Spectral signatures of psilocybin, lysergic acid diethylamide (LSD) and ketamine in healthy volunteers and persons with major depressive disorder and treatment-resistant depression: A systematic review.

BACKGROUND: Electrophysiologic measures provide an opportunity to inform mechanistic models and possibly biomarker prediction of response. Serotonergic psychedelics (SPs) (i.e., psilocybin, lysergic acid diethylamide (LSD)) and ketamine represent new investigational and established treatments in mood disorders respectively. There is a need to better characterize the mechanism of action of these agents. METHODS: We conducted a systematic review investigating the spectral signatures of psilocybin, LSD, and ketamine in persons with major depressive disorder (MDD), treatment-resistant depression (TRD), and healthy controls. RESULTS: Ketamine and SPs are associated with increased theta power in persons with depression. Ketamine and SPs are also associated with decreased spectral power in the alpha, beta and delta bands in healthy controls and persons with depression. When administered with SPs, theta power was increased in persons with MDD when administered with SPs. Ketamine is associated with increased gamma band power in both healthy controls and persons with MDD. LIMITATIONS: The studies included in our review were heterogeneous in their patient population, exposure, dosing of treatment and devices used to evaluate EEG and MEG signatures. Our results were extracted entirely from persons who were either healthy volunteers or persons with MDD or TRD. CONCLUSIONS: Extant literature evaluating EEG and MEG spectral signatures indicate that ketamine and SPs have reproducible effects in keeping with disease models of network connectivity. Future research vistas should evaluate whether observed spectral signatures can guide further discovery of therapeutics within the psychedelic and dissociative classes of agents, and its prediction capability in persons treated for depression.

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.

Modulation of long-term potentiation following microdoses of LSD captured by thalamo-cortical modelling in a randomised, controlled trial.

BACKGROUND: Microdosing psychedelics is a phenomenon with claimed cognitive benefits that are relatively untested clinically. Pre-clinically, psychedelics have demonstrated enhancing effects on neuroplasticity, which cannot be measured directly in humans, but may be indexed by non-invasive electroencephalography (EEG) paradigms. This study used a visual long-term potentiation (LTP) EEG paradigm to test the effects of microdosed lysergic acid diethylamide (LSD) on neural plasticity, both acutely while on the drug and cumulatively after microdosing every third day for six weeks. Healthy adult males (n = 80) completed the visual LTP paradigm at baseline, 2.5 h following a dose of 10 µg of LSD or inactive placebo, and 6 weeks later after taking 14 repeated microdoses. Visually induced LTP was used as indirect index of neural plasticity. Surface level event-related potential (ERPs) based analyses are presented alongside dynamic causal modelling of the source localised data using a generative thalamocortical model (TCM) of visual cortex to elucidate underlying synaptic circuitry. RESULTS: Event-related potential (ERP) analyses of N1b and P2 components did not show evidence of changes in visually induced LTP by LSD either acutely or after 6 weeks of regular dosing. However modelling the complete timecourse of the ERP with the TCM demonstrated changes in laminar connectivity in primary visual cortex. This primarily included changes to self-gain and inhibitory input parameters acutely. Layer 2/3 to layer 5 excitatory connectivity was also different between LSD and placebo groups. After regular dosing only excitatory input from layer 2/3 into layer 5 and inhibitory input into layer 4 were different between groups. CONCLUSIONS: Without modulation of the ERPs it is difficult to relate the findings to other studies visually inducing LTP. It also indicates the classic peak analysis may not be sensitive enough to demonstrate evidence for changes in LTP plasticity in humans at such low doses. The TCM provides a more sensitive approach to assessing changes to plasticity as differences in plasticity mediated laminar connectivity were found between the LSD and placebo groups. TRIAL REGISTRATION:  ANZCTR registration number ACTRN12621000436875; Registered 16/04/2021 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=381476 .

Psychedelics for alzheimer's disease-related dementia: Unveiling therapeutic possibilities and pathways.

