Psychedelic-assisted therapy for treating anxiety, depression, and existential distress in people with life-threatening diseases.

BACKGROUND: Psychedelic-assisted therapy refers to a group of therapeutic practices involving psychedelics taken under therapeutic supervision from physicians, psychologists, and others. It has been hypothesised that psychedelic-assisted therapy may reduce symptoms of anxiety, depression, and existential distress in patients facing life-threatening diseases (e.g. cancer). However, these substances are illegal in most countries and have been associated with potential risks. OBJECTIVES: To assess the benefits and harms of psychedelic-assisted therapy compared to placebo or active comparators (e.g. antidepressants) for treatment of anxiety, depression, and existential distress in people with life-threatening diseases. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and two trial registers on 30 March 2024. In addition, we undertook reference checking, citation searching, and contact with study authors to identify additional studies. We used no language or date restrictions. SELECTION CRITERIA: We included randomised controlled trials (RCTs), with no restrictions regarding comorbidity, sex, or ethnicity. Interventions comprised a substance-induced psychedelic experience preceded by preparatory therapeutic sessions and followed by integrative therapeutic sessions. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. MAIN RESULTS: We included six studies in the review, which evaluated two different interventions: psychedelic-assisted therapy with classical psychedelics (psilocybin ('magic mushrooms') and lysergic acid diethylamide (LSD)), and psychedelic-assisted therapy with 3,4-methylenedioxymethamphetamine (MDMA or 'Ecstasy'). The studies randomised 149 participants with life-threatening diseases and analysed data for 140 of them. The age range of participants was 36 to 64 years. The studies lasted between 6 and 12 months, and were conducted in outpatient settings in the USA and in Switzerland. Drug companies were not involved in study funding, but funding was provided by organisations that promote psychedelic-assisted therapy. Primary outcomes (at 1 to 12 weeks) Anxiety Psychedelic-assisted therapy using classical psychedelics (psilocybin, LSD) may result in a reduction in anxiety when compared to active placebo (or low-dose psychedelic): State Trait Anxiety Inventory (STAI-Trait, scale 20 to 80) mean difference (MD) -8.41, 95% CI -12.92 to -3.89; STAI-State (scale 20 to 80) MD -9.04, 95% CI -13.87 to -4.21; 5 studies, 122 participants; low-certainty evidence. The effect of psychedelic-assisted therapy using MDMA on anxiety, compared to placebo, is very uncertain: STAI-T MD -14.70, 95% CI -29.45 to 0.05; STAI-S MD -16.10, 95% CI -33.03 to 0.83; 1 study, 18 participants; very low certainty evidence. Depression Psychedelic-assisted therapy using classical psychedelics (psilocybin, LSD) may result in a reduction in depression when compared to active placebo (or low-dose psychedelic): Beck Depression Inventory (BDI, scale 0 to 63) MD -4.92, 95% CI -8.97 to -0.87; 4 studies, 112 participants; standardised mean difference (SMD) -0.43, 95% CI -0.79 to -0.06; 5 studies, 122 participants; low-certainty evidence. The effect of psychedelic-assisted therapy using MDMA on depression, compared to placebo, is very uncertain: BDI-II (scale: 0 to 63) MD -6.30, 95% CI -16.93 to 4.33; 1 study, 18 participants; very low certainty evidence. Existential distress Psychedelic-assisted therapy using classical psychedelics (psilocybin, LSD) compared to active placebo (or low-dose psychedelic) may result in a reduction in demoralisation, one of the most common measures of existential distress, but the evidence is very uncertain (Demoralisation Scale, 1 study, 28 participants): post treatment scores, placebo group 39.6 (SEM 3.4), psilocybin group 18.8 (3.6), P ≤ 0.01). Evidence from other measures of existential distress was mixed. Existential distress was not measured in people receiving psychedelic-assisted therapy with MDMA. Secondary outcomes (at 1 to 12 weeks) Quality of life When classical psychedelics were used, one study had inconclusive results and two reported improved quality of life, but the evidence is very uncertain. MDMA did not improve quality of life measures, but the evidence is also very uncertain. Spirituality Participants receiving psychedelic-assisted therapy with classical psychedelics rated their experience as being spiritually significant (2 studies), but the evidence is very uncertain. Spirituality was not assessed in participants receiving MDMA. Adverse events No treatment-related serious adverse events or adverse events grade 3/4 were reported. Common minor to moderate adverse events for classical psychedelics were elevated blood pressure, nausea, anxiety, emotional distress, and psychotic-like symptoms (e.g. pseudo-hallucination where the participant is aware they are hallucinating); for MDMA, common minor to moderate adverse events were anxiety, dry mouth, jaw clenching, and headaches. Symptoms subsided when drug effects wore off or up to one week later. Certainty of the evidence Although all six studies had intended to blind participants, personnel, and assessors, blinding could not be achieved as this is very difficult in studies investigating psychedelics. Using GRADE criteria, we judged the certainty of evidence to be low to very low, mainly due to high risk of bias and imprecision (small sample size). AUTHORS' CONCLUSIONS: Implications for practice Psychedelic-assisted therapy with classical psychedelics (psilocybin, LSD) may be effective for treating anxiety, depression, and possibly existential distress, in people facing a life-threatening disease. Psychedelic-assisted therapy seemed to be well tolerated, with no treatment-emergent serious adverse events reported in the studies included in this review. However, the certainty of evidence is low to very low, which means that we cannot be sure about these results, and they might be changed by future research. At the time of this review (2024), psychedelic drugs are illegal in many countries. Implications for research The risk of bias due to 'unblinding' (participants being aware of which intervention they are receiving) could be reduced by measuring expectation bias, checking blinding has been maintained before cross-over, and using active placebos. More studies with larger sample sizes are needed to reduce imprecision. As the US Drug Enforcement Administration (DEA) currently classifies psychedelics as Schedule I substances (i.e. having no accepted medical use and a high potential for abuse), research involving these drugs is restricted, but is steadily increasing.

