NEUROSCIENCE | +80 articles

[mr peabody]

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​

 

[mr peabody]

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​

 

[mr peabody]

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/​

 

[mr peabody]

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.​

How psychedelic drug psilocybin works on brain

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.

www.sciencedaily.com

 

[mr peabody]

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.

LSD and magic mushrooms could repair brain circuits 'shrivelled' by depression, finds study

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

www.independent.co.uk

 

[mr peabody]

Cambridge

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​

 

[mr peabody]

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.”

Psychedelic Drugs LSD and DMT Reshape Neurons, Showing Healing Potential

Psychedelics could show the way to a new generation of medicine.

www.inverse.com

 

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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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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 :

How Psychedelics Could Help Treat Depression with Neuroscience Ph.D. Student Lindsay Cameron

Quick Summary On the hunt for therapeutics to treat mood disorders, UC Davis researchers have turned to compounds found in psychedelics Neuroscience Ph.D. student Lindsay Cameron is on the forefront of this research Her research with the Olson Lab has shown that microsdosing rats with DMT...

biology.ucdavis.edu

 

[mr peabody]

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/​

 

[mr peabody]

The Neuroscience of Psychedelic Drugs
Your Brain on Psilocybin With Frederick Streeter Barrett

by Ruairi J Mackenzie | Technology Networks | 20 Dec 2019

Psychedelic drugs have long been exiled to the fringes of medicine, dismissed as recreational drugs with limited therapeutic potential. That all changed with the breakthrough therapy status granted last year to psilocybin, the active compound found in psychedelic mushrooms, for its ability to rapidly reverse treatment-resistant depression. This has led to an explosion of interest in the field, with new institutes opening and new disorders identified as targets for psychedelic therapy. In our latest interview series, we discuss the potential of psychedelics to revolutionize clinical neuroscience with thought leaders in the field.

Fred Barrett is an Assistant Professor of Psychiatry and Behavioral Sciences at Johns Hopkins University in Baltimore. In this interview, we discuss his work with the active component of magic mushrooms, psilocybin. Fred explains how this compound affects the brain, its potential to combat visceral pain, and its links to so-called mystical experiences.

Ruairi Mackenzie (RM): Could you tell us about psilocybin’s mode of action on the brain?

Fred Barrett (FB): This goes back to the very beginning of research for psychedelics, through the ‘70s and then ‘80s and ‘90s as well. People have been thinking about this for decades.

I think there are a couple of interesting hypotheses, but two in particular which are not necessarily independent or mutually exclusive hypotheses. One of the hypotheses was that psilocybin
-related drugs essentially alter thalamic gating. So, what the hell does that mean? Here’s a crash course.

The thalamus is almost like a switchboard for sensory information being transmitted to higher cortical areas. The thalamus acts as a gate if you will in many instances. It’s responsible for routing sensory information and in that duty it’s also responsible for holding back some sensory information. It’s often under the direction of higher prefrontal and executive cortices and so depending on what you need to pay attention to, the routing through the thalamus will change to attend to one or another sensory stimulus or modality. This is what happens in a normal healthy waking conscious brain.

Some of the experiences people have with psychedelics include an almost overwhelming sensorium and the cognition that you’re sensing things with psychedelics that you don’t normally sense. I’m hopefully not getting too scandalous by saying this but I think that if you were to really look for the “reducing valve” that Huxley was talking about, it would be the thalamus. It reduces the sensory information coming through to your cortex. The hypothesis was that psychedelics reduce the gating of the thalamus. They impair the thalamus’s reduction of sensory information and open the valve. That’s an interesting hypothesis; one of the things working against that hypothesis is that there are no serotonin 2A receptors in the thalamus [5-HT2A receptors are central to the action of psilocybin], but that’s okay because the thalamus undergoes top-down control from a number of other cortical regions that do have lots of serotonin 2A receptors.

One of those areas is the prefrontal cortex. Another theory that came up around this time was that psychedelics increase activity in the prefrontal cortices or they somehow inhibit the top-down control of the prefrontal cortices on other sensory and sub-cortical regions.

This is, like I said, not mutually exclusive, it could be that both are working together. It could be that. Evidence has been generated for both hypotheses. Studies back in the mid-'90s found evidence across several different psychedelic substances that there was a relative increase in frontal activity and a decrease in other cortical activity and most recently Katrin Preller, from Franz Vollenweider’s group, has published a couple of papers that have shown a vast alteration of the connectivity of the thalamus to other cortical brain regions. These are two hypotheses that seem reasonable. They’re not likely to explain everything that goes on with psychedelics but they are very likely to explain at least some of the sensory aspects as well as some of the feelings of loss of control that people experience when they’re under the acute effects of psychedelics, and some of the cognitive changes.

RM: Is there evidence that psilocybin could have a role in minimizing pain and suffering in illness?

FB: That’s the story that came out of some cancer studies that were published where the explicit aim to see if we could reduce suffering, emotional pain, psychological pain and suffering. That brings up an interesting additional potential pathway which is for the direct treatment of pain, like physical visceral pain. There are reasons to think that psilocybin and related drugs may have anti-nociceptive properties.

You can think of two obvious hypotheses why that might be, one is that there are some kind of biomechanical anti-nociceptive effects; maybe psilocybin alters ascending nociceptive pathways or alters periaqueductal gray, all the brain stem-mediated pain receptor-type mechanisms, that there’s some effect on these mechanisms that reduce pain. I collaborate with an anesthesiologist at the Bayview Medical Center here at Hopkins. When we first started collaborating and I told him what I was doing with psychedelics, he said, “Have you studied pain, because I’ve seen patients in the ER who say they’ve taken acid and they can’t feel a thing. They’re hitting their heads against the wall, maybe got into a car accident, they don’t feel anything!” Isn’t that fascinating? Frankly if we need people to be under the acute effects of psychedelics to have them not experiencing pain, then that may really limit the potential application of these drugs in pain reduction.