Psychedelics have traditionally been used for spiritual and recreational purposes, but recent developments in psychotherapy have highlighted their potential as therapeutic agents. These compounds, which act as potent 5-hydroxytryptamine (5HT) agonists, have been recognized for their ability to enhance neural plasticity through the activation of the serotoninergic and glutamatergic systems. However, the implications of these findings for the treatment of neurodegenerative disorders, particularly dementia, have not been fully explored. In recent years, studies have revealed the modulatory and beneficial effects of psychedelics in the context of dementia, specifically Alzheimer's disease (AD)-related dementia, which lacks a definitive cure. Psychedelics such as N,N-dimethyltryptamine (DMT), lysergic acid diethylamide (LSD), and Psilocybin have shown potential in mitigating the effects of this debilitating disease. These compounds not only target neurotransmitter imbalances but also act at the molecular level to modulate signalling pathways in AD, including the brain-derived neurotrophic factor signalling pathway and the subsequent activation of mammalian target of rapamycin and other autophagy regulators. Therefore, the controlled and dose-dependent administration of psychedelics represents a novel therapeutic intervention worth exploring and considering for the development of drugs for the treatment of AD-related dementia. In this article, we critically examined the literature that sheds light on the therapeutic possibilities and pathways of psychedelics for AD-related dementia. While this emerging field of research holds great promise, further studies are necessary to elucidate the long-term safety, efficacy, and optimal treatment protocols. Ultimately, the integration of psychedelics into the current treatment paradigm may provide a transformative approach for addressing the unmet needs of individuals living with AD-related dementia and their caregivers.

Repeated microdoses of LSD do not alter anxiety or boldness in zebrafish.

The therapeutic use of lysergic acid diethylamide (LSD) has resurfaced in the last decade, prompting further scientific investigation into its effectiveness in many animal models. Zebrafish (Danio rerio) are a popular model organism in medical sciences and are used to examine the repeated administration of pharmacological compounds. Previous zebrafish research found acute LSD altered behaviour and cortisol levels at high (250 µg/L) but not low (5-100 µg/L) levels. In this study, we used a motion tracking system to record and analyze the movement patterns of zebrafish after acute and repeated 10-day LSD exposure (1.5 µg/L, 15 µg/L, 150 µg/L) and after seven days of withdrawal. The open-field and novel object approach tests were used to examine anxiety-like behaviour, boldness, and locomotion. In the acute experiments we observed a significant decrease in high mobility with 1.5 µg/L, 15 µg/L, and 150 µg/L of LSD compared to the control and a decrease in velocity with 1.5 and 15 µg/L. In repeated experiments, there were no significant differences in the levels of anxiety, boldness, or locomotion between all LSD groups and controls immediately after 10-day treatment or after withdrawal.

Older adults in psychedelic-assisted therapy trials: A systematic review.

BACKGROUND: Growing clinical interest in psychedelic-assisted therapies has led to a second wave of research involving psilocybin, lysergic acid diethylamide (LSD), 3,4-methylenedioxymethamphetamine (MDMA) and other substances. Data suggests that these compounds have the potential to treat mental health conditions that are especially prevalent in older adults such as depression, anxiety, existential distress, and posttraumatic stress disorder. AIMS: The goal of this study was to quantify the prevalence of older adults enrolled in psychedelic clinical trials and explore safety data in this population. METHODS: A systematic review was conducted following the 2020 PRISMA guidelines. Search criteria included all trials published in English using psychedelic substances to treat psychiatric conditions, including addiction as well as existential distress related to serious illness. Articles were identified from literature searches on PubMed, EBSCO, and EMBASE. RESULTS: 4376 manuscripts were identified, of which 505 qualified for further review, with 36 eventually meeting eligibility criteria. Of the 1400 patients enrolled in the 36 studies, only 19 were identified as 65 or older, representing less than 1.4% of all trial participants. For 10 of these 19 older adults, detailed safety data was obtained. No serious adverse events (AEs) occurred in any older adults and only transient mild-to-moderate AEs related to anxiety, gastrointestinal upset, and hypertension were reported during the psychedelic dosing sessions. CONCLUSIONS: While existing data in older adults is limited, it suggests that psychedelic-assisted psychotherapy can be safe and well tolerated in older adults. Therefore, psychedelic-assisted psychotherapy should be more rigorously investigated for the treatment of psychiatric conditions in this population.