Validation of the Swiss Psychedelic Side Effects Inventory: Standardized assessment of adverse effects in studies of psychedelics and MDMA.

INTRODUCTION: Studies of psychedelic-assisted therapy with LSD, psilocybin, MDMA, and related substances show clinical promise but inadequately assess side effects. Measuring side effects is challenging because they are not always easily differentiated from treatment effects or disease symptoms and show high heterogeneity, variable duration and impact, and sensitivity to context. A systematic questionnaire describing important characteristics of side effects of psychedelics and MDMA would greatly improve on previous methods. We aimed to create a standardized tool for recording clinically relevant side effects of psychedelics and MDMA, including their severity, duration, impact, and treatment-relatedness. METHODS: We constructed the Swiss Psychedelic Side Effects Inventory (SPSI) based on insights from previous research. It was pilot tested in 145 participants from three studies. Structured feedback from an expert panel was used to improve validity and feasibility. RESULTS: The final SPSI contains 32 side effects and standardized follow-up questions about their severity, impact, treatment-relatedness, and duration. It is compatible with any study design and can be administered as an interview or self-report at any timepoint after treatment with psychedelics or MDMA. LIMITATIONS: The SPSI omits relatively unimportant side effects for brevity's sake, though space for additional symptoms is given. Future studies are needed to confirm its validity in different contexts. CONCLUSIONS: The SPSI is available in English and German for collecting systematic data on side effects from psychedelics and MDMA. This information is vital for improving clinical decisions, informed consent, and patient safety.