Another hypothesis; a big part of pain can be catastrophizing. To the degree that psychedelic drugs can alter our view of our relationship of the world around us, to the degree that psilocybin can reduce anxiety and put us at ease and allow us to be present and at peace with the state of our lives. That maybe reduce catastrophizing which can have a direct impact on pain and suffering. There are certainly some more psychological theories and hypotheses about what psychedelics are doing, a couple of theories that maybe psychedelics increase psychological flexibility. Maybe psychedelic experiences increase an individual’s insight into their life and their relationships. Maybe psychedelics allow people to identify and then jettison undesirable behaviors in their lives. All of these things can load on to the factor of reducing pain and suffering through lots of different ways. Researchers around the world I think are really piling onto this to see if the way they understand psychology and the way they understand the mind and their theories apply to psychedelics. It seems like all of these things may be at play so I think we have a really interesting future ahead of us in seeing what really shakes out.

RM: Could you briefly outline the relationship between psilocybin and mystical or religious experiences?

FB: Early on in the study of psychedelic experiences there were a number of people who seemed to think that there was a clear relationship between psychedelic experiences and what might be described as mystical experiences. It seems to me that mystical and religious experiences can be two different things. There’s a philosopher of religion, Walter Stace, who scoured all the literature he could find to try and identify examples of what might be a mystical experience. From that he developed a philosophical model of mystical experiences where he identified six or seven factors, depending on how you read it, of mystical experience.

These being:​

• Deeply felt positive mood​
• Sacredness​
• Reverence​
• Ineffability​
• Timelessness and spacelessness​
• Internal or external unity​

External unity being the feeling of oneness with everything around you and internal unity being a bit deeper in that with external unity you may still say, “I am one with everything” and then with internal unity, you say, “There is only one, there’s nothing, there are no differences.”

One of the early researchers in psilocybin was Walter Pahnke who was an investigator here in Maryland, at Spring Grove Psychiatric Centre and Maryland Psychiatric Institute. Walter wanted to understand if he could evoke religious experiences with psilocybin. Are you familiar with the Good Friday experiment? He conducted this experiment at the seminary associated with Harvard University and he recruited a number of seminary students. Before attending this Good Friday Mass, he gave half of the individuals in the study a high dose of psilocybin and the other half a high dose of Niacin and everybody went into church and participated in this Mass. There are lots of amazing features of the study.

There are a lot of completely problematic features of the study too, but after everybody got out of mass and came down from their experience, he had everybody complete a questionnaire to try and quantify in some way the dimensions of the experiences people had. He based this questions on Stace’s work. He asked questions that probed and targeted each of these potential features of mystical experience. His theory being that that’s what psychedelics do, they evoke a mystical experience, so why not put this in a religious context to maximize the potential that we get the experience in seminary students.

RM: Research was… different back then.

FB: Yeah, much different. An interesting point in our history is that one of the investigators at the time, in Spring Grove and Maryland Psychiatric was Bill Richards. There are lots of interesting digressions here we could go down but of course the psychedelic research program eventually closed. Bill went about his life as a therapist and when Roland Griffiths here at Hopkins reignited the psychedelic research, well started his first study he was fortunate enough to get Bill Richards to come and be the clinical director of that first study. Bill basically started, picked up where they left off. And so, since the beginning of our program we’ve been following that thread of using the framework of mystical experiences to describe the unique phenomenology of psychedelics.

It may have been a terrible error in marketing, in that the word mystical itself can bring up all kinds of misconceptions in people, “Oh it’s mystical, you can’t describe it. It’s something that can’t be described while you’re trying to study it, or mystical in a sense that it’s like the initiation of a religion, “Only a few can get to this place.” Or that it’s religious, you have to be a Judeo-Christian or be from a given tradition to understand it.”

It really, at its heart, transcends religious definitions and boundaries. A mystical experience, despite the scary-sounding name, is actually somewhat of an operationally-defined construct [meaning that the way it will be measured can be articulated] . In psychology we’re really excited about operational definitions. What’s your operation definition for attention? People will argue about that. Lots of people might be able to agree on basics. What’s your operational definition of memory? That’s a little bit more concrete. What’s your operational definition of decision making? These are things that you have to operationally define before you experimentally interrogate them.

We don’t ask people did you have a mystical experience? We have a questionnaire that systematically addresses each of the theoretical domains that Stace proposed. The original version of our questionnaire that we started using in 2000 hit all of Stace’s domains. More recently, Catherine McLean from survey data and I from experimental data did some real hardcore psychometric evaluation of the questionnaire and we pared it down at least from the way that the questions and responses behaved. It seems like there really are four factors. People who felt positive mood, ineffability, timelessness and spacelessness and a general what we call mystical factor which includes external, internal and sacredness questions.

We have this study and questionnaire. Every good psychologist has a questionnaire, right? It has good reliability; it has validity and has a nice, well-behaved factor structure. We use this as a heuristic framework for trying to describe the profound, wild experiences that people have with these drugs. We recently completed a [psychedelic dosing] study on individuals who have a long-term meditation practice and by and large these were people who were following Buddhist practices, although many of them wouldn’t self-identify as Buddhist because they didn’t like the idea of self-identifying as something. Certainly not Western Judeo-Christian or people of the book type of religious folk.

They were able to, without using the term mystical – a lot of them bristled at the term mystical – but they were able to complete this questionnaire in such a way that comported quite well and quite beautifully with all of the other responses we’ve got in other studies. So, do you believe in religion, do you believe in mystical experience? That doesn’t matter, fill this questionnaire out. Did your sense of time and space deteriorate. Were you able to orient yourself in space and time? Did you experience joy or peace or love? How well are you able to describe the experience using words? Can you agree with the following statements: I felt at one with everything around me; boundaries between self and other began to erode? Things like that. Yeah to all of them? Mystical experience.

Do we want to call it a religious experience? I mean people can have religious experiences with these drugs but I think at the end of the day what that really is, is an attempt by an individual who may have a religious predisposition to try to make sense of it using whatever language they have available to them, or whatever frameworks they have available to them. The interesting thing with that is that if you ascribe to a certain tradition, that doesn’t mean you’ll see imagery in your [psychedelic] session related to that image and that tradition. Christians have seen Hindu imagery, Hindus have seen Christian imagery, that’s a brief example.

We’ve recently completed a study that I wasn’t involved in with giving psilocybin to religious professionals, with the acknowledgement that many religious professionals experience some pretty deep and profound burnout in their ministry. The question being can psilocybin help people to recover from that burnout, reignite the faith?

