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Neuropharmacology Jan 2023Mescaline (3,4,5-trimethoxyphenethylamine) is one of the oldest hallucinogens, with evidence of use dating back 5700 years. Mescaline is a naturally occurring alkaloid... (Review)
Review
INTRODUCTION
Mescaline (3,4,5-trimethoxyphenethylamine) is one of the oldest hallucinogens, with evidence of use dating back 5700 years. Mescaline is a naturally occurring alkaloid found in cacti, mainly in the peyote cactus (Lophophora williamsii) and in the cacti of the Echinopsis genus. Since the prohibition of psychoactive substances in the early 70s, research on mescaline and other classical psychedelics has been limited.
OBJECTIVES
This article aims to review the pharmacology and behavioural effects of mescaline, focusing on preclinical and clinical research.
FINDINGS
Mescaline is a serotonin 5HT2A/2C receptor agonist, with its main hallucinogenic effects being mediated via its 5HT2A receptor agonist action. It also exerts effects via agonist binding at α1A/2A noradrenaline and D1/2/3 dopamine receptors. Overall, mescaline has anxiolytic-like effects in animals and increases prosocial behaviour, locomotion, and response reactivity. In humans, mescaline can induce euphoria, hallucinations, improvements in well-being and mental health conditions, and psychotomimetic effects in a naturalistic or religious setting.
CONCLUSION
The pharmacological mechanisms of mescaline are similar to those of other classical psychedelics, like psilocybin and lysergic acid diethylamide (LSD). Mescaline appears to be safe to consume, with most intoxications being mild and easily treatable. Improvement in mental well-being and its ability to overcome alcoholism render mescaline potentially beneficial in clinical settings. This article is part of the Special Issue on 'Psilocybin Research'.
Topics: Animals; Humans; Mescaline; Hallucinogens; Psilocybin; Lysergic Acid Diethylamide; Serotonin 5-HT2 Receptor Agonists; Memory Disorders
PubMed: 36252614
DOI: 10.1016/j.neuropharm.2022.109294 -
Frontiers in Psychiatry 2022The interest in psilocybin as a therapeutic approach has grown exponentially in recent years. Despite increasing access, there remains a lack of practical guidance on... (Review)
Review
The interest in psilocybin as a therapeutic approach has grown exponentially in recent years. Despite increasing access, there remains a lack of practical guidance on the topic for health care professionals. This is particularly concerning given the medical complexity and vulnerable nature of patients for whom psilocybin-assisted psychotherapy may be considered. This article aims to provide health care professionals with an overview of practical considerations for psilocybin therapy, rooted in a patient safety focus. Within this piece we will review basic psilocybin pharmacology and pharmacokinetics, indications, practical therapeutic strategies (e.g., dosing, administration, monitoring) and safety considerations (e.g., contraindications, adverse events, and drug interactions). With this information, our goal is to increase the knowledge and comfort of health care professionals to discuss and counsel their patients on psilocybin therapy, ultimately improving patient care and safety.
PubMed: 36532184
DOI: 10.3389/fpsyt.2022.1040217 -
The International Journal of... Mar 2023Psychedelics are a unique class of drug that commonly produce vivid hallucinations as well as profound psychological and mystical experiences. A grouping of...
Psychedelics are a unique class of drug that commonly produce vivid hallucinations as well as profound psychological and mystical experiences. A grouping of interconnected brain regions characterized by increased temporal coherence at rest have been termed the Default Mode Network (DMN). The DMN has been the focus of numerous studies assessing its role in self-referencing, mind wandering, and autobiographical memories. Altered connectivity in the DMN has been associated with a range of neuropsychiatric conditions such as depression, anxiety, post-traumatic stress disorder, attention deficit hyperactive disorder, schizophrenia, and obsessive-compulsive disorder. To date, several studies have investigated how psychedelics modulate this network, but no comprehensive review, to our knowledge, has critically evaluated how major classical psychedelic agents-lysergic acid diethylamide, psilocybin, and ayahuasca-modulate the DMN. Here we present a systematic review of the knowledge base. Across psychedelics there is consistent acute disruption in resting state connectivity within the DMN and increased functional connectivity between canonical resting-state networks. Various models have been proposed to explain the cognitive mechanisms of psychedelics, and in one model DMN modulation is a central axiom. Although the DMN is consistently implicated in psychedelic studies, it is unclear how central the DMN is to the therapeutic potential of classical psychedelic agents. This article aims to provide the field with a comprehensive overview that can propel future research in such a way as to elucidate the neurocognitive mechanisms of psychedelics.
