Psychedelic Therapy: A Primer for Primary Care Clinicians-Psilocybin.

BACKGROUND: The primary psychoactive drug in magic mushrooms, psilocybin, induces profound alterations in consciousness through the 5-HT2A receptor. This review consolidates current research findings to elucidate the pharmacology, safety profile, and clinical applications of psilocybin. AREAS OF UNCERTAINTY: Despite initial concerns that psilocybin could cause psychosis, contemporary research has demonstrated that psilocybin is generally safe. The most common adverse effects are nausea and headache, yet both tend to be transient. Serious adverse events can generally be avoided in controlled settings such as clinical trials. However, in the largest clinical trial to date, there were a total of 7 reported cases of suicidal ideation, up to 12 weeks after receiving a single 25 mg dose of psilocybin. That being said, all 7 cases did not respond to the treatment. Although selective serotonin reuptake inhibitors may blunt the hallucinogenic qualities of psilocybin, preliminary research suggests that they may enhance its antidepressant effects. THERAPEUTIC ADVANCES: In clinical trials, psilocybin has shown promise for treating major depressive disorder and treatment-resistant depression. Initial studies indicated that 42%-57% of patients underwent remission after psilocybin-assisted therapy, which suggests that psilocybin is more effective than existing antidepressant medications. Clinical data have also demonstrated that psilocybin can manage substance use disorders and end-of-life anxiety with clinical outcomes that are sustained for months and sometimes years after 1 or 2 doses. LIMITATIONS: However, larger Phase II trials with more than 100 depressed participants have shown a much smaller remission rate of 25%-29%, though these studies still observed that psilocybin causes a significant reduction in depressive symptoms. CONCLUSIONS: Aside from ketamine, psilocybin is the most clinically well-researched psychedelic drug, with trials that have enrolled hundreds of participants and multiple therapeutic applications. Phase III trials will determine whether psilocybin lives up to the promise that it showed in previous clinical trials.

[Psychedelics and treatment of mental disorders: A survey of attitudes and knowledge among psychiatrists, general practitioners and psychologists in Iceland].

INTRODUCTION: Interest in the use of psychedelics has increased following reports of their possible therapeutic potential. However, little is known about the knowledge of and attitudes towards the substances among health care professional who provide treatment for mental disorders in Iceland. An online survey was therefore conducted among members of the Icelandic associations of psychiatrists, general practitioners and psychologists. METHODS: Respondents were 256 in total, including 177 psychologists, 38 psychiatrists and 41 general practitioners that provided information on their background, type of work, knowledge of and attitude towards different types of psychedelic substances and their views on optimal service delivery if psychedelics were approved by licencing authorities and used for treatment. RESULTS: Around half of psychiatrists reported having received questions about treatment with psychedelics in their clinical work, compared to only 14,6% of general practitioners and 17,5% of psychologists. The majority of respondents had little, or no knowledge of the substances targeted in the survey. A majority also expressed negative attitudes towards treatment with psilocybin mushrooms, but was positive towards ongoing scientific research and felt that such a treatment should be prescribed and provided by psychiatrists. Moreover, the majority view was that psilocybin treatment should be provided in specialised clinics or psychiatric units in a hospital setting. Scientific articles on the topic, discussions with colleagues and information in the media were identified as having had most influence on respondents´ attitudes towards psychedelics. Most respondents were interested in further education on psychedelics. CONCLUSIONS: Respondents among these three professions felt that the time has not yet come to use psychedelics in the treatment of mental disorders in Iceland but thought more education on psychedelics, their potential efficacy and adverse health effects is important given the increased interest in psychedelics.

Potential use of psilocybin drugs in the treatment of depression.