LSDDEP2: study protocol for a randomised, double-dummy, triple-blind, active placebo-controlled, parallel groups trial of LSD microdosing in patients with major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) poses a significant global health burden with available treatments limited by inconsistent efficacy and notable side effects. Classic psychedelics, including lysergic acid diethylamide (LSD), have garnered attention for their potential in treating psychiatric disorders. Microdosing, the repeated consumption of sub-hallucinogenic doses of psychedelics, has emerged as a self-treatment approach for depression within lay communities. Building upon preliminary evidence and the successful completion of an open-label pilot trial of microdosing LSD for depression (LSDDEP1), this protocol outlines a phase 2b randomised controlled trial (LSDDEP2). The main objective of LSDDEP2 is to assess the modification of depressive symptoms, measured by the Montgomery-Åsberg Depression Rating Scale (MADRS), following a regimen of LSD microdoses versus placebo. METHODS: This is a randomised, double-dummy, triple-blind, active placebo-controlled, parallel groups trial of LSD microdosing in patients meeting DSM-5 criteria for major depressive disorder. Participants will undergo an 8-week LSD microdosing regimen using the titratable MB-22001 formulation taking two doses a week. All doses will be self-administered at home and will be titratable from 4 to 20 µg based on subjective perception and tolerability. In addition to depression symptoms, outcome will include psychiatric and personality inventories, sleep and activity tracking, electroencephalography (EEG), blood biomarkers, semi-structured interviews, and safety (e.g. adverse event, laboratory exam) measures. DISCUSSION: This study will be the first randomised controlled trial to administer controlled microdoses of LSD for treatment of MDD in participants' naturalistic environment. The measures included are designed to assess the drug's safety, mechanism, and treatment efficacy over placebo in this population. The results of this study will be important for assessing the viability of psychedelic microdosing as an additional treatment option and for informing the direction of future clinical trials. TRIAL REGISTRATION: ANZCTR, ACTRN12624000128594. Prospectively Registered on 13 February 2024.

Comparative oral monotherapy of psilocybin, lysergic acid diethylamide, 3,4-methylenedioxymethamphetamine, ayahuasca, and escitalopram for depressive symptoms: systematic review and Bayesian network meta-analysis.

OBJECTIVE: To evaluate the comparative effectiveness and acceptability of oral monotherapy using psychedelics and escitalopram in patients with depressive symptoms, considering the potential for overestimated effectiveness due to unsuccessful blinding. DESIGN: Systematic review and Bayesian network meta-analysis. DATA SOURCES: Medline, Cochrane Central Register of Controlled Trials, Embase, PsycINFO, ClinicalTrial.gov, and World Health Organization's International Clinical Trials Registry Platform from database inception to 12 October 2023. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials on psychedelics or escitalopram in adults with depressive symptoms. Eligible randomised controlled trials of psychedelics (3,4-methylenedioxymethamphetamine (known as MDMA), lysergic acid diethylamide (known as LSD), psilocybin, or ayahuasca) required oral monotherapy with no concomitant use of antidepressants. DATA EXTRACTION AND SYNTHESIS: The primary outcome was change in depression, measured by the 17-item Hamilton depression rating scale. The secondary outcomes were all cause discontinuation and severe adverse events. Severe adverse events were those resulting in any of a list of negative health outcomes including, death, admission to hospital, significant or persistent incapacity, congenital birth defect or abnormality, and suicide attempt. Data were pooled using a random effects model within a Bayesian framework. To avoid estimation bias, placebo responses were distinguished between psychedelic and antidepressant trials. RESULTS: Placebo response in psychedelic trials was lower than that in antidepression trials of escitalopram (mean difference -3.90 (95% credible interval -7.10 to -0.96)). Although most psychedelics were better than placebo in psychedelic trials, only high dose psilocybin was better than placebo in antidepression trials of escitalopram (mean difference 6.45 (3.19 to 9.41)). However, the effect size (standardised mean difference) of high dose psilocybin decreased from large (0.88) to small (0.31) when the reference arm changed from placebo response in the psychedelic trials to antidepressant trials. The relative effect of high dose psilocybin was larger than escitalopram at 10 mg (4.66 (95% credible interval 1.36 to 7.74)) and 20 mg (4.69 (1.64 to 7.54)). None of the interventions was associated with higher all cause discontinuation or severe adverse events than the placebo. CONCLUSIONS: Of the available psychedelic treatments for depressive symptoms, patients treated with high dose psilocybin showed better responses than those treated with placebo in the antidepressant trials, but the effect size was small. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42023469014.

New-Onset Seizures in an Adolescent Following Use of LSD while on Low-Dose Lithium Therapy: A Case Study.

