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.

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.

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 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.

Assessing the risk-benefit profile of classical psychedelics: a clinical review of second-wave psychedelic research.

RATIONALE: A broad reassessment of the potential benefits of psychedelic drugs has led to the initiation of multiple major clinical trials in an effort to advance their status to become FDA-approved medications, as well as local legislative efforts to legalize or decriminalize their use. OBJECTIVES: To use recently published data to assess potential risks and benefits of psychedelic drugs as therapeutics, as well as to synthesize what is currently known in order to generate fruitful future research directions. METHODS: A review of studies conducted since 1991 identified 14 clinical trials of classical psychedelics, including 11 of psilocybin (N = 257 participants), 1 of lysergic acid diethylamide (N = 12 participants), and 2 of ayahuasca (N = 46 participants). Other published studies (e.g., of healthy volunteers, survey studies, case reports, neuroimaging) were also considered for review. RESULTS: Published studies since 1991 largely support the hypothesis that small numbers of treatments with psychedelic-assisted psychotherapy can offer significant and sustained alleviation to symptoms of multiple psychiatric conditions. No serious adverse events attributed to psychedelic therapy have been reported. Existing studies have several limitations, including small sample sizes, inherent difficulty in blinding, relatively limited follow-up, and highly screened treatment populations. CONCLUSIONS: Substantial data have been gathered in the past 30 years suggesting that psychedelics are a potent treatment for a variety of common psychiatric conditions, though the ideal means of employing these substances to minimize adverse events and maximize therapeutic effects remains controversial. Unique factors related to study design are vital for clinical researchers in the field to address.

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.

The potential role of lysergic acid diethylamide for psychological assisted therapy: A meta-analysis of randomised controlled trials in healthy volunteers.

OBJECTIVE: In recent years, interest in using lysergic acid diethylamide (LSD) in psychiatric research and corresponding therapy has increased rapidly. In this meta-analysis, we explored the effects of LSD on healthy subjects with respect to subjective drug effects, blood pressure, heart rate, body temperature and side effects. METHOD: PubMed, Embase, and the Cochrane Library were searched from January 2010 to December 2020 for randomized controlled trials (RCTs) on the effects of LSD in healthy people. Subsequently, 5 RCTs with 132 healthy people which focused on the effects of LSD were enrolled in our study. RESULT: We found that taking 50, 100 and 200 mcg LSD doses were associated with a significant increase in the maximal difference from the baseline compared to the placebo group among the outcomes of AMRS (Adjective Mood Rating Scale) score. Significant differences existed between the LSD and placebo groups when taking 100 and 200 mcg LSD in acute adverse effects (100 mcg: SMD = .97, 95% confidence interval [CI], .50, 1.44, Z = 4.04, p < .001; 200 mcg: SMD = 1.18, 95% CI, 0.65, 1.72, Z = 4.32, p < .001). CONCLUSIONS: Meta-analysis of the subjective effects of LSD in healthy people revealed moderate significant effect sizes in favor of LSD with no significant adverse effects. A 100 mcg dose of LSD has potential for use in psychological-assisted therapy and may improve the mental fitness of patients with disease-related psychiatric distress. Additional clinical trials are necessary to explore the efficacy and safety of LSD as a psychological-assisted therapy.

Safety pharmacology of acute LSD administration in healthy subjects.

RATIONALE: Lysergic acid diethylamide (LSD) is used in psychiatric and psychological research and investigated as a potential treatment for medical and psychiatric disorders, including depression, anxiety, and cluster headache. OBJECTIVES: Safety data on clinical safety are available from small studies but not from larger samples. We report safety pharmacology data from a large pooled study sample on acute effects of LSD in healthy subjects. METHODS: We conducted a pooled analysis of four double-blind, randomized, placebo-controlled, crossover studies that included a total of 83 healthy subjects and 131 single-dose administrations of LSD. LSD administrations were matched to dose groups according to measured LSD peak plasma concentrations to adjust for uncertainties in the correct LSD dose in some studies. Single doses were 25, 50, 100, and 200 µg of LSD base. We investigated subjective effects (self-rated any drug effect, good drug effect, bad drug effect, and anxiety), blood pressure, heart rate, body temperature, duration of the acute LSD response, acute (12 h) and subacute (24 h) adverse effects, reports of flashbacks, and liver and kidney function before and after the studies. RESULTS: LSD dose-dependently increased subjective, physiologic, and adverse effects. The dose-response curves for the proportions of subjects with a certain amount of a subjective effect were steeper and reached a higher maximum for positive acute subjective effects compared with negative acute subjective effects. Maximal ratings of > 50% good drug effects were reached in 37%, 91%, 96%, and 91% of the LSD administrations at 25, 50, 100, and 200 µg. Maximal ratings of > 50% bad drug effects were reached in 0%, 9%, 27%, 31% at 25, 50, 100, and 200 µg, respectively. Mean ratings of Oceanic Boundlessness were 10%, 25%, 41%, and 44%, and mean ratings of Anxious Ego-Dissolution were 3.4%, 13%, 20%, and 22% at 25, 50, 100, and 200 µg, respectively. The physiologic effects of LSD were moderate. None of the subjects had systolic blood pressure > 180 mmHg at any time. Peak heart rate > 100 beats/min was observed in 0%, 6%, 20%, and 25% of the subjects at 25, 50, 100, and 200 µg, respectively. Maximal heart rates of 129 and 121 beats/min were observed in one subject at the 50 and 200 µg doses, respectively. Peak body temperature > 38° was observed in 0%, 11%, 7%, and 34% at 25, 50, 100, and 200 µg, respectively. Mean acute adverse effect scores on the List of Complaints were 5.6, 9.2, 12, and 13 at 25, 50, 100, and 200 µg, respectively. Kidney and liver function parameters were unaltered. Six subjects reported transient flashback phenomena. CONCLUSIONS: The single-dose administration of LSD is safe in regard to acute psychological and physical harm in healthy subjects in a controlled research setting.