INTRODUCTION: Depression is a common disabling psychiatric disorder, which - in extreme cases - may lead to suicide if untreated or inadequately treated. Despite the availability of various treatments for depression, including pharmacotherapy, there is still a need to search for new agents with higher effectiveness and faster onset of action, especially for patients with treatment-resistant depression. AREAS COVERED: A substance that has attracted considerable attention for nearly a decade is psilocybin, a natural psychedelic found in psilocybin mushrooms. In this study, we evaluated the efficacy and safety of psilocybin in the treatment of depression, based on pivotal randomized clinical trials. Moreover, we used findings from observational studies regarding recreational use. We also looked at ongoing clinical trials and discussed the registration status and clinical potential of the drug. EXPERT OPINION: Clinical phase I-II trials published to date reported promising results for psilocybin in the treatment of patients with major depressive disorder and treatment-resistant depression, in a relatively short time after administration. However, before psilocybin is approved for use and administered to patients with depression, the results of large ongoing phase III clinical trials are needed to confirm its efficacy and safety and to change the way it is perceived by physicians and patients.

The Need for Psychiatric Treatment among Polish Users of Psychoactive Substances Is Increasing: This and Other Results from the Newest PolDrugs Survey.

Background and Objectives: PolDrugs is the largest Polish naturalistic nationwide survey to present basic demographic and epidemiological data that could potentially prevent harm from illicit substances intake in drugs users. The most recent results were presented in 2021. The goal of this year's edition was to re-present the above data and compare it to the previous edition's data to identify and describe the differences. Materials and Methods: The survey included original questions about basic demographics, substance use, and psychiatric treatment. The survey was administered via the Google Forms platform and promoted via social media. The data was collected from 1117 respondents. Results: People of all ages use a variety of psychoactive substances in many situations. The three most commonly used drugs are marijuana, 3,4-methylenedioxymethamphetamine, and hallucinogenic mushrooms. The most common reason for seeking professional medical help was amphetamine use. A total of 41.7 percent of respondents were receiving psychiatric treatment. The three most common psychiatric diagnoses among the respondents were depressive disorders, anxiety disorders, and ADHD. Conclusions: Key findings include increases in the use of psilocybin and DMT, increases in the use of heated tobacco products, and a near doubling in the percentage of individuals receiving psychiatric help in the past two years. These issues are discussed in the discussion section of this paper, which also addresses the limitations to the article.

If the Doors of Perception Were Cleansed, Would Chronic Pain be Relieved? Evaluating the Benefits and Risks of Psychedelics.

Psychedelic substances have played important roles in diverse cultures, and ingesting various plant preparations to evoke altered states of consciousness has been described throughout recorded history. Accounts of the subjective effects of psychedelics typically focus on spiritual and mystical-type experiences, including feelings of unity, sacredness, and transcendence. Over the past 2 decades, there has been increasing interest in psychedelics as treatments for various medical disorders, including chronic pain. Although concerns about adverse medical and psychological effects contributed to their controlled status, contemporary knowledge of psychedelics suggests that risks are relatively rare when patients are carefully screened, prepared, and supervised. Clinical trial results have provided support for the effectiveness of psychedelics in different psychiatric conditions. However, there are only a small number of generally uncontrolled studies of psychedelics in patients with chronic pain (eg, cancer pain, phantom limb pain, migraine, and cluster headache). Challenges in evaluating psychedelics as treatments for chronic pain include identifying neurobiologic and psychosocial mechanisms of action and determining which pain conditions to investigate. Truly informative proof-of-concept and confirmatory randomized clinical trials will require careful selection of control groups, efforts to minimize bias from unblinding, and attention to the roles of patient mental set and treatment setting. PERSPECTIVE: There is considerable promise for the use of psychedelic therapy for pain, but evidence-based recommendations for the design of future studies are needed to ensure that the results of this research are truly informative.

Neural mechanisms underlying psilocybin's therapeutic potential - the need for preclinical in vivo electrophysiology.