This case report presents an occurrence of three generalized seizures within 30 minutes of ingestion of lysergic acid diethylamide (LSD) in a 15-year-old female patient with treatment-resistant depressive disorder recently started on low-dose lithium therapy. She had no personal or family history of seizure, brain injury or other neurological disorder. The patient had a history of monthly LSD use on several occasions in the setting of ongoing fluoxetine and longacting bupropion (Wellbutrin XL) treatment, with seizures occurring only after initiation of lithium. Although the definitive causal link cannot be established, this case report suggests an increased seizure risk with combination of LSD and lithium, even at subtherapeutic serum lithium levels. This case emphasizes the need for further research, careful clinical practice, and patient education regarding the potential dangers of using psychedelic substances with psychopharmacological treatment.

Tripping into the unknown: Exploring the experiences of first-time LSD users through global drug survey insights.

BACKGROUND: The recreational use of LSD, a synthetic psychedelic drug, has surged in recent years, coinciding with a renewed research focus on its potential psychotherapeutic properties. AIM: This study aims to describe the experiences and perceptions of individuals engaging in LSD use for the first time, derived from a large international sample. METHODS: This study utilised 2018 Global Drug Survey data collected from 6 November 2017 to 10 January 2018. Participants who initiated LSD use in the preceding 12 months answered questions on their experiences, social settings, harm-reduction behaviours, and demographics. Descriptive statistics were employed, and characteristics of those seeking emergency medical treatment (EMT) and those not planning further LSD use were compared with other respondents. RESULTS: Among 3340 respondents who used LSD in the past year, their first-time experiences generally exceeded expectations, with 97.7% expressing excitement. Adverse and unwanted side effects were rarely reported, and only 17 individuals needed EMT. Feelings of fear were reported by most (64.1%), but only very mildly and not enough to put them off from wanting to use LSD again. DISCUSSION: Although the occurrence of unwanted side effects seems low and the LSD experience is generally pleasurable, vigilance amid the rising illicit use of LSD through harm-reduction education is still important in preventing possible risks.

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.

Psychedelic Therapy: A Primer for Primary Care Clinicians-Lysergic Acid Diethylamide (LSD).

BACKGROUND: Lysergic acid diethylamide (LSD) is a hallucinogenic agent. In the mid-20th century, it was used to augment psychoanalysis and to treat alcohol use disorder. However, LSD was banned in 1970 in part because of concerns that it could bring about or exacerbate mental illness. Its therapeutic potential remains incompletely understood. AREAS OF UNCERTAINTY: While uncontrolled recreational use of LSD can, in rare instances, lead to long-term psychosis, adverse events in clinical trials of LSD, such as anxiety, headache, and nausea, have almost always been mild and transient. Serious adverse events, such as intense panic, suicidal ideation, and psychosis, were reported in either none or very few of the participants. However, patient selection criteria, optimal dosing strategy, and appropriate clinical follow-up guidelines remain to be established. THERAPEUTIC ADVANCES: Preliminary data suggest that LSD may be effective for the management of alcohol use disorder, anxiety, and depression. In trials of LSD for treating anxiety and depression associated with life-threatening illnesses, 77% of participants demonstrate durable relief at 1 year post-treatment. Top-line data from a large-scale phase IIb trial (n = 198) indicate that 50% of participants experience remission from generalized anxiety disorder after a single 100 µg dose of LSD. According to a meta-analysis of RCTs on LSD from the mid-20th century, single-dose regimens of LSD significantly improve alcohol use disorder (P < 0.0003) with an odds ratio (OR) of 1.96. LIMITATIONS: Only one large-scale clinical trial (>50 participants) has been conducted on LSD in the contemporary era of psychedelic research. Further studies with large sample sizes are needed to explore potential clinical applications. CONCLUSIONS: Preliminary data suggest that LSD may be one of the most potent treatments for anxiety in patients both with and without a life-threatening illness. LSD may also be beneficial for treating depression and substance use disorders.

Modern Psychedelic Microdosing Research on Mental Health: A Systematic Review.

