organizational features, albeit different from the normal state, as suggested by the first part of the analysis. Further work is required to identify the exact functional significance of these edges. Nonetheless, it is interesting to look at the community structure of the persistence homological scaffolds in figure 6.


Figure 6.

Simplified visualization of the persistence homological scaffolds. The persistence homological scaffolds Inline Formula (a) and Inline Formula (b) are shown for comparison. For ease of visualization, only the links heavier than 80 are shown. In both networks, colours represent communities obtained by modularity optimization on the placebo persistence scaffold using the Louvain method [50] and are used to show the departure of the psilocybin connectivity structure from the placebo baseline. The width of the links is proportional to their weight and the size of the nodes is proportional to their strength. Note that the proportion of heavy links between communities is much higher (and very different) in the psilocybin group, suggesting greater integration. A labelled version of the two scaffolds is available as GEXF graph files as the electronic supplementary material.


The two pictures are simplified cartoons of the placebo (figure 6a) and psilocybin (figure 6b) scaffolds. In figure 6a,b, the nodes are organized and coloured according to their community membership in the placebo scaffold. This is done in order to highlight the striking difference in connectivity structure in the two cases. When considering the edges in the tail of the distribution, weight greater than or equal to 80, only 29 of the 374 edges present in the truncated psilocybin scaffold are shared with the truncated placebo scaffold (165 edges). Of these 374 edges, 217 are between placebo communities and are observed to mostly connect cortical regions. This supports our idea that psilocybin disrupts the normal organization of the brain with the emergence of strong, topologically long-range functional connections that are not present in a normal state.

The two key results of the analysis of the homological scaffolds can therefore be summarized as follows (i) there is an increased integration between cortical regions in the psilocybin state and (ii) this integration is supported by a persistent scaffold of a set of edges that support cross modular connectivity probably as a result of the stimulation of the 5HT2A receptors in the cortex.

We can speculate on the implications of such an organization. One possible by-product of this greater communication across the whole brain is the phenomenon of synaesthesia which is often reported in conjunction with the psychedelic state. Synaesthesia is described as an inducer-concurrent pairing, where the inducer could be a grapheme or a visual stimulus that generates a secondary sensory output—like a colour for example. Drug-induced synaesthesia often leads to chain of associations, pointing to dynamic causes rather than fixed structural ones as may be the case for acquired synaesthesia. Broadly consistent with this, it has been reported that subjects under the influence of psilocybin have objectively worse colour perception performance despite subjectively intensified colour experience.

To summarize, we presented a new method to analyse fully connected, weighted and signed networks and applied it to a unique fMRI dataset of subjects under the influence of mushrooms. We find that the psychedelic state is associated with a less constrained and more intercommunicative mode of brain function, which is consistent with descriptions of the nature of consciousness in the psychedelic state.

https://royalsocietypublishing.org/doi/full/10.1098/rsif.2014.0873
 
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Psychedelic neuroplasticity

by James L. Kent, 2010 | Psychedelic Information Theory

Neural axons in the human brain are always branching and creating new synaptic connections to facilitate learning and development. Like the toning and bulking of muscle mass, neural connectivity, developmental growth, and plasticity are based partly on genetics and partly on the “use it or lose it” principle; the more you use a neural pathway the more robust and responsive it will become, the less you use a pathway the weaker it will become. Training and repetition build faster and more responsive connections. The more a neuron or assembly of neurons is used in a specific exercise, the faster and more responsive those neurons will become when performing that exercise. This is how the brain learns new things and integrates new skills. Training, repetition, and reinforcement leads to long term changes in synaptic connectivity. These are the basics of neuroplasticity.

Neuroplasticity is the physical mechanism which makes shamanism and psychedelic therapy viable. In dreaming neuroplasticity is stimulated in response to daily routine and anxiety; in hypnosis neuroplasticity is stimulated in response to suggestion and reinforcement. In shamanism neuroplasticity is stimulated in response to dose, set, and setting. The efficacy of psychedelics in both shamanic transformation and clinical therapy relies on their unique ability to decouple the cortex, disassociate ego structures, and stimulate archetypal identity regression and personal transformation. No other class of drugs can claim to have such a radical effect on personality; radical personality changes in response to brief psychedelic exposure implies neuroplasticity.

While there is no laboratory research to indicate that psychedelics stimulate neuroplasticity, there is evidence that psychedelics can produce long-term changes in personality. People who take psychedelics sometimes adopt a new manner of dress, a new spirituality, perhaps even a new name to go with their new identity. Self-reinvention is an integral part of psychedelic metaprogramming and subculture. The forging of a new identity does not always happen in a single psychedelic session, but psychedelic experimentation can easily become a catalyst for sudden and radical personality transformation. These basic observations make a case for psychedelics as facilitators of long term identity modification and neuroplasticity.

The case for psychedelic neuroplasticity

Psychedelics can stimulate recall of lost memories and can also generate false memories; lost memory reconsolidation and false memory imprinting implies neuroplasticity. The brain builds tolerance to psychedelics quickly, but psychedelic tolerance can be surpassed by successively ingesting larger doses. Successive dosing and increasing levels of tolerance implies stress-based neuroplasticity. In the case of hallucinogen persisting perception disorder (HPPD), the subject retains some of the visual effects of hallucinogens long after the drug should have metabolized; persisting reactions to neural stress imply neuroplasticity. Psychedelics have been used to facilitate cult induction and programming; indoctrination implies identity-based neuroplasticity. Psychedelics induce peer and mate bonding in tribal subcultures; bonding implies identity-based neuroplasticity. Psychedelics can create positive long-term changes in mood and outlook; long term outlook changes imply neuroplasticity. Finally, while lying in darkened silence the psychedelic state resembles a deep dream-like trance; dreaming is known to facilitate memory compression and long-term memory potentiation (LTP). Any drug which facilitates extended dream-like states should also facilitate memory compression, LTP, and neuroplasticity.