Topics: Hallucinogens; Default Mode Network; Psilocybin; Lysergic Acid Diethylamide; Brain; Magnetic Resonance Imaging
PubMed: 36272145
DOI: 10.1093/ijnp/pyac074 -
Neuropsychopharmacology : Official... Oct 2017Plant-based psychedelics, such as psilocybin, have an ancient history of medicinal use. After the first English language report on LSD in 1950, psychedelics enjoyed a... (Review)
Review
Plant-based psychedelics, such as psilocybin, have an ancient history of medicinal use. After the first English language report on LSD in 1950, psychedelics enjoyed a short-lived relationship with psychology and psychiatry. Used most notably as aids to psychotherapy for the treatment of mood disorders and alcohol dependence, drugs such as LSD showed initial therapeutic promise before prohibitive legislature in the mid-1960s effectively ended all major psychedelic research programs. Since the early 1990s, there has been a steady revival of human psychedelic research: last year saw reports on the first modern brain imaging study with LSD and three separate clinical trials of psilocybin for depressive symptoms. In this circumspective piece, RLC-H and GMG share their opinions on the promises and pitfalls of renewed psychedelic research, with a focus on the development of psilocybin as a treatment for depression.
Topics: Animals; Hallucinogens; History, 20th Century; History, 21st Century; Humans; Mental Disorders; Psilocybin
PubMed: 28443617
DOI: 10.1038/npp.2017.84 -
Proceedings of the National Academy of... Apr 2021Depression is a widespread and devastating mental illness and the search for rapid-acting antidepressants remains critical. There is now exciting evidence that the...
Depression is a widespread and devastating mental illness and the search for rapid-acting antidepressants remains critical. There is now exciting evidence that the psychedelic compound psilocybin produces not only powerful alterations of consciousness, but also rapid and persistent antidepressant effects. How psilocybin exerts its therapeutic actions is not known, but it is widely presumed that these actions require altered consciousness, which is known to be dependent on serotonin 2A receptor (5-HT2AR) activation. This hypothesis has never been tested, however. We therefore asked whether psilocybin would exert antidepressant-like responses in mice and, if so, whether these responses required 5-HT2AR activation. Using chronically stressed male mice, we observed that a single injection of psilocybin reversed anhedonic responses assessed with the sucrose preference and female urine preference tests. The antianhedonic response to psilocybin was accompanied by a strengthening of excitatory synapses in the hippocampus-a characteristic of traditional and fast-acting antidepressants. Neither behavioral nor electrophysiological responses to psilocybin were prevented by pretreatment with the 5-HT2A/2C antagonist ketanserin, despite positive evidence of ketanserin's efficacy. We conclude that psilocybin's mechanism of antidepressant action can be studied in animal models and suggest that altered perception may not be required for its antidepressant effects. We further suggest that a 5-HT2AR-independent restoration of synaptic strength in cortico-mesolimbic reward circuits may contribute to its antidepressant action. The possibility of combining psychedelic compounds and a 5-HT2AR antagonist offers a potential means to increase their acceptance and clinical utility and should be studied in human depression.
Topics: Animals; Depression; Drug Evaluation, Preclinical; Hallucinogens; Hippocampus; Ketanserin; Male; Mice, Inbred C57BL; Psilocybin; Receptors, Serotonin, 5-HT2; Serotonin 5-HT2 Receptor Agonists; Stress, Psychological; Mice
PubMed: 33850049
DOI: 10.1073/pnas.2022489118 -
Translational Psychiatry Aug 2022The use of low sub-perceptual doses of psychedelics ("microdosing") has gained popularity in recent years. Although anecdotal reports claim multiple benefits associated... (Randomized Controlled Trial)
Randomized Controlled Trial
The use of low sub-perceptual doses of psychedelics ("microdosing") has gained popularity in recent years. Although anecdotal reports claim multiple benefits associated with this practice, the lack of placebo-controlled studies severely limits our knowledge of microdosing and its effects. Moreover, research conducted in standard laboratory settings could fail to capture the motivation of individuals engaged or planning to engage in microdosing protocols, thus underestimating the likelihood of positive effects on creativity and cognitive function. We recruited 34 individuals starting to microdose with psilocybin mushrooms (Psilocybe cubensis), one of the materials most frequently used for this purpose. Following a double-blind placebo-controlled experimental design, we investigated the acute and short-term effects of 0.5 g of dried mushrooms on subjective experience, behavior, creativity (divergent and convergent thinking), perception, cognition, and brain activity. The reported acute effects were significantly more intense for the active dose compared to the placebo, but only for participants who correctly identified their experimental condition. These changes were accompanied by reduced EEG power in the theta band, together with preserved levels of Lempel-Ziv broadband signal complexity. For all other measurements there was no effect of microdosing except for few small changes towards cognitive impairment. According to our findings, low doses of psilocybin mushrooms can result in noticeable subjective effects and altered EEG rhythms, but without evidence to support enhanced well-being, creativity and cognitive function. We conclude that expectation underlies at least some of the anecdotal benefits attributed to microdosing with psilocybin mushrooms.
