Efficacy and safety of psychedelics for the treatment of mental disorders: A systematic review and meta-analysis.

We aim to systematically review and meta-analyze the effectiveness and safety of psychedelics [psilocybin, ayahuasca (active component DMT), LSD and MDMA] in treating symptoms of various mental disorders. Web of Science, Embase, EBSCO, and PubMed were searched up to February 2024 and 126 articles were finally included. Results showed that psilocybin has the largest number of articles on treating mood disorders (N = 28), followed by ayahuasca (N = 7) and LSD (N = 6). Overall, psychedelics have therapeutic effects on mental disorders such as depression and anxiety. Specifically, psilocybin (Hedges' g = -1.49, 95% CI [-1.67, -1.30]) showed the strongest therapeutic effect among four psychedelics, followed by ayahuasca (Hedges' g = -1.34, 95% CI [-1.86, -0.82]), MDMA (Hedges' g = -0.83, 95% CI [-1.33, -0.32]), and LSD (Hedges' g = -0.65, 95% CI [-1.03, -0.27]). A small amount of evidence also supports psychedelics improving tobacco addiction, eating disorders, sleep disorders, borderline personality disorder, obsessive-compulsive disorder, and body dysmorphic disorder. The most common adverse event with psychedelics was headache. Nearly a third of the articles reported that no participants reported lasting adverse effects. Our analyses suggest that psychedelics reduce negative mood, and have potential efficacy in other mental disorders, such as substance-use disorders and PTSD.

Potential analgesic effects of psychedelics on select chronic pain conditions: A survey study.

BACKGROUND: Chronic pain is a major cause of suffering and disability and is often associated with psychiatric complications. Current treatments carry the risk of severe side effects and may lead to limited or no relief at all in a relevant portion of this patient population. Preliminary evidence suggests that classical psychedelics (e.g. LSD and psilocybin) may have analgesic effects in healthy volunteers, and in certain chronic pain conditions and observational studies reveal that they are used in naturalistic settings as a means to manage pain. METHODS: In order to gain insight on the effectiveness of such compounds in chronic pain conditions, we set up a survey addressed to chronic pain patients inquiring about psychedelic use and the relief levels achieved with both conventional treatments, full psychedelic doses and microdoses. We analysed data related to five conditions selected based on diagnostic homogeneity within each of them: fibromyalgia, arthritis, migraine, tension-type headache and sciatica. RESULTS: Except for sciatica, volunteers reported that psychedelics led to better pain relief compared to conventional medication in all examined conditions. More specifically, full doses performed better than conventional medication. Microdoses led to significantly better relief compared to conventional medication in migraines and achieved comparable relief in the remaining three categories. Implications for future research are discussed. CONCLUSIONS: Full doses and microdoses may hold value in the treatment of some specific chronic pain conditions. SIGNIFICANCE: Psychedelic substances are receiving increasing attention from the scientific literature because of evidence showing beneficial effects on several measures related to mental health in clinical samples and healthy volunteers samples. Previous evidence suggests that people suffering from chronic pain are using psychedelics to seek relief and the present paper presents the results of a survey study investigating their use and analgesic effects among individuals suffering from fibromyalgia, arthritis, migraine, tension-type headache and sciatica.

Use of Psychedelics for Pain: A Scoping Review.

Chronic pain is a public health concern that affects approximately 1.5 billion people globally. Conventional therapeutic agents including opioid and non-opioid analgesics have been associated with adverse side effects, issues with addiction, and ineffective analgesia. Novel agents repurposed to treat pain via different mechanisms are needed to fill the therapeutic gap in chronic pain management. Psychedelics such as lysergic acid diethylamide and psilocybin (the active ingredient in psychedelic mushrooms) are thought to alter pain perception through direct serotonin receptor agonism, anti-inflammatory effects, and synaptic remodeling. This scoping review was conducted to identify human studies in which psychedelic agents were used for the treatment of pain. Twenty-one articles that assessed the effects of psychedelics in treating various pain states were included. The present scarcity of clinical trials and small sample sizes limit their application for clinical use. Overall, psychedelics appear to show promise for analgesia in patients with certain headache disorders and cancer pain diagnoses. Future studies must aim to examine the combined effects of psychotherapy and psychedelics on chronic pain.