There have been studies in this relationship between psilocybin and mystical experience or religious experience, I’d say from the very beginning. What we’ve found is that strength of mystical experiences as we’ve operationally defined it actually seems to mediate the effect of psilocybin on depression and anxiety. The statement really is that the subjective effects are important in realizing the therapeutic outcomes.

The Neuroscience of Psychedelic Drugs: Your Brain on Psilocybin With Frederick Streeter Barrett

Fred Barrett is an Assistant Professor of Psychiatry and Behavioral Sciences at Johns Hopkins University in Baltimore. In this interview, we discuss his work with the active component of magic mushrooms, psilocybin. Fred explains how this compound affects the brain, its potential to combat...

www.technologynetworks.com

 

[mr peabody]

RESEARCH INTO PSYCHEDELIC-ASSISTED THERAPY AND NEUROSCIENCE

Neuro Assessment & Development Center

Since 2006, the Third Wave of clinical research and therapeutic applications of psychedelics has been underway. Far from the recreational stigma, Psychedelics have evolved into an accepted treatment of significant issues. Microdosing has become an established method for dealing with ADHD, Depression, and Unlocking creativity. Anyone trapped by the old paradigms will be very surprised.

LSD versus placebo. Research investigating classic psychedelics as treatments for addiction was initiated in the first wave of classic psychedelic research in the mid twentieth-century, but was ultimately terminated as a result of misinformation, stigma, lack of funding, and legal proscription. For the most part, plant medicine and use of psychedelics is misrepresented. There is a taboo in society still. The outspoken work of Michael Pollan, Paul Stamets and many researchers has ushered us to the Third Wave, a tipping point where modern research and communication is informing the public. People are talking about the benefits, though often in corners and in whispers. Ancient and Sacred ceremonies by shamans have been part of every culture, though often demonized. This led to the First Wave of investigation and the discovery of LSD in 1938 by Albert Hoffman, a chemist working for a pharmaceutical company. The benefits evolved quickly and by the 1950's and 60's, the Scientific Method was applied to create the Second Wave. The clinical benefits of psychedelics were well established by research and clinical application was wide spread for those that suffered with Depression, Anxiety, PTSD, Addiction, and other debilitating conditions within major institutions and rehabilitaton centers. The research and clinical applications came to a crashing halt when recreational use and mind expansion efforts overtook clinical application. Psychologists such as Timothy Leary and Ram Dass at Harvard opened the floodgates with uncontrolled experimentation. Then the conservative Nixon-era shut down funding for research and created a negative stigma around these substances with false images and many exaggerations about deaths related to use. This scared the public and created the taboo. It is noted by many researchers that LSD and Psilocybin has no known lethal dosage level and is non-addictive.

It is noted that in the 60's, these drugs were classified as Schedule I, indicating they have a high potential for abuse, not currently accepted as a medical treatment, and lack safety even under the supervision of a doctor. We believe this is not correct and will be re-evaluated very soon. LSD and Psilocybin are about to enter Stage 3 Clinical Trials for Depression and Addicion, meaning that their status will have to change from Schedule I to Schedule III, with widespread clinical application around the corner. There needs to be an End to the Ban and a change in social thought. For further history and why these medicines have been demonized by government and pharmaceutical lobbies, the interested reader is referred to Michael Pollan's 2018 book How to Change your Mind. It likely will.

After remaining hidden for three decades, researchers began bringing Psychedelic Medicine out of the shadows in 2006. Griffiths 2006 study, funded by NIH, opened the doors to legitimate study once again. Many researchers are now investigating the benefits in double-blind trials with major funding. As of 2018, 50 U.S. based researchers hold Class I drug licenses from the DEA to investigate the benefits of LSD, Psilocybin, MDMA, Ketamine, Ayahuasca, and many other substances. Although there is still a taboo amongst the majority when the word "Psychedelic" is said, we believe that like Cannabis, the majority will see the benefits of Psychedlics very soon and that it will be legalized and used in therapeutic, under the guidance and supervision of doctors. The data from research is very hard to argue with. The effectiveness of LSD and Psilocybin to treat Depression and Addiction in research trials has reached rates as high as 80%, without a return of symptoms for six months. There are no treatments (medications or therapies) that come close to the effective benefit. Government will resist and society will remember the stigma. Pharmaceuticals will fight against, because their expensive medications are not as effective. But the conversation has become universal and the benefits are undeniable. This is why large scale studies are beginning and reseachers are opening their vision to the world.

Neuroscience and Psychedelic Research and Therapy

LSD, Psilocybin, Psychedelic-assisted therapy, mushrooms, Mind Expansion, Psychedelic Research and Therapy

www.neurodevelop.com

 

[mr peabody]

Hippocampal neurogenesis: The effects of psychedelic drugs

Briony J. Catlow, Ahmad Jalloh, Juan Sanchez-Ramos

Neurogenesis, or the birth of new neurons, occurs throughout the human life span in the hippocampus, a structural node in the neural circuitry responsible for memory and learning. The process of neurogenesis involves proliferation of neural stem/progenitor cells and their differentiation into mature neurons, followed by integration into hippocampal circuitry. The function of new neurons in the hippocampus is not completely understood. The formation of new synaptic connections (and pruning of synapses) between neurons in the hippocampal dentate gyrus and fibers to and from the cerebral cortex is important in the acquisition of new associations (learning), recall of those associations (memory), and extinction of associations (forgetting). Very likely, the new neurons play a role in encoding temporal aspects of episodic memory. Neurogenesis is influenced by many factors, including physical activity, stress, depression, seizures, irradiation, aging, and a variety of psychoactive drugs. Psychedelic drugs are shown to have an impact on hippocampal neurogenesis in a dose-dependent manner and to alter some aspects of memory and learning.

https://www.sciencedirect.com/science/article/pii/B9780128002124000777

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Alkaloids of B. caapi found to stimulate adult neurogenesis in vitro*

Jose Morales-Garcia, Mario de la Fuente Revenga, Sandra Alonso-Gil, Maria Isabel Rodriguez-Franco, Amanda Feilding, Ana Perez-Castillo, Jordi Riba

Banisteriopsis caapi is the basic ingredient of ayahuasca, a psychotropic plant tea used in the Amazon for ritual and medicinal purposes, and by interested individuals worldwide. Animal studies and recent clinical research suggests that B. caapi preparations show antidepressant activity, a therapeutic effect that has been linked to hippocampal neurogenesis. Here we report that harmine, tetrahydroharmine and harmaline, the three main alkaloids present in B. caapi, and the harmine metabolite harmol, stimulate adult neurogenesis in vitro. In neurospheres prepared from progenitor cells obtained from the subventricular and the subgranular zones of adult mice brains, all compounds stimulated neural stem cell proliferation, migration, and differentiation into adult neurons. These findings suggest that modulation of brain plasticity could be a major contribution to the antidepressant effects of ayahuasca. They also expand the potential application of B. caapi alkaloids to other brain disorders that may benefit from stimulation of endogenous neural precursor niches.