Psilocybin is a naturally occurring psychedelic compound with profound perception-, emotion- and cognition-altering properties and great potential for treating brain disorders. However, the neural mechanisms mediating its effects require in-depth investigation as there is still much to learn about how psychedelic drugs produce their profound and long-lasting effects. In this review, we outline the current understanding of the neurophysiology of psilocybin's psychoactive properties, highlighting the need for additional preclinical studies to determine its effect on neural network dynamics. We first describe how psilocybin's effect on brain regions associated with the default-mode network (DMN), particularly the prefrontal cortex and hippocampus, likely plays a key role in mediating its consciousness-altering properties. We then outline the specific receptor and cell types involved and discuss contradictory evidence from neuroimaging studies regarding psilocybin's net effect on activity within these regions. We go on to argue that in vivo electrophysiology is ideally suited to provide a more holistic, neural network analysis approach to understand psilocybin's mode of action. Thus, we integrate information about the neural bases for oscillatory activity generation with the accumulating evidence about psychedelic drug effects on neural synchrony within DMN-associated areas. This approach will help to generate important questions for future preclinical and clinical studies. Answers to these questions are vital for determining the neural mechanisms mediating psilocybin's psychotherapeutic potential, which promises to improve outcomes for patients with severe depression and other difficulty to treat conditions.

Adverse experiences resulting in emergency medical treatment seeking following the use of magic mushrooms.

BACKGROUND: Psilocybin-containing mushrooms are used for recreational, spiritual, self-development and therapeutic purposes. However, physiologically relatively nontoxic, adverse reactions are occasionally reported. AIMS: This study investigated the 12-month prevalence and nature of magic mushroom-related adverse reactions resulting in emergency medical treatment seeking in a global sample of people reporting magic mushroom use. METHODS: We use data from the 2017 Global Drug Survey - a large anonymous online survey on patterns of drug use conducted between November 2016 and January 2017. RESULTS: Out of 9233 past year magic mushroom users, 19 (0.2%) reported having sought emergency medical treatment, with a per-event risk estimate of 0.06%. Young age was the only predictor associated with higher risk of emergency medical presentations. The most common symptoms were psychological, namely anxiety/panic and paranoia/suspiciousness. Poor 'mindset', poor 'setting' and mixing substances were most reported reasons for incidents. All but one respondent returned back to normality within 24 h. CONCLUSIONS: The results confirm psilocybin mushrooms are a relatively safe drug, with serious incidents rare and short lasting. Providing harm-reduction information likely plays a key role in preventing adverse effects. More research is needed to examine the detailed circumstances and predictors of adverse reactions including rarer physiological reactions.

Psilocybin Therapy of Psychiatric Disorders Is Not Hampered by hERG Potassium Channel-Mediated Cardiotoxicity.

Psilocybin, a hallucinogen contained in "magic" mushrooms, holds great promise for the treatment of various psychiatric disorders, and early clinical trials are encouraging. Adverse cardiac events after intake of high doses of psilocybin and a trial reporting QT interval prolongation in the electrocardiogram attributed to the drug's main metabolite, psilocin, gave rise to safety concerns. Here we show that clinical concentrations of psilocin do not cause significant human ether-a-go-go-related gene (hERG) potassium channel inhibition, a major risk factor for adverse cardiac events. We conclude that hERG channel blockage by psilocin is not liable for psilocybin- associated cardiotoxic effects.

Ayahuasca and the traveller: A scoping review of risks and possible benefits.

BACKGROUND: Ayahuasca is a psychotropic drink made from the Amazonian vine Banisteriopsis caapi. Active components include beta-carboline alkaloids and the hallucinogen N-N-dimethyltryptamine (DMT). This review aimed to identify and summarize the literature on the safety and effectiveness of ayahuasca among recreational users. METHOD: A comprehensive literature search was done on November 1, 2019 in the following six databases: PubMed(MEDLINE), Ovid Embase, Ovid International Pharmaceutical Abstracts, LILACS, Scopus, and Web of Science. Articles were included if they were original research published in English, Spanish, or Portuguese, among human participants using oral ayahuasca for neuropsychiatric effects. Chemical or pharmacological analyses, brain imaging studies, and studies examining the use of ayahuasca within a religious context were excluded. RESULTS: 5750 unique titles were identified through the database searches, with an additional 19 titles identified through manual searches. Ultimately, 39 met all the criteria for inclusion. Articles were organized into 4 themes: (1) Case reports and case series; (2) The use of ayahuasca for depression or grief; (3) The use of ayahuasca and other psychiatric or neuropsychological outcomes; and (4) Studies examining ayahuasca use and physiologic outcomes. Ayahuasca use is associated with a risk of both psychiatric and non-psychiatric events including hallucinations, agitation or aggression, vomiting, seizure, and rhabdomyolysis. Five fatalities have been reported in the literature following ayahuasca use. Open-label studies assessing ayahuasca use in depression found favorable results persisting across 21 days. Ayahuasca was also found to influence the MINDSENS scale for mindfulness, with mixed results observed for impact of ayahuasca on cognitive function and creativity, and benefits observed for measures of self-acceptance and overall wellbeing. CONCLUSIONS: To date, evidence on benefits for the management of depression, anxiety, and other mental health disorders is mixed, with some evidence suggesting improvements in mindfulness measures and creativity that are generally short-lived, and multiple case reports suggesting the potential for harm and interactions.