In programmatic terms the hallucinogenic interrupt can be thought of as a back-door or reboot mechanism that allows the subject to enter a visually driven ego programming and debugging matrix; this state would be similar to hypnosis mixed with an element of lucid dreaming or creative visualization. To stretch the computer metaphor further, in the absence of hypnotic suggestion or shamanic control, the psychedelic debugging matrix will naturally drop into a maintenance mode where anxieties are brought to the fore like a screen-saver programmed to browse through repressed salient forms arising within chaotic patterns. All of these programmatic metaphors for psychedelics are accurate, and all imply a spontaneous cataloging, compression, or re-organization of existing synaptic memory via nonlinear eidetic emotional cues; this implies synaptic testing, bonding, and neuroplasticity.

Physiology of psychedelic neuroplasticity

Hallucinogens which target the 5-HT2A receptor can influence cellular functioning via the activation of G proteins and secondary messengers. The signaling pathways mediated by the 5-HT2A receptor include the activation of PKC and MAPK, protein kinases which energize enzymes to perform complex cellular maintenance. The activation of PKC undoubtedly plays an active role in the production and maintenance of long term memory. Evidence shows that inhibiting PKC activation in the cortex for as little as a few hours can cause the rapid erasure of long-term memory associations. It is obvious that this kinase is a fundamental part of memory formation and retention, and it is not unreasonable to assume that drugs which stimulate PKC activity may enhance or alter the processes of memory formation, recall, retention, and plasticity.

The processes by which PKC mediates memory associations is still unknown, but the primary assumption is that PKC interacts with diglycerides (DAG) at the intracellular membrane to mark energetic signaling areas for receptor formation and synaptic strengthening. The secondary signaling cascade goes like this: The 5-HT2A receptor is stimulated, activating phospholipase C (PLC) in the cell membrane, which then chops a phospholipid (PIP2 or PI) at the membrane into an IP3 group and DAG. The DAG stays near the membrane while IP3 activates the release of Ca2+ from the endoplasmic reticulum, which then activates PKC, which allows PKC to carry energy back to the cell membrane near the DAG site before activating other enzymes and intracellular substrates. PKC performs its job by moving phosphate groups around the cytoplasm and activating cellular enzymes such as adenosine which forms into AMP, ADP, and ATP by carrying phosphate groups in chains of up to three at once, allowing metabolic energy to move to other sites throughout the cell. The addition and removal of phosphates to and from proteins is a fundamental part of all organic metabolic processes; 5-HT2A agonists stimulate this phosphorylation process through PLC, IP3, Ca2+, and subsequent PKC activation.

The fact that 5-HT2A agonists stimulate PKC and fundamental metabolic processes indicates a strong case for psychedelic neuroplasticity. It is interesting to note that Salivinorin A, from Salvia divinorum, also appears to activate these same phosphorylation pathways through the k-Opiod receptor. And, of all the hallucinogenic compounds that occur in nature, psilocybin (found in magic mushrooms) is the only one that comes with its own phosphate group, and it also appears to be the weakest tryptamine agonist at the 5-HT2A receptor. While it is tempting to assert that PKC phosporylation is at the root of all hallucinogenesis and psychedelic effect, it has been demonstrated that 5-HT2A mediated PI hydrolosis is not always a good indicator of psychedelic potency. Although there are multiple factors responsible for hallucinogenesis, psychedelic stimulation of PKC activity undoubtedly plays a role in perturbing and stimulating persistent memory functions and promoting potential potent neuroplasticity.

Other research indicates that LSD activates intracellular mechanisms to promote expression of genes responsible for encoding c-Fos and Arc proteins, particularly in the pre-frontal cortex (PFC). c-Fos is essential to cell proliferation, differentiation, and cellular defense, while Arc (activity-regulated cytoskeleton-associated protein) regulates the structure and plasticity of neural cytoskeleton architecture, the very scaffolding which maintains neural shape and stability. By activating expression of c-Fos and Arc proteins in PFC neurons, LSD may promote plasticity, cell proliferation, cell repair, and synaptic generation in neurons responsible for identity. Presumably any selective 5-HT2A agonist will produce similar results, making hallucinogenic tryptamines primary candidates for cellular signal strengthening and identity-based neuroplasticity.

Positive and negative plasticity

Shamanic transformation may stimulate neuroplasticity by helping the subject realize a more transcendent or spiritually integrated vision of themselves. The logic follows that transformation of the inner self will then reinforce positive personality traits and drive outer behavioral changes to synchronize with inner idealization. The shamanic transformation is not instantaneous, but instead follows an integrative process of synaptic testing and reinforcement over a period of days to weeks. Some psychedelic therapy stimulates neuroplasticity using techniques similar to the ten-step program employed by Alcoholics Anonymous (AA), where the subject takes a clinical inventory of their life and behaviors and assesses each area where they need forgive, accept, or make changes. In psychedelic therapy the process of uncovering and working through maladaptive pathways is called catharsis; the process of wiring new synaptic pathways and reinforcing new behaviors is called integration. These are examples of positive psychedelic plasticity used to maximize positive social integration. These processes are sometimes slow and require an amount of mental discipline and behavioral follow-through for success.

There are many examples of negative psychedelic neuroplasticity. Renegade schools of ayahuasca sorcery and witchcraft employ some of the most elaborate and lethal mind-games ever devised, including the constant fear of attack by rival sorcerers through poisons, curses, dream invasion, and magical darts that may induce paralysis, cancer, death, or insanity. The traditional shaman's constant stress of exposure to the effects of black magic mirrors paranoid psychosis and post-traumatic stress disorder; this implies negative plasticity. Exposing any subject to extended and repeated psychedelic sessions may force stress-driven neuroplasticity associated with PTSD, torture, isolation, and sensory deprivation. Psychedelics may speed techniques of ego deprogramming and imprinting associated with brainwashing or cult-indoctrination; this implies mind control and negative neuroplasticity. Psychedelics may aid in imprinting or reinforcing delusional, messianic, paranoid, sociopathic, antisocial and megalomaniacal identity traits; this also implies negative neuroplasticity.