Due to their ubiquitous presence in ayahuasca, it can be hypothesized that the β-carbolines contribute to the CNS effects of the tea. Studies in animals have shown that harmine has antidepressant effects in behavioral animal models of depression. Responses after harmine in the forced swim and open field tests are analogous to those obtained with ayahuasca infusions prepared from B. caapi and P. viridis and containing DMT. These findings suggest that DMT is not essential for the behavioral responses observed in animals. Additionally, in contrast with more traditional antidepressants such as imipramine, harmine increases BDNF levels in the hippocampus after both acute and chronic administration. These data suggest that harmine and potentially the other β-carbolines present in B. caapi contribute to the therapeutic effects of ayahuasca observed in clinical studies involving patients with depression.

At the cellular level, antidepressant drug action has been linked to the ability of drugs to stimulate adult neurogenesis. Neurogenesis is the process of generating functional neurons from progenitor cells. In the adult brain of mammals, neurogenesis occurs in two main niches: the subventricular zone of the lateral ventricle and the subgranular zone of the dentate gyrus of the hippocampus. Neural stem cells in these areas can be induced to asymmetrically divide, generating new stem cells, and astrocytes, oligodendrocytes or neurons. These newly generated neurons have the capacity to migrate and integrate into existing neural circuits. The activity and phenotypic fate of neural stem cells is determined by both endogenous and exogenous factors. Beyond understanding the mechanisms of adult neurogenesis, we are ultimately interested in its therapeutic capacity. Specifically, despite their various mechanism of action, clinically-effective antidepressants share the common feature of inducing neural stem cell proliferation and differentiation into new neurons.

In conclusion, here we showed that the β-carboline alkaloids present in B. caapi, the plant source of the ayahuasca tea, promote neurogenesis in vitro by stimulating neural progenitor pool expansion, and by inducing cellular migration and differentiation into a neuronal phenotype. The stimulation of neurogenic niches in the adult brain may substantially contribute to the antidepressant effects reported for ayahuasca in recent clinical studies. The versatility and full neurogenic capacity of the B. caapi β-carbolines warrant further investigation of these compounds. Their ability to modulate brain plasticity indicates their therapeutic potential for a broad range of psychiatric and neurologic disorders.

*From the study here :
https://www.nature.com/articles/s41598-017-05407-9​

 

[mr peabody]

LSD and psilocybin could heal damaged brain cells in people suffering from depression, study shows

by Alex Matthews-King | 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.

https://www.independent.co.uk/news/h...-a8395511.html​

 

[mr peabody]

Psychedelics may help the brain repair itself, study finds

Calvin Ly, Alexandra Greb, Lindsay Cameron, Kassandra Ori-McKenney, John Gray, David Olson

A new study in Cell Reports has found that psychedelics promote structural and functional neural plasticity.

In recent years, psychedelic party drugs such as LSD and MDMA have been studied by scientists for their potential ability to treat mental health problems like depression and anxiety—often in microdoses much smaller than the what a person would take to trip. But while the research into these drugs is promising, there’s still a lot we don’t understand about how they affect the brain. A new study, published Tuesday in Cell Reports, seems to offer the strongest evidence yet that they can actually help repair the brain’s circuitry and function.

The researchers, primarily from the University of California, Davis, exposed lab-cultured neurons from humans, rats, and other animals to various psychedelics. Drugs from different classes were used, including the amphetamine MDMA, the tryptamine psilocin, and the ergoline LSD. The neurons were taken from the prefrontal cortex, an area of the brain thought to be crucial in the development of certain mental illnesses.

Most of the psychedelics tested, the researchers found, promoted the growth of new dendrites from a neuron cell, which help transmit information from other neurons to the cell, as well as increased the density of small protrusions on these dendrites, known as dendritic spines. They also jumpstarted the growth of new connections, or synapses, between individual neurons. Similar effects were also seen in the brains of living test animals.

The net result of these changes, the authors say, is that they improve the brain’s plasticity, which includes its ability to repair itself from damage caused by things like stress or trauma. These changes, the researchers noted, are the reverse of what seems to happen in the brains of people living with chronic depression, post-traumatic stress disorder, or addiction. And they resemble the changes seen in people who take ketamine, an anesthetic and recreational drug that has been retooled in recent years as a fast-acting, if still experimental, antidepressant that some research has found can quickly tamp down suicidal thoughts.

“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,” said lead author David Olson, an assistant professor in the Departments of Chemistry and of Biochemistry and Molecular Medicine, in a statement. “What is really exciting is that psychedelics seem to mirror the effects produced by ketamine.”

It’s exciting, the authors say, because it means there’s more than one way for drugs to quickly improve a person’s brain plasticity. And the more options available, the better the chances someone can benefit from treatment, especially if other current drugs haven’t worked. Ultimately, it also provides researchers like Olson that many more avenues to pursue in developing more palatable versions of the psychedelic drugs we have available (i.e., versions that don’t cause long, mind-bending trips). The team even wants to rebrand these drugs as “psychoplastogens.”

“Ketamine is no longer our only option,” Olson said. “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.”