Acute Psychological Adverse Reactions in First-Time Ritual Ayahuasca Users: A Prospective Case Series.

BACKGROUND: In recent decades, ritualistic use of ayahuasca has spread throughout the world. Retrospective studies have suggested a good psychological safety profile, but prospective studies involving ceremony ayahuasca-naive participants are lacking. METHODS: We conducted the study using a subsample from a previous study, for which first-time ceremony ayahuasca participants were recruited. The subsample consisted of 7 subjects who experienced acute and challenging psychological reactions. The semistructured Mini-International Neuropsychiatric Interview and psychometric questionnaires were administered before participants attended the ayahuasca ceremony and at 1 and 6 months after exposure. Subjective experiences were also recorded. RESULTS: Seven subjects from a sample of 40 reported having experienced intense challenging psychological effects during the ayahuasca ceremony. Four of those 7 subjects met the diagnostic criteria for 1 or more psychiatric disorder before the ayahuasca ceremony. One month after the ceremony, 2 of those subjects no longer showed psychiatric symptoms, whereas the symptoms of the other 2 were reduced considerably. Those results persisted at the 6-month follow-up. Inappropriate setting/context (poor guiding skills and screening) contributed to some of the challenging reactions. Most of the participants (6 of 7) did not take ayahuasca again during the study period. CONCLUSIONS: Based on the cases reported here, we suggest that although it is possible that participating in ayahuasca ceremonies may entail acute psychological negative reactions, those challenging experiences can also have positive long-term effects. Prospective research on the safety profile of ayahuasca and how it is affected by the context of different practices and safety strategies is therefore necessary.

Post-acute psychological effects of classical serotonergic psychedelics: a systematic review and meta-analysis.

BACKGROUND: Scientific interest in the therapeutic effects of classical psychedelics has increased in the past two decades. The psychological effects of these substances outside the period of acute intoxication have not been fully characterized. This study aimed to: (1) quantify the effects of psilocybin, ayahuasca, and lysergic acid diethylamide (LSD) on psychological outcomes in the post-acute period; (2) test moderators of these effects; and (3) evaluate adverse effects and risk of bias. METHODS: We conducted a systematic review and meta-analysis of experimental studies (single-group pre-post or randomized controlled trials) that involved administration of psilocybin, ayahuasca, or LSD to clinical or non-clinical samples and assessed psychological outcomes ⩾24 h post-administration. Effects were summarized by study design, timepoint, and outcome domain. RESULTS: A total of 34 studies (24 unique samples, n = 549, mean longest follow-up = 55.34 weeks) were included. Classical psychedelics showed significant within-group pre-post and between-group placebo-controlled effects on a range of outcomes including targeted symptoms within psychiatric samples, negative and positive affect-related measures, social outcomes, and existential/spiritual outcomes, with large between-group effect in these domains (Hedges' gs = 0.84 to 1.08). Moderator tests suggest some effects may be larger in clinical samples. Evidence of effects on big five personality traits and mindfulness was weak. There was no evidence of post-acute adverse effects. CONCLUSIONS: High risk of bias in several domains, heterogeneity across studies, and indications of publication bias for some models highlight the need for careful, large-scale, placebo-controlled randomized trials.

Psychedelics as a novel approach to treating autoimmune conditions.