Objective: To investigate the relationship between psychedelic microdosing and its effects on mental health, aiming to understand if microdosing can improve mental well-being.Data Sources: PubMed and Scopus were searched on December 25, 2022, using search terms related to psychedelics, microdosing, and mental health. The inclusion criteria focused on studies published between January 1, 2012, and November 30, 2022. There were no language restrictions for the initial search; however, for the study selection, only articles in English were considered.Study Selection: A total of 45 articles were initially identified. After removing duplicates, 27 unique articles were screened based on their titles and abstracts, resulting in 19 articles included in the final review. The studies were selected based on their relevance to the relationship between mental health and psychedelic microdosing.Data Extraction: The extracted data from the selected studies included sample sizes, demographics, survey designs, and qualitative and quantitative analyses related to the outcomes of individuals with mental health issues who also engaged in psychedelic microdosing. The QualSyst Quality Assessment Checklist was used to assess the methodological rigor and quality of each study. The data extraction process involved systematically reviewing each article and summarizing key findings related to the impact of microdosing on mental health.Results: The review revealed that microdosing psychedelics, such as lysergic acid diethylamide and psilocybin, showed potential benefits on mental health. Users reported positive effects, including improved mood, increased focus, and better daily function. However, there were also challenges reported, such as physiologic discomfort and increased anxiety. Some studies observed that positive expectations about microdosing led to positive outcomes. The studies varied in design, with some being observational, others placebo-controlled, and some relying on self-reported data.Conclusions: There is a growing body of evidence suggesting a positive correlation between psychedelic microdosing and improved mental well-being. However, due to the limited number of controlled studies and the small sample sizes in some of the studies, the causal relationship between microdosing and mental health improvement remains uncertain. The review calls for further research with double-blind experiments, control groups, and larger sample sizes that represent the general population to better understand the potential benefits and risks of psychedelic microdosing on mental health.Prim Care Companion CNS Disord 2024;26(1):23r03581.Author affiliations are listed at the end of this article.

Lysergic Acid Diethylamide (LSD) for the Treatment of Anxiety Disorders: Preclinical and Clinical Evidence.

Anxiety disorders (ADs) represent the sixth leading cause of disability worldwide, resulting in a significant global economic burden. Over 50% of individuals with ADs do not respond to standard therapies, making the identification of more effective anxiolytic drugs an ongoing research priority. In this work, we review the preclinical literature concerning the effects of lysergic acid diethylamide (LSD) on anxiety-like behaviors in preclinical models, and the clinical literature on anxiolytic effects of LSD in healthy volunteers and patients with ADs. Preclinical and clinical findings show that even if LSD may exacerbate anxiety acutely (both in "microdoses" and "full doses"), it induces long-lasting anxiolytic effects. Only two randomized controlled trials combining LSD and psychotherapy have been performed in patients with ADs with and without life-threatening conditions, showing a good safety profile and persisting decreases in anxiety outcomes. The effect of LSD on anxiety may be mediated by serotonin receptors (5-HT1A/1B, 5-HT2A/2C, and 5-HT7) and/or transporter in brain networks and circuits (default mode network, cortico-striato-thalamo-cortical circuit, and prefrontal cortex-amygdala circuit), involved in the modulation of anxiety. It remains unclear whether LSD can be an efficacious treatment alone or only when combined with psychotherapy, and if "microdosing" may elicit the same sustained anxiolytic effects as the "full doses". Further randomized controlled trials with larger sample size cohorts of patients with ADs are required to clearly define the effective regimens, safety profile, efficacy, and feasibility of LSD for the treatment of ADs.

The risk of chronic psychedelic and MDMA microdosing for valvular heart disease.