Olson’s team is already studying whether non-hallucinogenic analogs of these psychedelics can still improve brain plasticity, and they note that researchers elsewhere are in the middle of developing safer analogs of ketamine, which has some potential for addiction and abuse.

https://www.cell.com/cell-reports/fulltext/​

 

[mr peabody]

Conor Liston

Ketamine found to reverse the neurodegenerative effects of chronic stress*

Ruth Williams | The Scientist | 11 Apr 2019

Imaging of neurons in the brains of living mice reveals how synapses between cells are eliminated in response to stress and reinstated by an antidepressant dose of ketamine. The findings show that while ketamine-induced changes in behavior precede this synaptogenesis, the increased connectivity is required to maintain the drug-modified behavior.

“It’s beautiful work. It’s very elegant and technically sophisticated,” says neuroscientist Jason Radley of the University of Iowa who was not involved with the research. “I think this paper is poised to make a significant contribution.”

“They trace the whole [process] from before stress, after stress, and then after ketamine,” says psychiatrist and neuroscientist Alex Kwan of Yale School of Medicine who also did not participate in the research, “and they have some very interesting findings in terms of how ketamine affects prefrontal cortical circuits.”

The paper is also “quite timely,” continues Kwan, explaining that although last month the United States Food and Drug Administration approved esketamine—a relative of ketamine—for use as an antidepressant, “we still know very little about how [it] works on the brain.”

Depression and stress tend to afflict sufferers episodically with periods of anxiety, sadness, and feelings of hopelessness interspersed with periods of apparent happiness and health. What happens in the brain during the course of depression and remission, however, is poorly understood.

In clinical trials ketamine has been shown to have dramatic, fast-acting antidepressant effects, altering the mood and behavior of patients within hours. And the drug has similarly fast effects on stressed rodents, providing an experimental model in which to examine the neurological basis of mood transitions. Studies of chronic stress and ketamine treatment in rodents have indicated, for example, that stress leads to the loss of dendritic spines—cellular protrusions that form synapses—in brain cells, while ketamine promotes spine formation. With most data having been obtained from sacrificed animals, however, the dynamics of spine formation and whether it drives the behavioral changes is largely unknown.

Conor Liston of Weill Cornell Medicine and colleagues have now followed the course of chronic stress and treatment within live animals. The team used a previously developed imaging technique involving the permanent insertion of a tiny prism into the animal’s brain to enable visualization under a microscope of cells deep within the cortex.

Using this approach the team could view neurons engineered to produce fluorescent proteins and markers of activity in mice that had been chronically stressed. The animals were either repeatedly dosed with corticosterone—the main stress hormone in rodents—via their drinking water, or were repeatedly restrained, which also raises stress hormone levels. Behaviorally, such mice behave differently than unstressed animals, struggling less when suspended by their tails, showing a reduced preference for sucrose, and becoming less exploratory. When given ketamine, however, the animals revert to activities of a nonstressed animal within a few hours.

Imaging revealed that, during stress, prefrontal cortical neurons, as previously shown, lost numerous dendritic spines. In line with these losses, the cells also exhibited less functional connectivity. That is, the numbers of cortical cells firing in unison decreased, as did the frequency of such ensemble activities.

Upon ketamine treatment, these stress-associated cellular changes were largely reversed. However, while the unified firing activity was restored quickly—following a similar time path to that of the behavioral changes, spine regrowth was delayed by 12 to 24 hours. This was “unexpected,” says Liston. Based on previous studies, “the assumption was that spines played some critical role,” he adds.

Further experiments indicated that spine regrowth serves to maintain rather than promote the behavioral changes. When ketamine-induced spines were quickly eliminated (using a combination of clever genetics and light stimulation), the behavior of mice in the tail suspension test returned to that of apparently stressed mice when tested after two days. In treated mice whose synapses were not eliminated, by comparison, the nonstressed behavior lasted up to a week after the ketamine dose.

“This is a very important study that provides evidence that ketamine-induced changes in neuronal structure underlie its sustained antidepressant effects,” chemist and neuroscientist David Olson of the University of California, Davis. "Going forward," he adds, “Strategies aimed at stabilizing these structural changes could prolong the therapeutic effects of ketamine.”

*From the article here :

How the Brain Changes on Ketamine: A Live Animal Study

The drug promotes and sustains brain cell connectivity in mice, reversing the effects of chronic stress.

www.the-scientist.com

 

[mr peabody]

Can 5-MeO-DMT unlock the mystery of neurogenesis?

by Troy Farah | Psychedelic Times | 14 Nov 2018

2018 has been an incredible year for advances in psychedelic research, including psilocybin mushrooms, ketamine and more, not to mention a landmark year for MDMA and cannabis. Meanwhile, some research on a much lesser known psychedelic, 5-MeO-DMT, has slipped past national attention.

Known as 5-methoxy-N,N-dimethyltryptamine, this potent little molecule is most famous for occurring in the venom of a desert toad species, but it’s also present in many plant species or can be made synthetically. It’s in a class of chemicals called tryptamines, which includes DMT, psilocybin and even serotonin and melatonin.

Like many psychedelics, 5-MeO-DMT is highly active at serotonin receptors, but also at acetylcholine, glutamate and dopamine receptors as well, although at much lower potency. This has led some scientists to theorize that many DMT-related drugs could help with mood disorders. Some case studies have shown tryptamines to help with depression, anxiety, PTSD and more—but scientists still aren’t sure how exactly it all works.

The answer may lie in neurogenesis. In a newly published study in Frontiers in Molecular Neuroscience, Brazilian researchers looked at whether 5-MeO-DMT can stimulate neurogenesis in mice. After a single injection of 100 micrograms, the rodents showed significant cell proliferation compared to placebo.

Neurogenesis is exactly what it sounds like—the creation of new brain cells. When you’re young, the brain is constantly making new neurons. This activity slows down in adulthood, except in a few key places in the brain, such as a part of the hippocampus called the dentate gyrus. By stimulating this process, we can potentially fight diseases like Alzheimer’s.

The DG may be small, but it is thought to help form new memories, modulate mood disorders, and may even play a role in addiction. The debate is still raging over this, of course, with some studies saying the DG makes hundreds of new neurons per day, and others showing little change. But one theory suggests neurogenesis may improve a range of cognitive processes, especially in older people.