Tribal imprinting and viral neuroplasticity

One of the most interesting aspects of psychedelic experimentation is that psychedelics can catalyze spontaneous organization of tribal subcultures and grassroots political movements. According to PIT, if you destabilize the top-down regulating influence of culture within a small group of peers, energetic nonlinear tribal organizations will spontaneously emerge within those groups. History has demonstrated that if you sprinkle LSD over a city then flower children will blossom and begin to reproduce. But close observation of modern psychedelic subcultures reveals that radical identity reinvention is not a function of spiritual freedom or political subversion, but is more a viral form of tribal bonding and indoctrination. For example, the hippies of 1960s and the ravers of 1990s each preached freedom and individuality, yet each culture had strictly controlled tribal uniforms, politics, musical styles, rituals, and so on, and ostracized outsiders as being un-hip. This indicates that psychedelic identity reinvention is not a function of freedom of expression or social liberation, but is instead driven by the typical rewards of social elitism, the fears of being ostracized, and the reinforcements of tribal acceptance; all of which strongly affect identity-based neuroplasticity. Presumably any tribe, cultural group, religion, cult, or government can employ psychedelic neuroplasticity to similar social organizing effect.

 
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Psychedelic drugs change the structure of neurons*

by Peter Hess | INVERSE | Jun 13 2018

The brain is continually reorganizing itself by forming new neural connections throughout life. This phenomenon is known as Neuroplasticity.

Psychedelic drugs - LSD, DMT, and psilocybin - have shaken off a lot of their stigma and reputation as party drugs in the past few years, as scientists begin to investigate their significant healing potential for people with mental illness. Similarly, the drug ketamine, best known as a rave drug, has also shown promise in rapidly treating medication-resistant depression, and like psychedelics, its effects persist after treatment has ended.

New research shows that the way psychedelics repair the brain is very similar to ketamine’s action, which could pave the way for a future class of fast-acting drugs to treat conditions like depression, post-traumatic stress disorder, and substance use disorders. In a paper published Tuesday in the journal Cell Reports, a team of researchers showed evidence that psychedelic drugs can induce structural changes in nerve cells — a trait called Neuroplasticity — that could, in turn, help repair brain dysfunction in people with mood and anxiety disorders.

“Psychedelics are some of the most powerful compounds known to impact brain function so I was very interested to know what their mechanisms of action are,” David Olson, Ph.D., an assistant professor of biochemistry and molecular medicine at UC Davis and the corresponding author on the study, tells Inverse. "This paper adds to the on growing body of psychedelic neuroscience research by showing some of the changes induced by psychedelics."

Through experiments conducted on cultured rat neurons, as well as the actual brains of fruit flies and rats, Olson and his colleagues found that LSD, DMT, and DOI (2,5-dimethoxy-4-iodoamphetamine, a potent psychedelic amphetamine) increased the number of dendrites (branches) in nerve cells, increased the density of dendritic spines (protrusions on dendrites that help the neurons receive input from other cells), and increased number of synapses (functional connections between neurons). Altogether, these findings suggest that psychedelics induce structural changes to the brain, which Olson says can help treat mental illness.

“The structure of neurons affects their function, and in the case of a lot of neuropsychiatric diseases, particularly mood and anxiety disorders, these are characterized by an atrophy of neurons in the prefrontal cortex, a key brain region that regulates emotion, fear, and reward,” says Olson. “Finding compounds that promote growth of those neurons we might enable us to repair the circuits are damaged in those diseases.”

Since prefrontal cortex helps control other areas of the brain involved in fear, anxiety, and reward, says Olson, it’s a critical region for the treatment of depression, PTSD, and substance use disorders.

But Olson and his co-authors aren’t just interested in using psychedelics to treat patients. They hope to use psychedelic compounds as tools to dig down into the biochemical signaling pathways that lead to the Neuroplasticity observed in this study. By identifying the specific ways in which psychedelics act on the nervous system, Olson and his colleagues hope that they can develop a new generation of drugs that will replicate — or improve upon — the rapid, long-lasting healing effects of ketamine and psychedelics, but without the potential for abuse or challenging experiences.

“That’s the ultimate goal: to use psychedelics as inspiration for better medicine,” Olson says.

Of course, this is just one snapshot of the neuronal changes induced by psychedelics, so further research will be necessary to find out long-term effects on brain function.

“Plasticity is not universally a good thing. We were hoping to induce plasticity in prefrontal cortex, which can be potentially useful for treating mood and anxiety disorders, but promoting plasticity in other parts of the brain, like the amygdala can induce anxiety,” says Olson. “It’s very unclear what the risks are right now.”

 
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Rethinking serotonin could lead to a shift in psychiatric care

Imperial College London | Sep 4, 2017

A better understanding of how a key chemical messenger acts in the brain could lead to a radical shift in psychiatric care, according to a new research paper.

Serotonin is a neurotransmitter which helps brain cells communicate with one another, playing important roles in stabilising mood and regulating stress.

Despite its importance, current models to explain serotonin's function in the brain remain incomplete.

Now, in a review paper published this month in the Journal of Psychopharmacology, researchers from Imperial College London suggest that serotonin pathways are more nuanced than previously thought.

They argue that the existing view should be updated to incorporate a 'two-pronged' model of how serotonin acts.

The researchers believe their updated model could have implications for treating recalcitrant mental health conditions, including depression, obsessive compulsive disorder and addiction, and could exploit the therapeutic potential of psychedelic drugs.

In the brain, serotonin acts via a number of sites called 'receptors' and serotonin has at least 14 of these. Brain drugs such antidepressants, antipsychotics and psychedelics are known to interact with serotonin receptors and two of these are thought to be particularly important -- the so-called serotonin 1A and 2A receptors.