Psychedelic microdosing is the practice of taking very low doses of psychedelic substances, typically over a longer period of time. The long-term safety of chronic microdosing is relatively uncharacterized, but valvular heart disease (VHD) has been proposed as a potential risk due to activation of the serotonin 5-HT2B receptor. However, this risk has not yet been comprehensively assessed. This analysis searched for all relevant in vitro, animal, and clinical studies related to the VHD risk of lysergic acid diethylamide (LSD), psilocybin, mescaline, N,N-dimethyltryptamine (DMT), and the non-psychedelic 3,4-methylenedioxymethamphetamine (MDMA). All five compounds and some metabolites could bind to the 5-HT2B receptor with potency equal to or greater than that of the 5-HT2A receptor, the primary target of psychedelics. All compounds were partial agonists at the 5-HT2B receptor with the exception of mescaline, which could not be adequately assessed due to low potency. Safety margins relative to the maximum plasma concentrations from typical microdoses were greater than known valvulopathogens, but not without potential risk. No animal or clinical studies appropriately designed to evaluate VHD risk were found for the four psychedelics. However, there is some clinical evidence that chronic ingestion of full doses of MDMA is associated with VHD. We conclude that VHD is a potential risk with chronic psychedelic microdosing, but further studies are necessary to better define this risk.

Adverse drug effects as a deterrent against willingness to use in the future among nightclub/festival attendees.

INTRODUCTION: It is largely unknown whether adverse effects experienced from recreational drug use affect willingness to use again. This study determined whether adverse effects from select party drugs affect reported willingness to use again in the next month among a high-risk population-people who attend electronic dance music parties at nightclubs or dance festivals. METHODS: Adults (age ≥ 18) entering nightclubs/festivals were surveyed in New York City in 2018-2022 (n = 2981). Participants were asked about past-month use of common party drugs (cocaine, ecstasy, lysergic acid diethylamide [LSD] and ketamine), whether they had experienced a harmful or very unpleasant effect after use in the past 30 days, and whether they intend to use again in the next 30 days if offered by a friend. The relationship between having experienced an adverse outcome and willingness to use again was examined in a bivariable and multivariable manner. RESULTS: Experiencing an adverse effect after past-month cocaine (adjusted prevalence ratio [aPR] = 0.58, 95% confidence interval [CI] 0.35-0.95) or ecstasy use (aPR = 0.45, 95% CI 0.25-0.80) was associated with lower risk for willingness to use again. Adverse effects related to LSD use were related to lower risk of being willing to use again in the bivariable model, but in multivariable models, risk was not attenuated for willingness to use LSD or ketamine again. DISCUSSION AND CONCLUSIONS: Personally experienced adverse effects can deter willingness to use certain party drugs again in this high-risk population. Interventions targeting cessation of recreational party drug use can likely benefit from focusing on deleterious effects of use that have been experienced.

To treat or not to treat? High-potency benzodiazepine use in a case of comorbid hallucinogen persisting perception disorder and alcohol use disorder.

Hallucinogen persisting perception disorder (HPPD) is characterized by visual disturbances that resemble psychedelic intoxication and linger after use has ceased. The most common substances precipitating HPPD, lysergic acid diethylamide (LSD) and psilocybin, are posited to do so via damage to serotonergic neurons involved in vision. Mr. N is a 37-year-old with a history of alcohol, cannabis, LSD, cocaine, and nicotine use disorders who described visual distortions that resolved when he drank heavily or received benzodiazepines for withdrawal. He did not appear psychotic. Over 20 years after his last LSD use, he continued to experience illusions of halos around objects, moving walls, and figures appearing cartoonish. He understood that his perceptual disturbances were not reality based. During hospitalization for suicidal ideation, laboratory tests, head computed tomography (CT), and electroencephalogram (EEG) studies offered no explanation for his visual disturbances other than HPPD. The visual distortions remitted with scheduled clonazepam treatment, although chemical dependency treatment programs were hesitant to accept him while on a benzodiazepine. This case emphasizes the importance of diagnostic clarification when patients present with perceptual disturbances that do not fit typical psychotic presentations. Our discussion will distinguish misperceptions from hallucinations and review the pathophysiology of HPPD. Last, we will discuss management strategies for patients with co-occurring HPPD and substance use disorders. It is necessary to discern the correct cause of visual disturbances in order to provide proper treatment. The risks and benefits of long-term benzodiazepine use must be weighed when deciding whether to prescribe them for patients with comorbid HPPD and alcohol use disorder. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

A Critical Appraisal of Evidence on the Efficacy and Safety of Serotonergic Psychedelic Drugs as Emerging Antidepressants: Mind the Evidence Gap.