With a rise in the incidence of autoimmune diseases (AiD), health care providers continue to seek out more efficacious treatment approaches for the AiD patient population. Classic serotonergic psychedelics have recently been gaining public and professional interest as novel interventions to a number of mental health afflictions. Psychedelics have also been shown to be able to modulate immune functions, however, while there has been great interest to researching into their psychotherapeutic applications, there has so far been very little exploration into the potential to treat inflammatory and immune-related diseases with these compounds. A handful of studies from a variety of fields suggest that psychedelics do indeed have effects in the body that may attenuate the outcome of AiD. This literature review explores existing evidence that psychedelic compounds may offer a potential novel application in the treatment of pathologies related to autoimmunity. We propose that psychedelics hold the potential to attenuate or even resolve autoimmunity by targeting psychosomatic origins, maladaptive chronic stress responses, inflammatory pathways, immune modulation and enteric microbiome populations.

Chronic pain and psychedelics: a review and proposed mechanism of action.

The development of chronic pain is a complex mechanism that is still not fully understood. Multiple somatic and visceral afferent pain signals, when experienced over time, cause a strengthening of certain neural circuitry through peripheral and central sensitization, resulting in the physical and emotional perceptual chronic pain experience. The mind-altering qualities of psychedelics have been attributed, through serotonin 2A (5-HT2A) receptor agonism, to 'reset' areas of functional connectivity (FC) in the brain that play prominent roles in many central neuropathic states. Psychedelic substances have a generally favorable safety profile, especially when compared with opioid analgesics. Clinical evidence to date for their use for chronic pain is limited; however, several studies and reports over the past 50 years have shown potential analgesic benefit in cancer pain, phantom limb pain and cluster headache. While the mechanisms by which the classic psychedelics may provide analgesia are not clear, several possibilities exist given the similarity between 5-HT2A activation pathways of psychedelics and the nociceptive modulation pathways in humans. Additionally, the alterations in FC seen with psychedelic use suggest a way that these agents could help reverse the changes in neural connections seen in chronic pain states. Given the current state of the opioid epidemic and limited efficacy of non-opioid analgesics, it is time to consider further research on psychedelics as analgesics in order to improve the lives of patients with chronic pain conditions.

Effects of ayahuasca on mental health and quality of life in naïve users: A longitudinal and cross-sectional study combination.

Ayahuasca is a hallucinogenic decoction used as a traditional medicine in several Amazonian regions. The ritualistic use of ayahuasca has spread throughout many countries, making it necessary to study its risks and benefits. Two sub-studies were designed for this investigation. In sub-study 1, a psychiatric interview and a battery of questionnaires were administered to subjects (n = 40) before their first ayahuasca use. Two follow-ups were conducted at 1 and 6 months. In sub-study 2, the same interview and battery of questionnaires were administered to long-term ayahuasca users (n = 23) and their scores were compared with those of the ayahuasca-naïve group. In the first assessment, nearly half (45%) of the naïve users were found to meet the diagnostic criteria for a psychiatric disorder. After the ayahuasca use, more than 80% of those subjects showed clinical improvements that persisted at 6 months. The questionnaires showed significant reductions in depression and psychopathology. Regarding sub-study 2, long-term users showed lower depression scores, and higher scores for self-transcendence and quality of life, as compared to their peers in sub-study 1. Further controlled and observational naturalistic studies assessing the eventual risks and potential benefits of ayahuasca are warranted.

Characterization and prediction of acute and sustained response to psychedelic psilocybin in a mindfulness group retreat.

Meditation and psychedelics have played key roles in humankind's search for self-transcendence and personal change. However, neither their possible synergistic effects, nor related state and trait predictors have been experimentally studied. To elucidate these issues, we administered double-blind the model psychedelic drug psilocybin (315 µg/kg PO) or placebo to meditators (n = 39) during a 5-day mindfulness group retreat. Psilocybin increased meditation depth and incidence of positively experienced self-dissolution along the perception-hallucination continuum, without concomitant anxiety. Openness, optimism, and emotional reappraisal were predictors of the acute response. Compared with placebo, psilocybin enhanced post-intervention mindfulness and produced larger positive changes in psychosocial functioning at a 4-month follow-up, which were corroborated by external ratings, and associated with magnitude of acute self-dissolution experience. Meditation seems to enhance psilocybin's positive effects while counteracting possible dysphoric responses. These findings highlight the interactions between non-pharmacological and pharmacological factors, and the role of emotion/attention regulation in shaping the experiential quality of psychedelic states, as well as the experience of selflessness as a modulator of behavior and attitudes. A better comprehension of mechanisms underlying most beneficial psychedelic experiences may guide therapeutic interventions across numerous mental conditions in the form of psychedelic-assisted applications.