For patients with depression, commonly prescribed drugs called SSRIs (Selective Serotonin Reuptake Inhibitors) can help to relieve symptoms by boosting levels of serotonin in the brain. Evidence suggests an important part of how they work is to increase activity at the serotonin 1A receptor, which reduces brain activity in important stress circuitry, thereby helping a person cope better.

In contrast, psychedelic compounds such as LSD and psilocybin (the psychoactive component of magic mushrooms), are thought to act primarily on the serotonin 2A receptor. Accumulating evidence suggests that psychedelics with psychotherapy can be an effective treatment for certain mental illnesses and, with a focus on the 2A receptor, the authors' paper attempts to explain why.

Writing in the review paper, the researchers say that while the traditional view of developing psychiatric treatments has been focused on promoting 1A activity and often blocking the 2A, the therapeutic importance of activating the 2A pathway -- the mechanism by which psychedelics have their effect -- has been largely overlooked.

"We may have got it wrong in the past," said Dr Robin Carhart-Harris, Head of Psychedelic Research at Imperial and lead author on the paper. "Activating serotonin 2A receptors may be a good thing, as it makes individuals very sensitive to context and to their environment. Crucially, if that is made therapeutic, then the combination can be very effective. This is how psychedelics work -- they make people sensitive to context and 'open' to change via activating the 2A receptor."

According to the researchers, the 1A and 2A pathways form part of a two-pronged approach which may have evolved to help us adapt to adversity. By triggering the 1A pathway, serotonin can make situations less stressful, helping us to become more resilient. However, they argue that this approach may not always be enough, and that in extreme crises, the 2A pathway may kick in to rapidly open a window of plasticity in which fundamental changes in outlook and behaviour can occur.

Growing evidence shows that in conditions such as treatment-resistant depression, obsessive compulsive disorder and addiction, certain brain circuitry may become 'stamped in' and resistant to change. The researchers suggest that in such cases, activating the 2A pathway -- such as through psychedelics -- could potentially offer a way to break the cycle, helping patients to change negative behaviours and thought patterns which have become entrenched.

By enabling the brain to enter into a more adaptive or 'plastic' state and providing patients with a suitably enriched clinical environment when they receive a drug treatment, clinicians could create a window for therapy, effectively making patients more receptive to psychotherapy.

According to the authors, their updated model of how serotonin acts in the brain could lead to a shift in psychiatric care, with the potential to move patients from enduring a condition using current pharmacological treatments, to actively addressing their condition by fundamentally modifying behaviours and thinking.

Professor David Nutt, Director of Neuropsychopharmacology in Imperial's Division of Brain Sciences, explained: "This is an exciting and novel insight into the role of serotonin and its receptors in recovery from depression that I hope may inspire more research into develop 5-HT2A receptor drugs as new treatments."

Dr Carhart-Harris added: "I think our model suggests that you cannot just administer a drug in isolation, at least certainly not psychedelics, and the same may also true for SSRIs. We need to pay more attention to the context in which medications are given. We have to acknowledge the evidence which shows that environment is a critical component of how our biology is expressed."

He added: "In psychiatry, as in science, things are rarely black and white, and part of the approach we're promoting is to have a more sophisticated model of mental healthcare that isn't just a drug or psychotherapy, it's both. I believe this is the future."

'Serotonin and brain function: a tale of two receptors'
by Robin Carhart-Harris and David Nutt is published in the Journal of Psychopharmacology.

https://www.sciencedaily.com/releases/2017/09/170904093724.htm
 
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Can ayahuasca prompt neurogenesis?

The Psychedelic Scientist | 15 April 2018

The past few months has seen an explosion of research into the therapeutic potential of ayahuasca, the traditional psychoactive brew used by indigenous South American peoples for generations. It’s now looking highly compelling that doses of the plant-based drink have antidepressant qualities, and could also be used to combat addiction and PTSD.

Earlier last year, the announcement that scientists had discovered a potential mechanism for ayahuasca’s antidepressant properties was met with great anticipation. Researchers reported that under laboratory conditions several compounds found in ayahuasca could encourage the growth of new brain cells. Since that announcement, we’ve been excited about getting our hands on the full study!

The researchers, partially funded by the Beckley Foundation, decided to investigate whether components of the ayahuasca brew could encourage the growth of new brain cells (neurogenesis). Many effective treatments for depression (such as fluoxetine, pirlindole, and even electroconvulsive therapy) promote neurogenesis in the brain, and this likely contributes to their therapeutic benefit.

If scientists could show that ayahuasca promotes neurogenesis in laboratory conditions, it would reveal a potential biological mechanism for the brew’s antidepressant effects.



Growing neurospheres with ayahuasca

In the study, the scientists took stem cells from the brains of adult mice and grew them in the lab. The well-established technique involved encouraging the stem cells to form “neurospheres,” which provide an environment where the cells are free to develop into fresh new neurons. It’s not a perfect model, but it gives us a good idea of how these cells would behave in an adult human brain.

The researchers grew the neurospheres in the presence of several compounds found in ayahuasca: harmine, THH, and harmaline. These are all extracts of the Banisteriopsis caapi vine. In the presence of these compounds, the neurospheres grew bigger than when in the presence of a control solution, suggesting that the ayahuasca compounds were encouraging the growth of the stem cells. In addition, the stem cells within the neurospheres began to migrate (an important step before stem cells can start to turn into new neurons) faster when in the presence of ayahuasca compounds, compared to controls.

When grown with ayahuasca compounds, the stem cells in the neurospheres also began to differentiate (change their properties) to resemble neurons more effectively than under control conditions. This means that the stem cells started to lose their stem-cell-like properties, and started making proteins that are found in adult neurons.

Overall, it seems that exposing neural stem cells to harmine, THH, and harmaline encourages them to grow and change into new neurons more effectively than under control conditions.

Could this mean that ayahuasca is stimulating the birth of new brain cells when humans ingest it? Could this be the root of ayahuasca’s antidepressant properties?