The Psychedelic Future of Post-Traumatic Stress Disorder Treatment.

Post-traumatic stress disorder (PTSD) is a mental health condition that can occur following exposure to a traumatic experience. An estimated 12 million U.S. adults are presently affected by this disorder. Current treatments include psychological therapies (e.g., exposure-based interventions) and pharmacological treatments (e.g., selective serotonin reuptake inhibitors (SSRIs)). However, a significant proportion of patients receiving standard-of-care therapies for PTSD remain symptomatic, and new approaches for this and other trauma-related mental health conditions are greatly needed. Psychedelic compounds that alter cognition, perception, and mood are currently being examined for their efficacy in treating PTSD despite their current status as Drug Enforcement Administration (DEA)- scheduled substances. Initial clinical trials have demonstrated the potential value of psychedelicassisted therapy to treat PTSD and other psychiatric disorders. In this comprehensive review, we summarize the state of the science of PTSD clinical care, including current treatments and their shortcomings. We review clinical studies of psychedelic interventions to treat PTSD, trauma-related disorders, and common comorbidities. The classic psychedelics psilocybin, lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT) and DMT-containing ayahuasca, as well as the entactogen 3,4-methylenedioxymethamphetamine (MDMA) and the dissociative anesthetic ketamine, are reviewed. For each drug, we present the history of use, psychological and somatic effects, pharmacology, and safety profile. The rationale and proposed mechanisms for use in treating PTSD and traumarelated disorders are discussed. This review concludes with an in-depth consideration of future directions for the psychiatric applications of psychedelics to maximize therapeutic benefit and minimize risk in individuals and communities impacted by trauma-related conditions.

Microdosing psychedelics and the risk of cardiac fibrosis and valvulopathy: Comparison to known cardiotoxins.

Though microdosing psychedelics has become increasingly popular, its long-term effects on cardiac health remain unknown. Microdosing most commonly involves ingesting sub-threshold doses of lysergic acid diethylamide (LSD), psilocybin, or other psychedelic drugs 2-4 times a week for at least several weeks, but potentially months or years. Concerningly, both LSD and psilocybin share structural similarities with medications which raise the risk of cardiac fibrosis and valvulopathy when taken regularly, including methysergide, pergolide, and fenfluramine. 3,4-Methylenedioxymethamphetamine, which is also reportedly used for microdosing, is likewise associated with heart valve damage when taken chronically. In this review, we evaluate the evidence that microdosing LSD, psilocybin, and other psychedelics for several months or more could raise the risk of cardiac fibrosis. We discuss the relationship between drug-induced cardiac fibrosis and the 5-HT2B receptor, and we make recommendations for evaluating the safety of microdosing psychedelics in future studies.

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.

Effects of External Stimulation on Psychedelic State Neurodynamics.

Recent findings have shown that psychedelics reliably enhance brain entropy (understood as neural signal diversity), and this effect has been associated with both acute and long-term psychological outcomes, such as personality changes. These findings are particularly intriguing, given that a decrease of brain entropy is a robust indicator of loss of consciousness (e.g., from wakefulness to sleep). However, little is known about how context impacts the entropy-enhancing effect of psychedelics, which carries important implications for how it can be exploited in, for example, psychedelic psychotherapy. This article investigates how brain entropy is modulated by stimulus manipulation during a psychedelic experience by studying participants under the effects of lysergic acid diethylamide (LSD) or placebo, either with gross state changes (eyes closed vs open) or different stimuli (no stimulus vs music vs video). Results show that while brain entropy increases with LSD under all of the experimental conditions, it exhibits the largest changes when subjects have their eyes closed. Furthermore, brain entropy changes are consistently associated with subjective ratings of the psychedelic experience, but this relationship is disrupted when participants are viewing a video─potentially due to a "competition" between external stimuli and endogenous LSD-induced imagery. Taken together, our findings provide strong quantitative evidence of the role of context in modulating neural dynamics during a psychedelic experience, underlining the importance of performing psychedelic psychotherapy in a suitable environment.