Neurophenomenology of induced and natural synaesthesia.

People with synaesthesia have additional perceptual experiences, which are automatically and consistently triggered by specific inducing stimuli. Synaesthesia therefore offers a unique window into the neurocognitive mechanisms underlying conscious perception. A long-standing question in synaesthesia research is whether it is possible to artificially induce non-synaesthetic individuals to have synaesthesia-like experiences. Although synaesthesia is widely considered a congenital condition, increasing evidence points to the potential of a variety of approaches to induce synaesthesia-like experiences, even in adulthood. Here, we summarize a range of methods for artificially inducing synaesthesia-like experiences, comparing the resulting experiences to the key hallmarks of natural synaesthesia which include consistency, automaticity and a lack of 'perceptual presence'. We conclude that a number of aspects of synaesthesia can be artificially induced in non-synaesthetes. These data suggest the involvement of developmental and/or learning components in the acquisition of synaesthesia, and they extend previous reports of perceptual plasticity leading to dramatic changes in perceptual phenomenology in adults. This article is part of a discussion meeting issue 'Bridging senses: novel insights from synaesthesia'.

Medical Cannabis Users' Comparisons between Medical Cannabis and Mainstream Medicine.

An evidence-based approach is needed to shape policies and practices regarding medical cannabis, thereby reducing harm and maximizing benefits to individuals and society. This project assesses attitudes towards and utilization of medical cannabis and the mainstream healthcare system among medical cannabis users. The research team administered brief hard copy surveys to 450 adults attending an annual public event advocating for cannabis law reform. Among usable responses (N = 392), the majority (78%) reported using cannabis to help treat a medical or health condition. Medical cannabis users reported a greater degree of use of medical cannabis and a greater degree of trust in medical cannabis compared to mainstream healthcare. In comparison to pharmaceutical drugs, medical cannabis users rated cannabis better on effectiveness, side effects, safety, addictiveness, availability, and cost. Due to the medical use of cannabis, 42% stopped taking a pharmaceutical drug and 38% used less of a pharmaceutical drug. A substantial proportion (30%) reported that their mainstream healthcare provider did not know that they used medical cannabis. Other issues identified included lack of access to mainstream healthcare, self-initiated treatment of health issues, little knowledge of psychoactive content, and heavy cannabis use.

Effect of Ritualistic Consumption of Ayahuasca on Hepatic Function in Chronic Users.

Ayahuasca is a beverage obtained from decoctions of the liana Banisteriopsis caapi plus the shrub Psychotria viridis. This beverage contains a combination of monoamine oxidase inhibitors (harmine, harmaline, and tetrahydroharmine) and N,N-dimethyltryptamine, the main substance responsible for its visionary effect. The ritualistic use of ayahuasca is becoming a global phenomenon. Most members of ayahuasca churches consume this beverage throughout their life, and many reports have discussed the therapeutic potential of this beverage. Ayahuasca is consumed orally, and the liver, as the major organ for the metabolism and detoxification of xenobiotics absorbed from the alimentary tract, may be susceptible to injury by compounds present in the ayahuasca decoction. In this study, we evaluated biochemical parameters related to hepatic damage in the serum of 22 volunteers who consumed ayahuasca twice a month or more for at least one year. There was no significant alteration in the following parameters: alanine aminotransferase, aspartate aminotransferase, bilirubin, creatinine, urea, lactate dehydrogenase, alkaline phosphatase, and gamma glutamyl transferase. These findings indicate that chronic ayahuasca consumption in a religious context apparently does not affect hepatic function.