For us to know for certain, there will have to be further studies. We’ll have to compare these findings to other antidepressants, so we can understand how powerful the neurogenic effects of harmine, THH, and harmaline are relative to other treatments. We’ll also want to see if we can get the same results using human cells rather than mouse cells, to make the findings more relevant.



What about the other components of ayahuasca?

Although the compounds used in this study (harmine, THH, and harmaline) are the most prevalent alkaloids in ayahuasca brews, they’re arguably not the most psychoactive components. DMT, found in many plants that are often included in ayahuasca preparation, is a powerful psychedelic compound that almost certainly has a crucial role in the psychological effects of ayahuasca.

It’s possible that the antidepressant effects of ayahuasca seen in human studies comes down to a combination of increased neurogenesis from the components of the B. caapi vine, and the spiritual benefits of a profound psychedelic experience induced by DMT. Multiple studies into the therapeutic effects of psychedelics have shown that the biggest positive changes are seen in patients who report the most profound spiritual experiences.

https://thepsychedelicscientist.com/...-neurogenesis/




Therapeutic potentials of ayahuasca: The possible role of DMT in tissue protection and neuroregeneration

Ede Frecska - Department of Psychiatry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

While DMT is a substance which produces powerful psychedelic experiences, it is better understood not as a hallucinogenic drug of abuse, but rather an agent with significant adaptive mechanisms such as neuroprotection, neuroregeneration, and immunity.

From a biological standpoint the extent to which DMT and harmine play a role in ayahuasca effects is difficult to judge since the brew contains a significant amount of bioactive substances in addition to the indole and β-carboline alkaloids. An important example of such compounds is the group of antioxidant polyphenols, which can also be linked to the observed immunomodulatory effects. Antioxidants are known for their capacity of reducing inflammatory processes or even stopping them. Malignant transformation is also inhibited by polynucleotides through providing protection against oxidative stress for other cellular compounds. In addition to the immunomodulatory effects, ayahuasca may also exhibit neuroprotective and neurorestorative qualities.

Hence, it has been suggested that ayahuasca can be applied therapeutically in Parkinson’s and other neurodegenerative diseases. Ayahuasca’s high content of bioactive materials points toward a combined mechanism of the various effect and the need for further clinical research to reveal the detailed pharmacology of its constituents.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4773875/
 
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Treating neurodegenerative disorders with cannabinoids

by Cornerstone Wellness | 17 Sep 2014

Neuroinflammation is known to play a significant role in essentially all neurodegenerative processes. Diseases such as Alzheimer’s, Multiple Sclerosis (MS), Huntington’s Disease, and Parkinson’s Disease all involve hyperactive microglia, which are the live-in macrophages of the brain, spinal cord, and central nervous system. Macrophages are immune cells that capture and dissolve foreign substances, germs, and cancer cells within the body. The microglia in the brain and spinal cord form the first line of immune defense in the central nervous system. Unfortunately, in the case of aforementioned diseases, these cells have become overactive causing them to secrete excess substances, such as cytokines (cell signals that regulate cell group growth and response), glutamate, and harmful free radicals. This excessive production of chemicals causes inflammation, which leads to further cell death.

Cannabis and the family of chemicals it produces are known to act on two major cell receptor types named CB1 and CB2 respectively. The CB1 receptor is most commonly found in neurons throughout the brain. The psychedelic effects of cannabis come from this receptor’s function, which re-wires the way neurons signal each other. The CB2 receptor on the other hand, is found throughout the body, especially within the immune system cells. The effects of activating the CB2 receptor are more myriad, but within the immune system specifically four groups of effects have been identified:

1. Induction of apoptosis or forced cell death

2. Suppression of cell proliferation

3. Induction of regulatory T cells

4. Inhibition of pro-inflammatory cytokine/chemokine production and increase in anti-inflammatory cytokines

The last of these effects is the basis upon exploring using cannabinoids to halt the progress of neurodegenerative disorders. The idea is that if cannabinoids can prevent excess production of cytokine, inflammation will decrease, and the resultant cell death around that inflammation will not occur. This would go a long measure toward slowing progression of neuro-inflammatory diseases. However, it is important to note that tempering inflammation would still not allow the brain to recover to its pre-disease state and slow neural damage would inevitably continue to occur. Likewise, modern medicine currently utilizes a variety of treatments in these diseases as more or less palliative care.

Based on these observations, research groups worldwide have been testing specific cannabinoids and other CB2 agonists with various models of neuro-inflammatory disease, generally in rodents.

The following is a general review of effects noticed, grouped by disease:

Alzheimer’s Disease – In Alzheimer’s cannabidiol has been shown to “reduce the transcription and expression of pro-inflammatory molecules in the hippocampus of an in-vivo model of induced neuroinflammation”. The hippocampus is the part of the brain that controls conversion of memory from short to long-term and controls spatial navigation. In Alzheimer’s, it’s one of the first areas of the brain to suffer damage and why patients have memory problems. Another agonist, which has the name SR141716A, also prevents amnesia induced by certain peptides, so these both promise a future in treating the disease.

Parkinson’s Disease – In this disease, the agonist WIN55,212-2 has been shown to protect mouse neurons from the neurotoxin MPTP, which is the chemical which leads to the death of dopaminergic neurons and causes Parkinson’s Disease.

Multiple Sclerosis (MS) – Although the cause of MS is unclear, researchers have determined that both genetic susceptibility and environmental trigger play a role. Some patients develop their symptoms of MS after contracting a virus. Likewise, testing rodents injected with a virus that intentionally lead to animal models of MS provided ground to investigate the effects that CB2 agonists might have on MS in humans. As is, cannabis concentrate is already prescribed under the name Sativex to alleviate neuropathic pain, spasticity, and overactive bladder symptoms associated with MS. Although some agonists did increase symptoms, several, including THC, delayed onset and reduced severity of symptoms. Three agonists, WIN55,212-2, ACEA, and JWH-015 were shown to improve motor function by attenuating microglia and immune cell infiltration into the spinal cord.