PURPOSE/BACKGROUND: There has been resurgence of interest in the therapeutic use of serotonergic ("classic") psychedelics in major depressive disorder (MDD) and end-of-life distress. This commentary offers a critical appraisal of current evidence for antidepressant effects of classic psychedelics from contemporary clinical trials and highlights pitfalls that should be addressed before clinical translation. METHODS/PROCEDURES: A narrative review was conducted to identify clinical trials of serotonergic psychedelics for the treatment of MDD and end-of-life distress. Trials published between January 1990 and May 2022 were identified on PubMed using combinations of search terms. FINDINGS/RESULTS: Psilocybin, lysergic acid diethylamide, and ayahuasca have clinical trials to evaluate antidepressant effects. Two studies showed preliminary positive effects of single-dose ayahuasca for treatment-resistant depression. Similar results were seen in lysergic acid diethylamide for end-of-life distress. Small randomized clinical trials (RCTs) of psilocybin combined with psychotherapy showed superiority to waitlist controls and comparable efficacy and safety to an active comparator in MDD, with additional RCTs showing efficacy in end-of-life distress. Adverse events associated with psychedelics were reported as mild and transient. Small homogenous samples, expectancy bias, functional unblinding, and lack of consensus and standardization of psychotherapy are major limitations of all studies. IMPLICATIONS/CONCLUSIONS: Given the methodological limitations of published RCTs, the evidence supporting the efficacy and safety of serotonergic psychedelics for depression is currently of low level. Future research should assess the role of expectancy and psychedelic effects in moderating and mediating treatment response. Innovative trial designs are needed to overcome functional unblinding. For now, psychedelics should remain experimental interventions used within clinical trials.

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.

Safety issues of psilocybin and LSD as potential rapid acting antidepressants and potential challenges.

INTRODUCTION: A limited number of preliminary open-label (n = 3) and placebo-controlled clinical trials (n = 5) have suggested psilocybin and LSD as potential rapid antidepressants. In this context, there is a growing need to verify and document their safety and tolerability as therapeutic agents, discuss the challenges associated with their administration, and develop safety protocols for their use as next-generation therapeutic agents. AREAS COVERED: We have analyzed all randomized, double-blind, and controlled trials that assessed the antidepressant effects of psilocybin and LSD in clinical populations to date, taking special attention to adverse events (AEs) related to their use. Prevalence, significance, and mechanisms of action related to AEs were systematically extracted, analyzed, and discussed. EXPERT OPINION: There were no serious AEs related to psilocybin and LSD administration. Most AEs were expected, manageable, and transient. Nevertheless, safety and tolerability concerns regarding some effects, such as dissociation, paranoia, and confusion, remain. Thus, randomized controlled trials with bigger samples are warranted to confirm their therapeutic effects and further investigate their safety and tolerability.

The promises and perils of psychedelic pharmacology for psychiatry.

Psychedelic drugs including psilocybin, N,N'-dimethyltryptamine (DMT) and lysergic acid diethylamide (LSD) are undergoing a renaissance as potentially useful drugs for various neuropsychiatric diseases, with a rapid onset of therapeutic activity. Notably, phase II trials have shown that psilocybin can produce statistically significant clinical effects following one or two administrations in depression and anxiety. These findings have inspired a 'gold rush' of commercial interest, with nearly 60 companies already formed to explore opportunities for psychedelics in treating diverse diseases. Additionally, these remarkable phenomenological and clinical observations are informing hypotheses about potential molecular mechanisms of action that need elucidation to realize the full potential of this investigative space. In particular, despite compelling evidence that the 5-HT2A receptor is a critical mediator of the behavioural effects of psychedelic drugs, uncertainty remains about which aspects of 5-HT2A receptor activity in the central nervous system are responsible for therapeutic effects and to what degree they can be isolated by developing novel chemical probes with differing specificity and selectivity profiles. Here, we discuss this emerging area of therapeutics, covering both controversies and areas of consensus related to the opportunities and perils of psychedelic and psychedelic-inspired therapeutics. We highlight how basic science breakthroughs can guide the discovery and development of psychedelic-inspired medications with the potential for improved efficacy without hallucinogenic or rewarding actions.