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.

Cannabis use and gastrointestinal tract illnesses: The National Health and Nutrition Examination Surveys, 2005-2018.

INTRODUCTION: The antiemetic properties of cannabis have motivated its use in the management of chemotherapy-induced nausea and vomiting. Conversely, case reports of intractable vomiting among heavy cannabis users have increasingly appeared in the literature. Studies on cannabis and gastrointestinal tract (GIT) health are scare. Here, we use data for the National Health and Nutrition Examination Surveys (NHANES, 2005-2018) to estimate the association between cannabis use and GIT illness. METHODS: The study sample included non-pregnant adult NHANES participants (20-59 years) without history of cancer or HIV (n = 18,753). Cannabis use was categorised into never, former (0 day in the past 30 days), infrequent (1-2 days), occasional (3-19 days) and frequent (20-30 days) use. Recent GIT illness was defined as experiencing GIT illness with vomiting or diarrhoea that started in the 30 days prior to NHANES. Logistic regression was used to regress GIT illness on cannabis use, adjusting for potential confounders. RESULTS: Compared to never use, frequent cannabis use was associated with higher odds of GIT illness (OR = 1.4; 95% confidence interval 1.04, 1.9). There were no associations between former, infrequent or occasional cannabis use and GIT illness. DISCUSSION AND CONCLUSIONS: Frequent cannabis use is associated with GIT illnesses in a large cross-sectional study of US residents. It is possible that frequent cannabis use adversely affects GIT health, consistent with clinical case reports. Alternatively, patients with GIT illness might self-medicate with cannabis given its antiemetic properties. Prospective studies are needed to understand the effects of cannabis use on GIT health.

Psychedelics for Patients With Cancer: A Comprehensive Literature Review.

OBJECTIVE: To assess the role of psychedelics in the treatment of anxiety or depression among patients with cancer. DATA SOURCES: PubMed search from inception to March 11, 2022, using the terms anxiety, depression, psychedelics, psilocybin, lysergic acid, methylenedioxymethamphetamine, or ayahuasca. STUDY SELECTION AND DATA EXTRACTION: Studies assessing patients with cancer receiving psychedelics for the treatment of anxiety or depression. DATA SYNTHESIS: Five unique randomized, double-blind, placebo-controlled trials were conducted. Significant reductions were found in 2 trials with 2 anxiety scales (State-Trait Anxiety Inventory-State, State-Trait Anxiety Inventory-Trait) and in 1 trial with 2 additional anxiety scales (Hamilton Rating Scale-Anxiety, Hospital Anxiety and Depression Scale-Anxiety). Significant reductions were found in 2 trials in 2 depression scales (Hospital Anxiety and Depression Scale-Depression, Beck Depression Inventory) and in 1 trial with an additional depression scale (Hamilton Rating Scale-Depression). Two studies assessed for clinically relevant reductions in anxiety and depression scores, and they occurred much more commonly in psychedelic-treated patients than those given placebo. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: There is a new potential option for treating patients with anxiety and depression along with cancer, which is important given the generally lackluster benefits with traditional antidepressants. Only a few sessions may also provide benefits extending out for 6 to 12 months and possibly beyond that. However, the studies were small, had many methodological limitations, and there were increases in blood pressure and heart rate. CONCLUSIONS: Psychedelics have a unique mechanism of action that might be well suited for treating anxiety and depression associated with cancer. This offers new promise for patients who are not being sufficiently treated with current antianxiety or antidepressant medications.

The Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force Report: Serotonergic Psychedelic Treatments for Major Depressive Disorder.

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.

Associations between MDMA/ecstasy use and physical health in a U.S. population-based survey sample.