Exactly how these effects are achieved is still unknown. Although it is presumed that the effects of the CB2 agonists (any molecules that can activate CB2 receptors, including cannabinoids) stem from CB2 receptor activation, other theories have been proposed. One research group at the University of Bari has explored the extra-cannabinoid receptor binding activity of cannabidiol (CBD). Researchers there found that CBD can surprisingly communicate with the nucleus of the cell directly through interaction with nuclear hormone receptors. There are several possible chemical pathways through which cannabinoids can achieve their effects, beyond CB2 receptors. Further research will illuminate these pathways.

https://cornerstonecollective.com/ho...der-treatment/
 
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Serotonin and brain function: a tale of two receptors*

Carhart-Harris, Nutt (2017)

Previous attempts to identify a unified theory of brain serotonin function have largely failed to achieve consensus. In this present synthesis, we integrate previous perspectives with new and older data to create a novel bipartite model centred on the view that serotonin neurotransmission enhances two distinct adaptive responses to adversity, mediated in large part by its two most prevalent and researched brain receptors: the 5-HT1A and 5-HT2A receptors.

We propose that passive coping is mediated by postsynaptic 5-HT1AR signalling and characterised by stress moderation. Conversely, we argue that active coping is mediated by 5-HT2AR signalling and characterised by enhanced plasticity (capacity for change). We propose that 5-HT1AR-mediated stress moderation may be the brain’s default response to adversity but that an improved ability to change one’s situation and/or relationship to it via 5-HT2AR-mediated plasticity may also be important – and increasingly so as the level of adversity reaches a critical point. We propose that the 5-HT1AR pathway is enhanced by conventional 5-HT reuptake blocking antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), whereas the 5-HT2AR pathway is enhanced by 5-HT2AR-agonist psychedelics. This bipartite model purports to explain how SSRIs and psychedelics that modulate the serotonergic system in different ways, can achieve complementary adaptive and potentially therapeutic outcomes.

The function of brain serotonin

Here we suggest that the principal function of brain serotonin is to enhance adaptive responses to adverse conditions via two distinct pathways: (1) a passive coping pathway which improves stress tolerability; and (2) an active coping pathway associated with heightened plasticity, which, with support, can improve an organism’s ability to identify and overcome source(s) of stress by changing outlook and/or behaviour. Crucially, we propose that these two functions are mediated by signalling at postsynaptic 5-HT1A and 5-HT2A receptors respectively, with 5-HT1AR signalling dominating under ordinary conditions but 5-HT2AR signalling becoming increasingly operative as the level of adversity reaches a critical point.

We suggest that the two functions of interest (5-HT1AR-mediated stress relief and 5-HT2AR-mediated plasticity) are sufficiently distinct – and may even be mutually oppositional in certain contexts, evoking dilemmas over whether it is better to passively endure or actively approach, and in so doing, initiate some sort of fundamental change – with the potential for major resolution. This rule may not be absolute however - the two functions may also be complementary, e.g. in the case of enhanced serotonin functioning with chronic SSRI use – or indeed with normal basal 5-HT functioning, facilitating improved endurance and plasticity.

Despite this complementarity, we do anticipate that conventional serotonergic antidepressants such as the SSRIs and classic psychedelics such as psilocybin may become competitive options for the treatments of certain disorders such as depression; most fundamentally because they work via distinct pathways, but also because they cannot easily be taken in combination, i.e. conventional antidepressants attenuate the characteristic psychological effects of psychedelics. SSRIs are established evidence-based treatments for anxiety and major depression, whereas psychedelics are experimental medicines in an early phase of development. However, if evidence supporting the therapeutic value of psychedelics accrues – as we anticipate, and it is increasingly shown that their therapeutic mechanisms are significantly distinct from those of conventional medications, then this will open-up new and potentially empowering options for patients and clinicians. For the brave new psychiatry of the future – that many would like to see – decisions about whether to passively endure or actively address, may become increasingly pertinent.

*From the article here: https://journals.sagepub.com/doi/10.1177/0269881117725915
 
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How psychedelics could help treat depression, with neuroscience*

by Greg Watry | UC Davis College of Biological Sciences | May 2 2019

Ask most people about the neurochemical origins of depression and you’ll likely hear how low serotonin levels are the cause. But today’s scientists know depression’s roots are more complex. One area of interest to them is the brain’s prefrontal cortex, a region responsible for motivational and goal-directed behavior.

“Without the right growth cues, the prefrontal cortex cannot communicate with other brain regions, and you can end up with depression,” said Lindsay Cameron, a neuroscience Ph.D. student.

“By stimulating growth in the prefrontal cortex, you are strengthening control over these other regions and restoring health.”

Cameron and other researchers at UC Davis are actively exploring drugs capable of spurring such neural growth and restoring health. And some dark horse candidates are psychedelics like LSD, psilocybin and DMT.

“Psychedelics can increase growth of neurons in the prefrontal cortex and they cause growth rapidly,” said Cameron, who was first author on an ACS Chemical Neuroscience study that showed microdosing rats with DMT can positively affect their mood and anxiety and a co-author on a Cell Reports study that showed psychedelics promote neural plasticity. “Psychedelics are some of the most powerful drugs out there and it’s ridiculous how little we know about them.”

According to Cameron, popular antidepressants, like SSRIs and SSNRIs, are designed with the serotonin hypothesis of depression in mind and are missing the mark for some patients. Research shows the drugs are about 70 percent effective, tend to lose their potency and can be slow-acting, taking weeks to kick in.

“We need a fundamentally new way of tackling these diseases,” said Cameron. “That’s what I am hoping to do with my Ph.D.”

“Lindsay is the kind of student that every principal investigator hopes to work with,”
said Assistant Professor David Olson, Department of Chemistry. “She has a voracious appetite for knowledge, is intensely curious and is driven to make discoveries that will benefit the world. Students like Lindsay are really the lifeblood of academic research.”