Safety, tolerability, pharmacokinetics, and subjective effects of 50, 75, and 100 µg LSD in healthy participants within a novel intervention paradigm: A proof-of-concept study.

BACKGROUND: Classic psychedelics hold promise as therapeutics for psychiatric disorders, but require scalable intervention protocols. This proof-of-concept study evaluated the safety, tolerability, pharmacokinetics, and subjective effects of 50, 75, and 100 µg lysergic acid diethylamide (LSD) in healthy adults within a novel intervention paradigm. METHODS: Up to three participants were administered LSD on the same day in separate rooms, each with a single attendant, after 1 day of preparation. An open-label design and a double-blind placebo-controlled design were used. RESULTS: Ninety-one percent of participants completed the study. Thirty-two adults (mean age = 28.8 years) received 50 (n = 3), 75 (n = 7), 100 (n = 3) LSD, 50 µg followed by 75 µg LSD (n = 9) 1 week apart, or placebo followed by a 75 µg LSD (n = 10) 1 week apart. There were no serious adverse events. Twenty-eight percent of participants experienced at least one expected mild adverse event, with one expected moderate adverse event. The maximum blood plasma levels occurred between 1.2 and 2 h post-administration, with an apparent half-life between 2.8 and 4.3 h. LSD largely induced greater subjective effects versus placebo. CONCLUSION: In the current novel intervention paradigm, 50, 75, and 100 µg LSD are tolerable with favourable safety profiles in healthy adults, only mild adverse events during the day of drug administration, and mystical-type subjective experiences. Future studies are needed to evaluate safety, tolerability, subjective effects, and cost-effectiveness in clinical populations.

Perceptions of safety, subjective effects, and beliefs about the clinical utility of lysergic acid diethylamide in healthy participants within a novel intervention paradigm: Qualitative results from a proof-of-concept study.

BACKGROUND: Classic psychedelics show promise in the treatment of mental health conditions; however, more scalable intervention protocols are needed to maximize access to these novel therapeutics. In this proof-of-concept study, perceptions of safety, subjective effects, and beliefs about the clinical utility of lysergic acid diethylamide (LSD) were evaluated among healthy participants (N = 31) administered 50 to 100 µg LSD in a treatment paradigm conceptualized as more scalable than traditional approaches to administering classic psychedelics. METHODS: Semi-structured interviews assessed participants' expectations, experience, and thoughts on the safety and efficacy of the study design. These interviews were transcribed for thematic analysis relating to perceptions of safety, subjective effects, and beliefs about the clinical utility of LSD. RESULTS: Most participants felt safe throughout the study, with a minority reporting concerns related to having a challenging experience that diminished over time. Participants attributed their feelings of safety to the study structure and support of their attendants, which allowed them to "let go" and immerse themselves in the experience without pre-occupation. Furthermore, participants reported transcendent, mystical-type experiences characteristic of classic psychedelics, with almost half highlighting the prominent role played by music during the acute period of drug action. Finally, participants endorsed support for the clinical utility of LSD in controlled environments, expressing the belief that LSD is safe and has the potential to help others. CONCLUSION: Findings provide preliminary support for the feasibility of this scalable interventional paradigm and set the stage for future critical research with clinical populations.

The potential of psychedelic medicine - A personal account.

In 1965, I was training in clinical toxicology in the pharmacology department of the University of California San Francisco (UCSF) and living in the Haight Ashbury. I studied various psychedelics, including LSD, mescaline, and ibogaine, in human and animal models. The psychedelics were then being used as a therapeutic drug in clinical settings and researched as a potential antipersonnel agent by the U.S. government. Then, using psychedelics became a rite of passage for the emerging countercultural movement. After adverse reactions and negative publicity, states began to criminalize these drugs, beginning in 1966. The federal government eventually moved these drugs to Schedule 1 classification, shutting down research almost entirely.