Perhaps 5-MeO-DMT can help us answer those questions. In the Brazilian study, the mice were injected with a drug called BrdU that helps scientists look at dividing cells in living tissue. Then, the mice were sacrificed by making them overdose on ketamine and xylazin. Unfortunately, it’s only possible to really look at these cell changes by cutting open the brains of mice—part of the reason this experiment hasn’t been done in humans—but at least they were euthanized peacefully.

The mice brains were washed and preserved, and the researchers found that 5-MeO-DMT not only produced more new neurons compared to controls, but they matured faster and survived better.

“Cells from animals submitted to a single 5-MeO-DMT injection showed dendrites with more branches and intersections,” the researchers wrote. Dendrites are the long branches of nerve cells that play an important role in brain chemistry. Like a tree, healthy branches means healthy brain cells. “Interestingly, chronic antidepressant therapy also accelerates the maturation of dendrites… To our knowledge, this work was the first to demonstrate a direct effect of a naturally occurring psychoactive compound in adult neurogenesis.”

There are some limitations to this research. For one, mice aren’t humans, so the conclusions that can be drawn are limited. Second, the researchers aren’t entirely sure how 5-MeO-DMT could be fostering neurogenesis, so what this means for the future of mental health remains to be seen.

With a few exceptions, there isn’t much new research on 5-MeO-DMT or related drugs. Last year, a different Brazilian team gave lab-grown mini-brains 5-MeO-DMT and found it had anti-inflammatory properties, and also promoted the growth of dendrites. Another rodent study shed some light on how 5-MeO-DMT works at serotonin receptors, but most studies are few and far between. There was also a first-of-its-kind epidemiological study that looked at spiritual and recreational use of 5-MeO-DMT, and concluded it has, “low potential for addiction, and might have psychotherapeutic effects.” Otherwise, that’s about it.

There may be a reason why 5-MeO-DMT research is largely ignored in the press. The chemical name is complex and difficult to remember, and most of this science is in very early stages.

There is still far too little research on 5-MeO-DMT to draw any strict conclusions on how it may benefit—or harm—humans; however, the positives seem stronger than the negatives. But this is exactly the point. While so much attention is centered on drugs like LSD and magic mushrooms, this compound is overlooked, and clearly could use more academic interest.

It would be wrong not to mention that federal scheduling has played a role in dampening this research. While 5-MeO-DMT has been used for centuries in some cultures, the United States only placed it in the highly illegal Schedule I category in 2011. Studying Schedule I drugs like marijuana, LSD and mescaline is notoriously difficult, so many institutions don’t even bother. If we really want to unlock the mysteries of this chemical—and what it can teach us about consciousness and the human mind—we must loosen restrictions on psychedelic research. The potential benefits are too important to ignore.

Can Toad Venom Unlock The Mystery Of Neurogenesis? New Insights on 5-MeO-DMT - Psychedelic Times

2018 has been an incredible time for advances in psychedelic research, including psilocybin mushrooms, ketamine and more, not to mention a landmark year for MDMA and cannabis. Meanwhile, some research […]

psychedelictimes.com

 

[mr peabody]

Psychoplastogens: a promising class of plasticity-promoting neurotherapeutics

by David Olson | Journal of Experimental Neuroscience | Sep 19, 2018

Neural plasticity—the ability to change and adapt in response to stimuli—is an essential aspect of healthy brain function and, in principle, can be harnessed to promote recovery from a wide variety of brain disorders. Many neuropsychiatric diseases including mood, anxiety, and substance use disorders arise from an inability to weaken and/or strengthen pathologic and beneficial circuits, respectively, ultimately leading to maladaptive behavioral responses. Thus, compounds capable of facilitating the structural and functional reorganization of neural circuits to produce positive behavioral effects have broad therapeutic potential. Several known drugs and experimental therapeutics have been shown to promote plasticity, but most rely on indirect mechanisms and are slow-acting. Here, I describe psychoplastogens—a relatively new class of fast-acting therapeutics, capable of rapidly promoting structural and functional neural plasticity. Psychoplastogenic compounds include psychedelics, ketamine, and several other recently discovered fast-acting antidepressants. Their use in psychiatry represents a paradigm shift in our approach to treating brain disorders as we focus less on rectifying “chemical imbalances” and place more emphasis on achieving selective modulation of neural circuits.

By definition, psychoplastogens are small molecules and thus plasticity-promoting proteins like BDNF do not fall into this category. To be classified as a psychoplastogen, a compound should produce a measurable change in plasticity (eg, changes in neurite growth, dendritic spine density, synapse number, intrinsic excitability, etc.) within a short period of time (typically 24-72 hours) following a single administration. Because their impact on neural plasticity enables subsequent stimuli to reshape neural circuits, they should produce relatively long-lasting changes in behavior that extend beyond the acute effects of the drug. In addition to ketamine, several other psychoplastogens have been identified, all of which produce fast-acting antidepressant effects in humans.

Recently, our group has demonstrated that psychedelic compounds such as lysergic acid diethylamide (LSD), N,N-dimethyltryptamine (DMT), and 2,5-dimethoxy-4-iodoamphetamine promote dendritic branching and/or increase spine/synapse number both in cultured cortical neurons and in vivo.3 These results provide a potential explanation for the known ability of these compounds to produce long-lasting changes in personality and positively impact circuits relevant to the treatment of mood, anxiety, and substance use disorders. Although our cellular studies have shown that a wide variety of psychedelic compounds produce psychoplastogenic effects similar to ketamine, our in vivo work thus far has primarily focused on the effects of DMT—the archetype for all tryptamine-containing psychedelics.

Our initial efforts investigating the plasticity-promoting properties of psychedelics focused on DMT for a variety of reasons. First, the simple structure of DMT represents the minimal pharmacophore for all tryptamine-containing psychedelics as others such as LSD, ibogaine, psilocybin, and 5-MeO-DMT can be considered either conformationally restricted or substituted analogues of DMT. Like ketamine, a single intraperitoneal injection of DMT increases dendritic spine density as well as the frequency and amplitude of spontaneous excitatory postsynaptic currents in the PFC of rats 24 hours after administration. As the half-life of DMT in rats is on the order of 15 minutes, the compound is cleared from the body within 24 hours and thus these changes in neuronal structure and function must reflect plasticity and not simply the acute effects of the drug. Moreover, DMT produces behavioral effects in rodents that mirror those of ketamine such as promoting fear extinction learning and reducing immobility in the forced swim test. In humans, a DMT-containing tisane known as ayahuasca has been shown to produce rapid and sustained antidepressant effects.