Opening the doors of scientific perception

The basis of Cameron’s curiosity is a desire to develop tools that’ll fix the body when its systems go haywire. She traces her interest in physiology back to her parents, who both worked in the healthcare industry.

While pursuing a degree in pharmacology at McGill University, Cameron learned how various drugs travel through and affect the body. She was particularly drawn to brain-altering drugs, delving into the largely marginalized scientific literature available on psychedelics and their effects on brain chemistry.

Following graduation, Cameron entered the workforce to pay off her bachelor’s degree debt before pursuing graduate school. She worked as a research assistant, an optometric assistant and at a health food store. She wound up at UC Davis after accepting a junior specialist position in the lab of Professor Hwai-Jong Cheng, who holds appointments in the Department of Neurobiology, Physiology and Behavior, Center for Neuroscience and the School of Medicine.

“Dr. Cheng really helped me figure out how to approach scientific problems,” said Cameron. “By the time I got into grad school and I started, I had a leg up of where I would’ve been right out of undergrad, so I’m really glad I ended up taking those years off.”

By the time Cameron enrolled in the Neuroscience Graduate Group, psychedelic research had fallen off her radar. She then attended a presentation given by Olson. The Olson Lab specializes in chemical neuroscience, specifically focusing on psychoplastogens, an Olson Lab-coined term that refers to the small molecules like psychedelics that promote neural plasticity.

“I chased him out of the building and I was like, ‘Are you taking students?’” recalled Cameron.

Microdoses, big implications

There’s a trend hitting the coast. Peruse Los Angeles Magazine or The Atlantic and you’ll read about people singing the praises of microdosing.

“It’s people taking really small doses of psychedelics without any hallucination effects every couple of days. People are saying anecdotally that it helps them with depression and anxiety. It’s increasing their sociability and their creativity at work,” said Cameron. “They’re basically saying it’s enhancing cognitive function.”

Such anecdotes led to experiments. Cameron and her Olson Lab colleagues administered microdoses of DMT to rats and measured the molecule’s effects on the rodents’ depression and anxiety behaviors.

To measure the antidepressant properties of psychedelics, the team performed a “swim test,” a staple rodent behavioral test for evaluating antidepressant drugs. During the test, researchers place a rodent in a small, water-filled tank after dosing the animal with either a psychedelic molecule or a placebo for a set period of time. Rodents with depression and anxiety-like symptoms typically just free-float in the water, but rodents dosed with DMT showcased motivational behavior, which in this case is swimming.

“This is one of the main tests generally used in the field and it’s been shown to correlate really well with if a drug will have antidepressant effects in humans or not,” said Cameron.

This is your brain on drugs

The team also tests the effects of psychedelics on the brain through neuronal cultures. Neurons from the prefrontal cortex are placed in a dish and then treated with a psychedelic molecule.

“What psychedelics and the novel therapeutics that we develop do is they specifically target neurons in the prefrontal cortex and they make them grow,” said Cameron. “Synapses are the connections between the cells and psychoplastogens increase the number of these connections.”

“The neurobiology of depression is directly linked to the neurobiology of plasticity,”
added Olson. “As psychedelics are among our most powerful tools for promoting neural plasticity, we can use them to elucidate the biochemical signaling pathways that give rise to plasticity, and in the process, gain insight into potential strategies for treating depression and related disorders.”

For Cameron and Olson, psychedelics are too powerful to ignore, but their stigmatization in popular culture, not to mention their illegality at the federal level, has hindered research. To mine the potential benefits of these psychedelics, scientists like Cameron and Olson need to perform more research. But doing so requires navigating the rocky terrain of public opinion.

Fortunately, perceptions are changing. The limitations of available pharmaceuticals in treating mood disorders is ushering in a new wave of scientific inquiry into psychedelics.

“The data that’s out there is remarkable and I think that if you can get past the stigma that’s associated with psychedelics, research into their therapeutic effects may yield important discoveries,” said Cameron. “When using these compounds in research, there is a need to be professional and treat it like any other science. Psychedelic compounds are important tools that I am using to understand the basic neurobiology of depression.”

*From the article here :
 
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This figure shows the effects of three psychedelics and one control (VEH) on cortical neurons.

Sprucing up your brain with potent psychedelics

A new study, published June 12 in the journal Cell Reports, found psychedelics, specifically DOI, DMT, and LSD, can change brain cells in rats and flies, making neurons more likely to branch out and connect with one another. The work supports the theory that psychedelics could help to fight depression, anxiety, addiction, and post-traumatic stress disorder.

“One of the hallmarks of depression is that the neurites in the prefrontal cortex — a key brain region that regulates emotion, mood, and anxiety — those neurites tend to shrivel up,” says Olson. These brain changes also appear in cases of anxiety, addiction, and post-traumatic stress disorder.

Psychedelics are not the most popular drugs for treating depression, but as we better understand how they promote the growth of new dendrites and synapses, we should be better able to develop safer and more effective antidepressants to accomplish the same effect.

More from Cell 12 June 2018:

Neuropsychiatric diseases, including mood and anxiety disorders, are some of the leading causes of disability worldwide and place an enormous economic burden on society. Approximately one-third of patients will not respond to current antidepressant drugs, and those who do will usually require at least 2–4 weeks of treatment before they experience any beneficial effects (Rush et al., 2006). Depression, post-traumatic stress disorder (PTSD), and addiction share common neural circuitry and have high comorbidity.

Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse number and function, as measured by fluorescence microscopy and electrophysiology. The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clinical effectiveness of these compounds. Our results underscore the therapeutic potential of psychedelics and, importantly, identify several lead scaffolds for medicinal chemistry efforts focused on developing plasticity-promoting compounds as safe, effective, and fast-acting treatments for depression and related disorders.