INTRODUCTION: 3,4-Methylenedioxymethamphetamine (MDMA/"ecstasy") is an empathogen that can give rise to increased pleasure and empathy and may effectively treat post-traumatic stress disorder. Although prior research has demonstrated associations between ecstasy use and favorable mental health outcomes, the associations between ecstasy and physical health have largely been unexplored. Thus, the goal of this study was to examine the associations between ecstasy use and physical health in a population-based survey sample. METHOD: This study utilized data from the National Survey on Drug Use and Health (2005-2018), a yearly survey that collects information on substance use and health outcomes in a nationally representative sample of U.S. adults. We used multinomial, ordered, and logistic regression models to test the associations between lifetime ecstasy use and various markers of physical health (self-reported body mass index, overall health, past year heart condition and/or cancer, past year heart disease, past year hypertension, and past year diabetes), controlling for a range of potential confounders. RESULTS: Lifetime ecstasy use was associated with significantly lower risk of self-reported overweightness and obesity (adjusted relative risk ratio range: 0.55-0.88) and lower odds of self-reported past year heart condition and/or cancer (adjusted odds ratio (aOR): 0.67), hypertension (aOR: 0.85), and diabetes (aOR: 0.58). Ecstasy use was also associated with significantly higher odds of better self-reported overall health (aOR: 1.18). CONCLUSION: Ecstasy shares protective associations with various physical health markers. Future longitudinal studies and clinical trials are needed to more rigorously test these associations.

Is psychedelic use associated with cancer?: Interrogating a half-century-old claim using contemporary population-level data.

BACKGROUND: In 1967, concerns about the carcinogenic potential of psychedelics arose after a study reported chromosomal damage in human leukocytes following in vitro lysergic acid (LSD) exposure. Worries were further heightened by subsequent reports of leukemia and other cancers in LSD users. Additional investigations of psychedelics' effects on chromosomes were published over the next decade, with the majority suggesting these concerns were unfounded. However, the relationship between psychedelics and cancer has been explored only minimally from an epidemiological perspective. AIMS: To determine whether associations exist between psychedelic use and either lifetime cancer or hematologic cancer diagnoses. METHODS: We analyzed data from adult participants in the 2015-2019 administrations of the National Survey on Drug Use and Health for associations between lifetime use of psychedelics and lifetime diagnosis of either any cancer or hematologic cancer. RESULTS: We identified no associations between lifetime psychedelic use and either lifetime cancer diagnosis or hematologic cancer diagnosis. Sub-analyses of lifetime lysergamide, phenethylamine, and tryptamine use also revealed no associations with lifetime cancer or hematologic cancer diagnosis. CONCLUSIONS: While laboratory studies and case reports from the 1960s and 1970s generated concerns about psychedelics' carcinogenic potential, this analysis of recent epidemiological data does not support an association between psychedelic use and development of cancer in general or hematologic cancer. Important study limitations to consider include a lack of information about psychedelic dosage, number of lifetime psychedelic exposures, and the temporal relationship between psychedelic use and cancer diagnosis.

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.

Modified climbing fiber/Purkinje cell synaptic connectivity in the cerebellum of the neonatal phencyclidine model of schizophrenia.

Environmental perturbations during the first years of life are a major factor in psychiatric diseases. Phencyclidine (PCP), a drug of abuse, has psychomimetic effects, and neonatal subchronic administration of PCP in rodents leads to long-term behavioral changes relevant for schizophrenia. The cerebellum is increasingly recognized for its role in diverse cognitive functions. However, little is known about potential cerebellar changes in models of schizophrenia. Here, we analyzed the characteristics of the cerebellum in the neonatal subchronic PCP model. We found that, while the global cerebellar cytoarchitecture and Purkinje cell spontaneous spiking properties are unchanged, climbing fiber/Purkinje cell synaptic connectivity is increased in juvenile mice. Neonatal subchronic administration of PCP is accompanied by increased cFos expression, a marker of neuronal activity, and transient modification of the neuronal surfaceome in the cerebellum. The largest change observed is the overexpression of Ctgf, a gene previously suggested as a biomarker for schizophrenia. This neonatal increase in Ctgf can be reproduced by increasing neuronal activity in the cerebellum during the second postnatal week using chemogenetics. However, it does not lead to increased climbing fiber/Purkinje cell connectivity in juvenile mice, showing the complexity of PCP action. Overall, our study shows that administration of the drug of abuse PCP during the developmental period of intense cerebellar synaptogenesis and circuit remodeling has long-term and specific effects on Purkinje cell connectivity and warrants the search for this type of synaptic changes in psychiatric diseases.