The advent of psychoplastogenic compounds has enabled us to move beyond simplistic therapeutic strategies aimed at controlling monoamine levels toward the selective modulation of neural circuits—a fundamental shift in our approach to treating CNS disorders. Significant progress has been made in recent years and provides hope that modern research on ketamine, psychedelics, and other psychoplastogens will lead to safe and effective strategies for harnessing neural plasticity to treat mood and anxiety disorders such as depression and PTSD. As the number of psychoplastogenic compounds continues to grow, so do our chances of identifying the next generation of medicines for treating neuropsychiatric and neurodegenerative diseases. Regardless, it is clear that psychoplastogens can serve as powerful tools for understanding the basic biology of neural plasticity.

Psychoplastogens: A Promising Class of Plasticity-Promoting Neurotherapeutics ​

 

[mr peabody]

Single dose of 5-MeO-DMT found to stimulate cell proliferation and neuronal survivability

Rafael Vitor Lima da Cruz, Thiago Moulin, Lyvia Lintzmaier Petiz, Richardson Leao

Psychoactive tryptamines are a class of molecules that act as neurotransmitter in the vertebrate brain. 5-MeO-DMT is found in a great variety of plants in South America, with an even greater diversity of chemical analogs. It is a serotonin agonist that acts in a non-selective manner in 5-HT2A >5-HT2C >5-HT1A receptors. However, 5-MeO-DMT also acts in many glutamate, dopamine and acetylcholine receptors. 5-MeO-DMT is one of the main active ingredient of Ayahuasca, a millenarian decoction used as sacrament by south American indigenous tribes, known to induce powerful hallucinogen states when administered together with monoamine oxidase inhibitors. At present, Ayahuasca is used by many syncretic churches ritualistically, as way to heal many physical and mental illness with or without scientific knowledge about the effects. Recent studies also suggest that Ayahuasca can potentially treat recurrent depression even in a placebo controlled frame.

Deficits in adult neurogenesis are associated with the physiopathology of depression and modulation of neurogenesis is behind the action of several antidepressants. Serotonin reuptake inhibitors, for example, rescue normal neurogenesis levels in animal models of depression. Adult neurogenesis is known to occur in two sites in the brain, the subgranular zone of the dentate gyrus and the subventricular zone of the lateral ventricle. There is some debate whether or not SVZ neurogenesis responds to mood disorders and psychoactive drugs, but the effect of mood disorders in SGZ Radial glial Like cell proliferation and neuronal survivor is prolifically described. Interestingly, alkaloids from one of the plants used in the Ayahuasca brew stimulate neurogenesis in vitro; however, it is not known whether in vivo adult neurogenesis is affected by psychoactive tryptamines.

In this study we tested if a single dose of 5-MeO-DMT affects neurogenesis in mice. We found that after a single intracerebroventricular injection of 5-MeO-DMT, cell proliferation in the DG was significantly larger in comparison to saline. Moreover, the number of DCX cells are also higher for experimental group, these same DG granule cells show more complex dendritic trees when compared to control animals. Finally, we found that after hyperpolarization, potential duration was shorter, and action potential threshold was higher in newborn neurons in mice treated with 5-MeO-DMT.

In this work we show that a single dose of 5-MeO-DMT increases proliferation of neural progenitors and accelerates the maturation of newborn GC. We first used BrdU staining to show that 5-MeO-DMT treatment increases proliferation in the DG Next, we used an inducible Cre recombinase line under the control of a marker of neurogenesis crossed with a fluorescent reporter to identify newborn neurons. We also show that the total number of DCX cells in the ventral hippocampus of adult mice are increased, and that those cells are indeed neurons. Dendritic trees of newborn neurons from 5-MeO-DMT-treated mice were significantly more complex as compared with saline-treated mice. AP threshold was lower and AHP potential was longer in newborn cells from 5-MeO-DMT-treated mice compared to controls.

The higher number of BrDU+ cells indicate that a larger number of cells are entering in the S-phase of cell-cycle, but cannot elucidate the type of progenitor cell that is being affected. Studies using antibodies against GFAP, nestin and Sox2, might confirm if those BrdU+ cells are indeed RGL cells, the neural stem progenitors cells from adult DG. Also, future experiments may confirm whether the increase in BrdU+ cells following 5-MeO-DMT injection is due to the lengthening of S-phase or a higher recruitment of RGL.

The choice of a single dose treatment, was made to address the gap between the molecular mechanisms, subjective and hormonal effects underlying Ayahuasca acute administration to depression diagnosed patients. The bulk of Ayahuasca tea, are composed of several psychoactive substances including DMT analogs and MAOi. The scope of present study is to unveil the effect of the main psychoactive compound in the Ayahuasca without adding any bias due to other psychoactive compounds also present in the concoction. To study the specific contribution of the 5-MeO-DMT to the adult neurogenic process, we needed to isolate the effect of the 5-MeO-DMT from another psychoactive components of the Ayahuasca. For example, the harmine and B-carbolines acting as MAOi, in such way, using oral or intraperitoneal administration may reduce the availability of 5-MeO-DMT to the central nervous system, since the monoamine oxidase will readily destroy any tryptamine, in the blood stream, gut and brain. Hence 5-MeO-DMT can be easily degraded, we choose to deliver the 5-MeO-DMT ICV to reduce the chemical inactivation prior to the arrival of the molecule to the brain. Additionally has been reported elsewhere that the harmine per se can increase neurogenesis at least in vitro cultured hippocampal cells.

Increased proliferation after 5-MeO-DMT injection does not indicate neuronal commitment. Thus, we performed histological analysis in mice injected with 5-MeO-DMT. Our results indicate a greater number of DCX cells in the ventral hippocampus of 5-MeO-DMT treated animals, showing that the total numbers of neuron that reach neuronal maturity are also increased, in addition to the initial increase in proliferation right after 5-MeO-DMT injection as evinced by our proliferation assay. Serotonin has been shown to increase granule cell proliferation in the adult DG. However, serotonin does not seem to affect specialization of newborn cells in the SGZ. Our results, on the other hand, suggest that 5-MeO-DMT not only has a positive effect on proliferation and survivability, but also on the maturation of GC. Hence, our results imply that the positive effect of 5-MeO-DMT in adult neurogenesis differs from that of serotonin alone.