Psychedelics promote structural and functional neural plasticity

The neuroplasticity described in the 12 June 2018 paper in Cell consists of “neuritogenesis,” or the growth of dendrites and synaptic buttons — providing a denser connectivity between neurons.

Another form of neuroplasticity which may take place under some conditions is “neurogenesis,” or the growth of stem cells which develop into neurons. In adults, this may occur in the hippocampus and along the ventricular lining of the brain.

The hippocampus is the region of the medial temporal lobes thought to play a prominent role in the retention of long term memories. More on hippocampal neurogenesis:

Here we assessed whole autopsy hippocampi from healthy human individuals ranging from 14 to 79 years of age. We found similar numbers of intermediate neural progenitors and thousands of immature neurons in the DG, comparable numbers of glia and mature granule neurons, and equivalent DG volume across ages. Nevertheless, older individuals have less angiogenesis and neuroplasticity and a smaller quiescent progenitor pool in anterior-mid DG, with no changes in posterior DG. Thus, healthy older subjects without cognitive impairment, neuropsychiatric disease, or treatment display preserved neurogenesis.

It is possible that some psychedelic mixtures may stimulate the transition of neural stem cells into functioning neurons:

When grown with ayahuasca compounds, the stem cells in the neurospheres also began to differentiate (change their properties) to resemble neurons more effectively than under control conditions. This means that the stem cells started to lose their stem-cell-like properties, and started making proteins that are found in adult neurons.

Overall, it seems that exposing neural stem cells to harmine, THH, and harmaline encourages them to grow and change into new neurons more effectively than under control conditions.

This is all very controversial

Many neuroscientists still doubt that adult human brains can generate new neurons past adolescence. Proving that psychedelics can promote the growth of new neurons in the brain (e.g. hippocampus) will take some time, and perhaps a somewhat different perspective on neuropharmaceutical ethics than is dominant at this time.

It is less controversial to pursue the use of ketamine derivatives to promote new “branching” of existing neurons. But ketamine does not seem to be as effective at neuritogenesis as LSD, DMT, or psilocybin. In other words, some old prejudices may need to fall in order to achieve a better solution to an age-old scourge of the human spirit.

Here at the Al Fin Institutes of Neuroscience, we prefer the use of occasional treatments for chronic ailments over the everyday medication of persons. As people age, their ailments may tend to accumulate — as do the number of treatments required. Many persons may take as many as 10 to 20 medication doses per day. The use of psychedelics or psychedelic analogs for treating depression would likely be of an intermittent nature, rather than daily, and would help to cut down on the total daily dosage regimen.

We actually prefer to avoid medication altogether

If possible, the avoidance of pharmaceuticals is best. Electromagnetic or photic approaches to treating depression are preferred, as are other alternatives such as advanced neurofeedback, mindfulness, and cognitive behavioural therapies.

Still, some people have experienced relief from depression lasting 6 months or longer from a single psychedelic experience, if well designed and overseen.

We have barely begun to understand all the productive approaches to functional neuroplasticity in the treatment of neurologic and neuropsychiatric disorders.

Renewed scientific interest in the use of psychedelics to treat disorders of the spirit can be seen as a positive sign.

https://alfinnextlevel.wordpress.com/2018/06/15/sprucing-up-your-brain-with-potent-psychedelics/
 
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DMT: The biosynthesis debate

by Shane O'Connor | PSR | Sep 11 2019

DMT is a psychedelic compound that belongs to the serotonergic class of psychedelics, including psilocybin and LSD. DMT, akin to all other serotonergic psychedelics, reliably evokes a multitude of subjective effects on brain functions such as cognition, perception and emotions.

In the last couple of decades, there has been much debate within the scientific community over whether the mammalian brain produces DMT endogenously. And if so, is the compound produced in sufficient quantities to initiate the remarkable psychoactive effects observed when administered exogenously? A debate has also ensued concerning the role of the pineal gland – a tiny neuroendocrine organ in the brain whose primary function is nighttime secretion of melatonin – in the synthesis of DMT. This article will give a brief overview of the history and current findings of DMT biosynthesis and will also aim to contextualize these findings.

Biosynthesis of DMT is dependent on the action of two enzymes, AADC) and INMT. First, the dietary amino acid tryptophan is converted to tryptamine via the action of AADC. Tryptamine then undergoes N, N-dimethylation. Following this, the synthesis of DMT from tryptamine requires double methylation reactions catalyzed by INMT.

A recent study that has garnered much media attention around the world demonstrated, for the first time, the co-expression of both IMNT and AADC in the cerebral cortex of the mammalian (rat) brain. This finding is crucial as it provides a credible process for endogenous synthesis of DMT in the mammalian neocortex. In fact, the research group detected DMT at slightly lower.

The study also shed light on the involvement of the pineal gland in the biosynthesis of DMT. The study did this by demonstrating similar levels of extracellular DMT in animals with or without the gland. These results suggest that biosynthesis of DMT is not dependant on the pineal gland.

Critics of Strassman have challenged the hypothesis that the pineal gland can produce enough DMT to induce an out of body experience. It would need to produce about 25 mg of DMT very rapidly (over the course of no more than a minute or two). The daily secretion of melatonin from the pineal gland is roughly 30 µg, about 0.001 of the weight of DMT needed to induce such “mystical” states. Taken together, the findings mentioned above suggest that the pineal gland lacks the ability to produce DMT at levels originally proposed by Strassman.

Frequently in science, experiments that produce robust results don’t resolve a debate but instead lead to more questions. Strassman’s claim that the mammalian brain has the capacity to endogenously synthesize DMT seem to have been substantiated. However, the same experiment appears to refute his claim that the pineal gland is the brain structure responsible for DMT synthesis. If anything, this experiment represents a stepping to stone, which will enable the scientific community to further our understanding of the complex pharmacodynamics of DMT. It is refreshing that in today’s scientific climate, the stigma of psychedelic research is slowly lifting, allowing for an evidence-based inquiry into such topics.

 
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