[Are psychedelics fast acting antidepressant agents?] / Sind Psychedelika schnell wirksame Antidepressiva?

BACKGROUND: Psychedelics, such as psilocybin represent one of the most promising current therapeutic approaches in psychiatry. OBJECTIVE: Psychedelics seem to have not only potent antidepressant effects. Do they also work particularly quickly, i.e. within one day? MATERIAL AND METHODS: The available literature on clinical studies of psychedelics in depressive syndromes is presented both from the period up to the prohibition of these substances in the late 1960s as well as after the resumption of research in the 2000s. One focus is the speed of onset of antidepressant action. RESULTS: Only the clinical studies published since 2016 that meet modern methodological standards have also systematically examined the speed of the antidepressant onset of action. The published studies, which were almost exclusively carried out with psilocybin, so far show small sample sizes (the total number of patients with depression treated in published clinical studies is < 200) and some of them have methodological weaknesses; however, they suggest a pronounced and very rapid onset of action within one day for depression, treatment-resistant depression and depression in the context of life-threatening cancer. CONCLUSION: The available studies indicate a potent, rapid onset and in many cases long-lasting antidepressant effect over several months. The currently conducted studies with three-digit patient numbers will provide final information about the potential of psilocybin for depression.

Psychedelics and health behaviour change.

Healthful behaviours such as maintaining a balanced diet, being physically active and refraining from smoking have major impacts on the risk of developing cancer, diabetes, cardiovascular diseases and other serious conditions. The burden of the so-called 'lifestyle diseases'-in personal suffering, premature mortality and public health costs-is considerable. Consequently, interventions designed to promote healthy behaviours are increasingly being studied, e.g., using psychobiological models of behavioural regulation and change. In this article, we explore the notion that psychedelic substances such as psilocybin could be used to assist in promoting positive lifestyle change conducive to good overall health. Psilocybin has a low toxicity, is non-addictive and has been shown to predict favourable changes in patients with depression, anxiety and other conditions marked by rigid behavioural patterns, including substance (mis)use. While it is still early days for modern psychedelic science, research is advancing fast and results are promising. Here we describe psychedelics' proposed mechanisms of action and research findings pertinent to health behaviour change science, hoping to generate discussion and new research hypotheses linking the two areas. Therapeutic models including psychedelic experiences and common behaviour change methods (e.g., Cognitive Behaviour Therapy, Motivational Interviewing) are already being tested for addiction and eating disorders. We believe this research may soon be extended to help promote improved diet, exercise, nature exposure and also mindfulness or stress reduction practices, all of which can contribute to physical and psychological health and well-being.

Psychedelics and Hallucinogens in Psychiatry: Finding New Pharmacological Targets.

BACKGROUND: The therapeutic options for neurobehavioral disorders are still limited, and in many cases, they lack a satisfactory balance between efficacy and side effects. OBJECTIVES: This work aims to review current evidence regarding the potential contribution of psychedelics and hallucinogens to the discovery of new drugs for treating different psychiatric disorders. DISCUSSION: Ayahuasca/N,N-dimethyltryptamine (DMT), lysergic acid diethylamide (LSD), and psilocybin have evidence supporting their use in depression, and psilocybin and ayahuasca have also shown good results in treatment-resistant depression. In randomized controlled trials (RCTs) conducted with anxious patients, there were symptomatic improvements with psilocybin and LSD. Psilocybin diminished Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores in a small obsessive- compulsive disorder (OCD) sample. The evidence is less robust regarding substance use disorders, but it suggests a possible role for LSD and psilocybin in alcohol use disorders and for psilocybin in tobacco addiction. In a clinical setting, these substances seem to be safe and well-tolerated. Their mechanisms of action are not fully elucidated, but there seems to be a preponderant role of 5-hydroxytryptamine (5HT) 2A agonism, as well as connectivity changes within the default mode network (DMN) and amygdala and some other molecular modifications. CONCLUSION: The studies underlying the conclusions have small samples and are heterogeneous in their methods. However, the results suggest that the use of psychedelics and hallucinogens could be considered in some disorders. More studies are needed to reinforce their evidence as potential new drugs.