Analytical and behavioral characterization of N-ethyl-N-isopropyllysergamide (EIPLA), an isomer of N6 -ethylnorlysergic acid N,N-diethylamide (ETH-LAD).

Preclinical investigations have shown that N-ethyl-N-isopropyllysergamide (EIPLA) exhibits lysergic acid diethylamide (LSD)-like properties, which suggests that it might show psychoactive effects in humans. EIPLA is also an isomer of N6 -ethylnorlysergic acid N,N-diethylamide (ETH-LAD), a lysergamide known to produce psychedelic effects in humans that emerged as a research chemical. EIPLA was subjected to analysis by various forms of mass spectrometry, chromatography (GC, LC), nuclear magnetic resonance (NMR) spectroscopy, and GC condensed-phase infrared spectroscopy. The most straightforward differentiation between EIPLA and ETH-LAD included the evaluation of mass spectral features that reflected the structural differences (EIPLA: N6 -methyl and N-ethyl-N-isopropylamide group; ETH-LAD: N6 -ethyl and N,N-diethylamide group). Proton NMR analysis of blotter extracts suggested that EIPLA was detected as the base instead of a salt, and two blotter extracts suspected to contain EIPLA revealed the detection of 96.9 ± 0.5 µg (RSD: 0.6%) and 85.8 ± 2.8 µg base equivalents based on LC-MS analysis. The in vivo activity of EIPLA was evaluated using the mouse head-twitch response (HTR) assay. Similar to LSD and other serotonergic psychedelics, EIPLA induced the HTR (ED50 = 234.6 nmol/kg), which was about half the potency of LSD (ED50 = 132.8 nmol/kg). These findings are consistent with the results of previous studies demonstrating that EIPLA can mimic the effects of known psychedelic drugs in rodent behavioral models. The dissemination of analytical data for EIPLA was deemed justifiable to aid future forensic and clinical investigations.

The revival of the psychedelic experience scale: Revealing its extended-mystical, visual, and distressing experiential spectrum with LSD and psilocybin studies.

BACKGROUND: Research with the Psychedelic Experience Questionnaire/Scale (PES) focuses on questions relating to mystical experience (Mystical Experience Questionnaire (MEQ)). The psychometric potential of the non-MEQ items of the PES remains largely unexplored. AIMS: We investigated whether the PES also yields subscales besides the MEQ30 subscales. METHODS: Data from 239 PES measurements (140 healthy participants) from six studies with moderate to high doses of lysergic acid diethylamide and/or psilocybin were included. New subscales (with items other than MEQ30) were created and validated as follows: (1) theoretical derivation of candidate items; (2) removal of items with rare experiences; (3) exploratory factor analysis; and (4) confirmatory factor analysis. Correlations of subscales within the PES and between the PES and the 5-Dimensional Altered States of Consciousness Scale (5D-ASC) were performed. In addition, a cluster analysis using all items (except rare experiences) was performed. RESULTS: The reliability of the four original factors of the MEQ30 was confirmed and four additional factors for the non-MEQ items were revealed: paradoxicality, connectedness, visual experience, and distressing experience. The first two additional factors were strongly correlated with the MEQ30 mystical subscale. Adding the new subscales to the MEQ30 subscales increased the explained variance with the 5D-ASC. The cluster analysis confirmed our main results and provided additional insights for future psychedelic psychometrics. CONCLUSION: The study yields a new validated 6-factor structure for extended mystical experience (MEQ40: MEQ30 + Paradoxicality + Connectedness) and covers psychedelic experience as a whole more comprehensively than has hitherto been possible within a single questionnaire (PES48). The entire PES (PES100) can also be used for further future psychedelic-psychometric research.