Our current-clamp recordings indicate that young neurons from 5-MeO-DMT-treated mice show faster maturation than cells from control animals. Mature GC show a higher AP threshold and are able to fire in higher frequencies. These differences in maturation were also found in the morphology of dendritic trees. Dendritic complexity is a major indicative of cell maturation. Cells from animals submitted to a single 5-MeO-DMT injection showed dendrites with more branches and intersections. Interestingly, chronic antidepressant therapy also accelerates the maturation of dendrites. Future studies should address how tryptamine analogs affect the temporal expression of voltage-dependent currents. Our preliminary results indicate that the hyperpolarizing-activated current, Ih, is larger in novel GC in animals injected with 5-MeO-DMT when compared with saline Also, it will be interesting to examine changes in Cl− reversal potential as GC show a depolarized potential until adolescence.

Dorsal Raphe Nucleus profusely targets the SGZ but a previous work have shown that lowering serotonin levels in the brain can increase neurogenesis. Yet, serotonin agonists and serotonin uptake inhibitors seem to increase neurogenesis. Hence, specific 5HT receptors might be involved in neurogenesis modulation. 5-HT1A, 5-HT2A and 5-HT2C, 5-MeO-DMT targets, are all expressed in the DG. While 5-MeO-DMT is a strong 5-HT2A and 5-HT2C agonist, this compound acts in other receptors. Hence, we cannot affirm that the effect of 5-MeO-DMT in neurogenesis occurs through 5-HT2A and 5-HT2C receptors. Future studies using agonists and antagonists are necessary for dissecting the molecular mechanism of 5-MeO-DMT action in neurogenesis.

In conclusion, we show here that a single dose of 5-MeO-DMT can increase proliferation, survivability and accelerate maturation of newborn neurons in the DG. To our knowledge, this work was the first to demonstrate a direct effect of a naturally occurring psychoactive compound in adult neurogenesis. New lines of investigation have suggested that serotoninergic hallucinogens can significantly improve severe depression and anxiety. Thus, the effect of 5-MeO-DMT in modulating neurogenesis could throw light on the mechanism behind the beneficial effects of hallucinogenic compounds in mood disorders.

https://www.frontiersin.org/articles/10.3389/fnmol.2018.00312/full​

 

[mr peabody]

Psychedelic drugs change the structure of neurons

by Andy Fell | UC Davis | Jun 12 2018

A team of scientists at the University of California, Davis, is exploring how psychedelic drugs impact the structure and function of neurons — research that could lead to new treatments for depression, anxiety and related disorders. In a paper published on June 12 in the journal Cell Reports, they demonstrate that a wide range of psychedelic drugs, including well-known compounds such as LSD and MDMA, increase the number of neuronal branches (dendrites), the density of small protrusions on these branches (dendritic spines), and the number of connections between neurons (synapses). These structural changes could suggest that psychedelics are capable of repairing the circuits that are malfunctioning in mood and anxiety disorders.

“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. What is really exciting is that psychedelics seem to mirror the effects produced by ketamine,” said David Olson, assistant professor in the departments of Chemistry and of Biochemistry and Molecular Medicine, who leads the research team.

Ketamine, an anesthetic, has been receiving a lot of attention lately because it produces rapid antidepressant effects in treatment-resistant populations, leading the U.S. Food and Drug Administration to fast-track clinical trials of two antidepressant drugs based on ketamine. The antidepressant properties of ketamine may stem from its tendency to promote neural plasticity — the ability of neurons to rewire their connections.

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

Psychedelics that show effects similar to ketamine

Olson’s group has demonstrated that other psychedelics mimic the effects of ketamine on neurons grown in a dish, and that these results extend to structural and electrical properties of neurons in animals. Rats treated with a single dose of DMT — a psychedelic compound found in the Amazonian herbal tea known as ayahuasca — showed an increase in the number of dendritic spines, similar to that seen with ketamine treatment. DMT itself is very short-lived in the rat: Most of the drug is eliminated within an hour. But the “rewiring” effects on the brain could be seen 24 hours later, demonstrating that these effects last for some time.

Behavioral studies also hint at the similarities between other psychedelics and ketamine. In another recent paper published in ACS Chemical Neuroscience, Olson’s group showed that DMT treatment enabled rats to overcome a “fear response” to the memory of a mild electric shock. This test is considered to be a model of post-traumatic stress disorder, or PTSD, and interestingly, ketamine produces the same effect. Recent clinical trials have shown that like ketamine, DMT-containing ayahuasca might have fast-acting effects in people with recurrent depression, Olson said.

These discoveries potentially open doors for the development of novel drugs to treat mood and anxiety disorders, Olson said. His team has proposed the term “psychoplastogen” to describe this new class of “plasticity-promoting” compounds.

“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,” Olson said.

Psychedelics vs. Psychoplastogens

Our group has coined the term “psychoplastogen” to refer to such compounds, and we believe that these molecules may hold the key to treating a wide variety of brain diseases.

Our studies on neurons grown in dishes, as well as experiments performed using fruit flies and rodents, have demonstrated that several psychoplastogens, including psychedelics and ketamine, encourage neurons to grow more branches and spines. It seems that all of these compounds work by activating mTOR – a key protein involved in cell growth.

The biochemical machinery that regulates mTOR activity is intricate. As we tease apart how psychedelics and other psychoplastogens turn on mTOR signaling, we might be able to engineer compounds that only produce the therapeutic effects on neuronal growth while bypassing pathways that lead to undesired hallucinations.

The field has known for some time now that psychedelics can produce lasting positive effects on brain function, and it’s possible that these long-lasting changes result from the psychoplastogenic effects of these drugs. If true, this would suggest that psychoplastogens might be used to repair circuits that are damaged in mood and anxiety disorders.

https://www.ucdavis.edu/news/psychedelic-drugs-change-structure-neurons/​