Behavioral characterization of ayahuasca treatment on Wistar rats in the open field test

Abstract Ayahuasca (AYA) is a psychedelic beverage with therapeutic potential for many mood and anxiety disorders. Although there are some preclinical studies, no published reports have tested the behavioral effects of AYA gavage in animal models. This investigation aimed to characterize the behavior of Wistar rats after acute ingestion of AYA for 40 min in the open field test (OFT). The sample consisted of three experimental groups treated with different dosages of AYA (125, 250, or 500 mg kg-1) and a control group. Each group consisted of 10 participants. After gavage, the number of crossings of the OFT grid lines, latency to enter the central area of the device, grooming frequency, and time spent in the central perimeter of the device were immediately evaluated. Analyses were based on one-way ANOVA and a linear-regression mixture model for longitudinal data. AYA intake did not interfere with habituation. The 500 mg kg-1 group showed a decrease in the time spent in the center of the device and in the number of crossings compared to the control group in the last 10 min. These results suggest that gavage with AYA did not interfere with the results, and the behavioral effects were perceived only between 30 and 40 min after gavage. Taken together, the results indicate that three aspects should be considered in OFT studies of AYA acute effects: the moment when the observation starts, the observation period, and the AYA dosage.

Relationships between patterns of cannabis use, abuse and dependence and recent stimulant use: Evidence from two national surveys in Ireland.

BACKGROUND AND OBJECTIVES: Epidemiological studies show that the use of cannabis is related to the use of other illicit drugs, including stimulants such as cocaine and ecstasy. However, few studies have examined how patterns of cannabis use relate to the use of stimulants. In this research we determined relationships between patterns of cannabis use and recent stimulant use, drawing on data from two large nationally representative surveys. We also explored how frequency of cannabis use relates to stimulant use and whether subjects with a cannabis use disorder (CUD)-defined as cannabis abuse or dependence-are more likely to be recent users of cocaine or ecstasy. MATERIALS AND METHODS: We analysed data from Ireland's 2010/11 and 2014/15 National Drug Prevalence Surveys,which recruited 5,134 and 7,005 individuals respectively, aged 15 years and over, living in private households. We included only those people who reported some past cannabis use. Multivariable logistic regression analysis was used to examine associations between patterns of cannabis use and recent stimulant use. RESULTS: Among survey participants who had used cannabis in the last month, 17.9% reported recent cocaine use, while almost one-quarter (23.6%) reported recent ecstasy use. There was a significant linear relationship between patterns of cannabis use and recent use of cocaine, ecstasy or any stimulant, with last month cannabis users displaying greater odds (OR = 12.03, 95% CI: 8.15-17.78) of having recent stimulant use compared to last year (OR = 4.48, 95% CI: 2.91-6.91) and former (reference) cannabis users. Greater frequency of cannabis use in the last 30 days was also significantly related to the use of stimulants. In addition, results demonstrated an association between CUD and recent use of cocaine or ecstasy (OR = 2.28, 95% CI: 1.55-3.35). CONCLUSIONS: Findings from this study suggest a relationship between patterns and frequency of cannabis use and recent use of stimulants and an association between CUD and stimulant use. As the use of cannabis with stimulants may increase the risk of negative health consequences, education in community and medical settings about polydrug use and its increased risks may be warranted.