Assessment of the acute subjective psychedelic experience: A review of patient-reported outcome measures in clinical research on classical psychedelics.

BACKGROUND: The classical psychedelics psilocybin, peyote, ayahuasca/ N, N-dimethyltryptamine, and lysergic acid diethylamide can temporarily produce altered states of consciousness, characterized by changes in sensory perception, thought, mood, and the sense of self-reality and meaning. It is important to have reliable instruments for quantifying these altered states in trials, due to a plausible link between the acute subjective experience and treatment outcome. METHODS: We conducted a review of outcome measures applied in research on classical psychedelics to assess one or more dimensions of the acute subjective psychedelic experience. Three relevant databases were searched electronically. Two reviewers independently conducted article selection and data extraction regarding the instruments, dimensions, geography, population, and psychedelic substance investigated in the included studies. We identified the five most utilized instruments for the most recent 6 years, as well as the five most utilized instruments for each psychedelic. RESULTS: We included 93 papers, which reported on 93 unique trials and utilized 17 different rating scales. Of these, the most utilized were the Five-Dimensional Altered States of Consciousness Questionnaire, visual analog or Likert scales specially developed for the trials, the Hallucinogen Rating Scale, the States of Consciousness Questionnaire, and the Abnormer Psychischer Zustand. DISCUSSION: Considerable variability was found in the instruments utilized in clinical trials on classical psychedelics. We advise and encourage the development of a core outcome set for psychedelic research to enable altered state comparisons across compounds, participants, and settings. We further advise that instruments be designed to assess the "setting" of a psychedelic experience.

The changing outlook of psychedelic drugs: The importance of risk assessment and occupational exposure limits.

Serotonergic psychedelics, such as lysergic acid diethylamide (LSD), psilocybin, dimethyltryptamine (DMT), and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), are currently being investigated for the treatment of psychiatric disorders such as depression and anxiety. Clinical trials with psilocybin and LSD have shown improvement in emotional and psychological scores. Although these drugs are reported to be safe in a controlled environment (such as clinical trials), exposure to low doses of these drugs can result in psychedelic effects, and therefore, occupational safety is an important consideration to prevent adverse effects in the workplace from low daily exposure. This article will discuss the factors involved in the derivation of occupational exposure limits (OELs) and risk assessment of these psychedelic drugs. To support the OEL derivations of psychedelic drugs, information regarding their mechanism of action, adverse effect profiles, pharmacokinetics, clinical effects, and nonclinical toxicity were considered. Additionally, psilocybin and LSD, which are the most extensively researched psychedelic substances, are employed as illustrative examples in case studies. The OELs derived for psilocybin and for LSD are 0.05 and 0.002 µg/m3 , respectively, which indicates that these are highly hazardous compounds, and it is important to take into account suitable safety measures and risk-management strategies in order to minimize workplace exposure.

Pharmacokinetics, pharmacodynamics and urinary recovery of oral lysergic acid diethylamide administration in healthy participants.

AIMS: Lysergic acid diethylamide (LSD) is currently investigated for several neurological and psychiatric illnesses. Various studies have investigated the pharmacokinetics and the pharmacokinetic-pharmacodynamic relationship of LSD in healthy participants, but data on urinary recovery and confirmatory studies are missing. METHODS: The present study characterized the pharmacokinetics, pharmacokinetic-pharmacodynamic relationship and urinary recovery of LSD at doses of 85 and 170 µg administered orally in 28 healthy participants. The plasma concentrations and subjective effects of LSD were continuously evaluated over a period of 24 h. Urine was collected during 3 time intervals (0-8, 8-16 and 16-24 h after LSD administration). Pharmacokinetic parameters were determined using compartmental modelling. Concentration-subjective effect relationships were described using pharmacokinetic-pharmacodynamic modelling. RESULTS: Mean (95% confidence interval) maximal LSD concentrations were 1.8 ng/mL (1.6-2.0) and 3.4 ng/mL (3.0-3.8) after the administration of 85 and 170 µg LSD, respectively. Maximal concentrations were achieved on average after 1.7 h. Elimination half-lives were 3.7 h (3.4-4.1) and 4.0 h (3.6-4.4), for 85 and 170 µg LSD, respectively. Only 1% of the administered dose was recovered from urine unchanged within the first 24 h, 16% was eliminated as 2-oxo-3-hydroxy-LSD. Urinary recovery was dose proportional. Mean (±standard deviation) durations of subjective effects were 9.3 ± 3.2 and 11 ± 3.7 h, and maximal effects (any drug effects) were 77 ± 18% and 87 ± 13% after 85 and 170 µg of LSD, respectively. CONCLUSION: The present novel study validates previous findings. LSD exhibited dose-proportional pharmacokinetics and first-order elimination kinetics and dose-dependent duration and intensity of subjective effects. LSD is extensively metabolized and shows dose-proportional urinary recovery.