Topics: Agaricales; Double-Blind Method; Hallucinogens; Humans; Motivation; Psilocybin
PubMed: 35918311
DOI: 10.1038/s41398-022-02039-0 -
International Journal of Molecular... Jun 2022Clinical studies provide evidence that ketamine and psilocybin could be used as fast-acting antidepressants, though their mechanisms and toxicity are still not fully...
Clinical studies provide evidence that ketamine and psilocybin could be used as fast-acting antidepressants, though their mechanisms and toxicity are still not fully understood. To address this issue, we have examined the effect of a single administration of ketamine and psilocybin on the extracellular levels of neurotransmitters in the rat frontal cortex and reticular nucleus of the thalamus using microdialysis. The genotoxic effect and density of glutamate receptor proteins was measured with comet assay and Western blot, respectively. An open field test, light-dark box test and forced swim test were conducted to examine rat behavior 24 h after drug administration. Ketamine (10 mg/kg) and psilocybin (2 and 10 mg/kg) increased dopamine, serotonin, glutamate and GABA extracellular levels in the frontal cortex, while psilocybin also increased GABA in the reticular nucleus of the thalamus. Oxidative DNA damage due to psilocybin was observed in the frontal cortex and from both drugs in the hippocampus. NR2A subunit levels were increased after psilocybin (10 mg/kg). Behavioral tests showed no antidepressant or anxiolytic effects, and only ketamine suppressed rat locomotor activity. The observed changes in neurotransmission might lead to genotoxicity and increased NR2A levels, while not markedly affecting animal behavior.
Topics: Animals; Antidepressive Agents; Behavior, Animal; Brain; DNA; Ketamine; Neurotransmitter Agents; Psilocybin; Rats; Receptors, Glutamate; gamma-Aminobutyric Acid
PubMed: 35743159
DOI: 10.3390/ijms23126713 -
Cureus Oct 2022Psilocybin is a plant alkaloid that is derived from precursors of tryptamine and is present in many different types of mushrooms. It has been utilized by indigenous... (Review)
Review
Psilocybin is a plant alkaloid that is derived from precursors of tryptamine and is present in many different types of mushrooms. It has been utilized by indigenous peoples of Central and South America for centuries in a ceremonial setting to promote spiritual experiences. Indigenous societies have long employed psilocybin and other 5-HT 2A agonist classic psychedelics in their rites. They were a focus in psychiatry in the middle of the 20th century as both experimental medicines and tools for studying brain function. Due to the fact that traditional psychedelics were being used for purposes other than medical research and in connection with the burgeoning counterculture by the late 1960s and early 1970s, these scientific investigations fell out of favor. However, thanks to a number of encouraging studies that validated the earlier research, interest in traditional psychedelics has surged among scientists in the 21st century. In this review, we examine therapeutic studies on psilocybin, the traditional psychedelic that has received the lion's share of recent attention. According to three controlled studies, psilocybin may reduce symptoms of depression and anxiety in the context of cancer-related psychological discomfort for at least six months after a single acute treatment for mood and anxiety disorders. Three months after two acute doses, individuals in a small, open-label study with treatment-resistant depression reported fewer depressive and anxiety symptoms. Small, open-label pilot studies on addiction have demonstrated encouraging success rates for alcohol and cigarette addiction. The review also briefly discusses the synthesis, mechanism of action, effects, molecular pharmacology, adverse effects, and contraindications of psilocybin.
PubMed: 36381758
DOI: 10.7759/cureus.30214 -
JAMA Psychiatry Oct 2022Although classic psychedelic medications have shown promise in the treatment of alcohol use disorder (AUD), the efficacy of psilocybin remains unknown.
Percentage of Heavy Drinking Days Following Psilocybin-Assisted Psychotherapy vs Placebo in the Treatment of Adult Patients With Alcohol Use Disorder: A Randomized Clinical Trial.
IMPORTANCE
Although classic psychedelic medications have shown promise in the treatment of alcohol use disorder (AUD), the efficacy of psilocybin remains unknown.
OBJECTIVE
To evaluate whether 2 administrations of high-dose psilocybin improve the percentage of heavy drinking days in patients with AUD undergoing psychotherapy relative to outcomes observed with active placebo medication and psychotherapy.
DESIGN, SETTING, AND PARTICIPANTS
In this double-blind randomized clinical trial, participants were offered 12 weeks of manualized psychotherapy and were randomly assigned to receive psilocybin vs diphenhydramine during 2 day-long medication sessions at weeks 4 and 8. Outcomes were assessed over the 32-week double-blind period following the first dose of study medication. The study was conducted at 2 academic centers in the US. Participants were recruited from the community between March 12, 2014, and March 19, 2020. Adults aged 25 to 65 years with a DSM-IV diagnosis of alcohol dependence and at least 4 heavy drinking days during the 30 days prior to screening were included. Exclusion criteria included major psychiatric and drug use disorders, hallucinogen use, medical conditions that contraindicated the study medications, use of exclusionary medications, and current treatment for AUD.