Assessing the effects of methodological differences on outcomes in the use of psychedelics in the treatment of anxiety and depressive disorders: A systematic review and meta-analysis.

BACKGROUND: Classical psychedelics are a group of drugs which act as agonists on the serotonin-2A (5-HT2A) receptor. Evidence suggests they may have a uniquely rapid and enduring positive effect on mood. However, marked heterogeneity between methodological designs in this emerging field remains a significant concern. AIMS: To determine how differences in the type of psychedelic agent used and the number of dosing sessions administered affect subjects' depression and anxiety outcomes and adverse drug reactions (ADR). METHODS: This review collected and screened 1591 records from the MEDLINE and Web of Science databases for clinical trials reporting objective data on mood for subjects with a known anxiety or depression. RESULTS: After screening, nine clinical trials met inclusion criteria. Meta-analysis of these studies showed significant, large positive effect sizes for measures of anxiety (Cohen's d = 1.26) and depression (Cohen's d = 1.38) overall. These positive effects were also significant at acute (⩽1 week) and extended (>1 week) time points. No significant differences were observed between trials using different psychedelic agents (psilocybin, ayahuasca or lysergic acid diethylamide (LSD)), however, a significant difference was observed in favour of trials with multiple dosing sessions. No serious ADR were reported. CONCLUSION: Psilocybin, ayahuasca and LSD all appear to be effective and relatively safe agents capable of producing rapid and sustained improvements in anxiety and depression. Moreover, the findings of the present analysis suggest that they may show a greater efficacy when given to patients over multiple sessions as compared to the more common single session used in many of the existing trials.

Early LSD treatment in Denmark from 1960 to 1974: An analysis of possible and long-lasting changes in the adult personality following psychedelic treatment. A historical retrospective cohort study.

ABSTRACT: In view of the renewed interest in psychedelics in psychiatry it is timely to analyze psychedelic treatment in historical cohorts. Recently the therapeutic efficacy of psychedelics has been linked to the so-called phenomenon of "connectedness." The aim of the present study was to explore whether long-lasting personality changes were observed in any of the 151 Danish psychiatric patients who were treated with Lysergic acid diethylamide (LSD) from 1960 to 1974.The exploration included a reanalysis of a subgroup as well from a 1964 Danish historical cohort. Medical records and other case materials of the above mentioned 151 patients are kept in the Danish State Archives. The present author was granted access to the LSD case materials in the Danish State Archives, and respected confidentiality per the Archives Law. According to the LSD Damages Law from 1986, they all received financial compensation for LSD-inflicted harm.Analysis did not reveal any personality changes such as "connectedness;" however, other lasting personality changes were observed in 2 to 4 patients and in quite a few patients unwanted effects persisted for weeks or months following acute treatment. In the present analysis of the 1964 cohort, the same percentage of patients improved with LSD treatment as in the historical analysis. In the latter, however, little attention was given to side effects, such as suicide attempts, suicides, and one homicide.Future psychedelic research with psychiatric patients should respect the potential toxicity of LSD and other psychedelics and meticulously monitor possible side effects.

MDLSD: study protocol for a randomised, double-masked, placebo-controlled trial of repeated microdoses of LSD in healthy volunteers.

BACKGROUND: Regular ingestion of sub-hallucinogenic doses of psychedelics, referred to as "microdosing", has gained increasing popularity and attention in the press and in online forums, with reported benefits across multiple cognitive and emotional domains. Rigorously controlled studies to date, however, have been limited in scope and have failed to produce results comparable to those reported in the grey literature. METHODS: Eighty healthy male participants will receive 14 doses of placebo or 10 µg lysergic acid diethylamide orally every 3rd day over a 6-week treatment protocol. A battery of personality, creativity, mood, cognition, and EEG plasticity measures, as well as resting-state fMRI imaging, will be administered at baseline and at the end of the protocol. Creativity, mood, and plasticity measures will additionally be assessed in the acute phase of the first dose. Daily functioning will be monitored with questionnaires and a wearable sleep and activity tracker. DISCUSSION: This study will rigorously examine the claims presented in the microdosing grey literature by pairing a comparable dosing protocol with objective measures. Potential therapeutic implications include future clinical trials to investigate microdosed psychedelics as a standalone treatment or as an augmentation of psychotherapy in the treatment of depression, addiction, eating disorders, obsessive-compulsive disorders, and palliative care. TRIAL REGISTRATION: ACTRN12621000436875 . Registered on 19 February 2021.