Lysergic acid diethylamide stimulates cardiac human H2 histamine and cardiac human 5-HT4-serotonin receptors.

Lysergic acid diethylamide (LSD) is an artificial hallucinogenic drug. Thus, we hypothesized that LSD might act 5-HT4 serotonin receptors and/or H2 histamine receptors. We studied isolated electrically stimulated left atrial preparations, spontaneously beating right atrial preparations, and spontaneously beating Langendorff-perfused hearts from transgenic mice with cardiomyocyte-specific overexpression of the human 5-HT4 receptor (5-HT4-TG) or of the H2-histamine receptor (H2-TG). For comparison, we used wild type littermate mice (WT). Finally, we measured isometric force of contraction in isolated electrically stimulated muscle strips from the human right atrium obtained from patients during bypass surgery. LSD (up to 10 µM) concentration dependently increased force of contraction and beating rate in left or right atrial preparations from 5-HT4-TG (n = 6, p < 0.05) in 5-HT4-TG atrial preparations. The inotropic and chronotropic effects of LSD were antagonized by 10 µM tropisetron in 5-HT4-TG. In contrast, LSD (10 µM) increased force of contraction and beating rate in left or right atrial preparations, from H2-TG. After pre-stimulation with cilostamide (1 µM), LSD (10 µM) increased force of contraction in human atrial preparations (n = 6, p < 0.05). The contractile effects of LSD in human atrial preparations could be antagonized by 10 µM cimetidine and 1 µM GR 125487. LSD leads to H2-histamine receptor and 5-HT4-receptor mediated cardiac effects in humans.

Drug-drug interactions involving classic psychedelics: A systematic review.

Classic psychedelics, including lysergic acid diethylamide (LSD), psilocybin, mescaline, N,N-dimethyltryptamine (DMT) and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), are potent psychoactive substances that have been studied for their physiological and psychological effects. However, our understanding of the potential interactions and outcomes when using these substances in combination with other drugs is limited. This systematic review aims to provide a comprehensive overview of the current research on drug-drug interactions between classic psychedelics and other drugs in humans. We conducted a thorough literature search using multiple databases, including PubMed, PsycINFO, Web of Science and other sources to supplement our search for relevant studies. A total of 7102 records were screened, and studies involving human data describing potential interactions (as well as the lack thereof) between classic psychedelics and other drugs were included. In total, we identified 52 studies from 36 reports published before September 2, 2023, encompassing 32 studies on LSD, 10 on psilocybin, 4 on mescaline, 3 on DMT, 2 on 5-MeO-DMT and 1 on ayahuasca. These studies provide insights into the interactions between classic psychedelics and a range of drugs, including antidepressants, antipsychotics, anxiolytics, mood stabilisers, recreational drugs and others. The findings revealed various effects when psychedelics were combined with other drugs, including both attenuated and potentiated effects, as well as instances where no changes were observed. Except for a few case reports, no serious adverse drug events were described in the included studies. An in-depth discussion of the results is presented, along with an exploration of the potential molecular pathways that underlie the observed effects.