INTERVENTIONS
Study medications were psilocybin, 25 mg/70 kg, vs diphenhydramine, 50 mg (first session), and psilocybin, 25-40 mg/70 kg, vs diphenhydramine, 50-100 mg (second session). Psychotherapy included motivational enhancement therapy and cognitive behavioral therapy.
MAIN OUTCOMES AND MEASURES
The primary outcome was percentage of heavy drinking days, assessed using a timeline followback interview, contrasted between groups over the 32-week period following the first administration of study medication using multivariate repeated-measures analysis of variance.
RESULTS
A total of 95 participants (mean [SD] age, 46 [12] years; 42 [44.2%] female) were randomized (49 to psilocybin and 46 to diphenhydramine). One participant (1.1%) was American Indian/Alaska Native, 3 (3.2%) were Asian, 4 (4.2%) were Black, 14 (14.7%) were Hispanic, and 75 (78.9%) were non-Hispanic White. Of the 95 randomized participants, 93 received at least 1 dose of study medication and were included in the primary outcome analysis. Percentage of heavy drinking days during the 32-week double-blind period was 9.7% for the psilocybin group and 23.6% for the diphenhydramine group, a mean difference of 13.9%; (95% CI, 3.0-24.7; F1,86 = 6.43; P = .01). Mean daily alcohol consumption (number of standard drinks per day) was also lower in the psilocybin group. There were no serious adverse events among participants who received psilocybin.
CONCLUSIONS AND RELEVANCE
Psilocybin administered in combination with psychotherapy produced robust decreases in percentage of heavy drinking days over and above those produced by active placebo and psychotherapy. These results provide support for further study of psilocybin-assisted treatment for AUD.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02061293.
Topics: Adult; Alcohol Drinking; Alcoholism; Diphenhydramine; Double-Blind Method; Female; Hallucinogens; Humans; Male; Middle Aged; Psilocybin; Psychotherapy; Treatment Outcome
PubMed: 36001306
DOI: 10.1001/jamapsychiatry.2022.2096 -
Canadian Journal of Psychiatry. Revue... Jan 2023Serotonergic psychedelics are re-emerging as potential novel treatments for several psychiatric disorders including major depressive disorder. The Canadian Network for... (Review)
Review
OBJECTIVE
Serotonergic psychedelics are re-emerging as potential novel treatments for several psychiatric disorders including major depressive disorder. The Canadian Network for Mood and Anxiety Treatments (CANMAT) convened a task force to review the evidence and provide a consensus recommendation for the clinical use of psychedelic treatments for major depressive disorder.
METHODS
A systematic review was conducted to identify contemporary clinical trials of serotonergic psychedelics for the treatment of major depressive disorder and cancer-related depression. Studies published between January 1990 and July 2021 were identified using combinations of search terms, inspection of bibliographies and review of other psychedelic reviews and consensus statements. The levels of evidence for efficacy were graded according to the Canadian Network for Mood and Anxiety Treatments criteria.
RESULTS
Only psilocybin and ayahuasca have contemporary clinical trials evaluating antidepressant effects. Two pilot studies showed preliminary positive effects of single-dose ayahuasca for treatment-resistant depression (Level 3 evidence). Small randomized controlled trials of psilocybin combined with psychotherapy showed superiority to waitlist controls and comparable efficacy and safety to an active comparator (escitalopram with supportive psychotherapy) in major depressive disorder, with additional randomized controlled trials showing efficacy specifically in cancer-related depression (Level 3 evidence). There was only one open-label trial of psilocybin in treatment-resistant unipolar depression (Level 4 evidence). Small sample sizes and functional unblinding were major limitations in all studies. Adverse events associated with psychedelics, including psychological (e.g., psychotomimetic effects) and physical (e.g., nausea, emesis and headaches) effects, were generally transient.
CONCLUSIONS
There is currently only low-level evidence to support the efficacy and safety of psychedelics for major depressive disorder. In Canada, as of 2022, psilocybin remains an experimental option that is only available through clinical trials or the special access program. As such, Canadian Network for Mood and Anxiety Treatments considers psilocybin an experimental treatment and recommends its use primarily within clinical trials, or, less commonly, through the special access program in rare, special circumstances.
Topics: Humans; Hallucinogens; Psilocybin; Depressive Disorder, Major; Canada; Anxiety; Neoplasms
PubMed: 35975555
DOI: 10.1177/07067437221111371