Search

There has been a resurgence of interest in the use of psychedelic therapies for several mental and substance use disorders. Psilocybin, a "classic" serotonergic psychedelic, has emerged as one of the primary compounds of interest in clinical research. While research on psilocybin's potential mental health benefits has grown, data on the safety and efficacy of other serotonergic psychedelics remain limited. A comprehensive scoping review on the use of mescaline, ibogaine, ayahuasca, N,N-dimethyltryptamine (DMT), and lysergic acid diethylamide (LSD) in the treatment of mental and substance disorders was conducted. Independent reviewers screened titles, abstracts, and full texts and conducted data extraction. Seventy-seven studies met the inclusion criteria. There were 43 studies of LSD, 24 studies of ayahuasca, 5 studies of DMT, 5 studies of ibogaine, and 5 studies of mescaline. Commonly reported benefits included improved mood and anxiety symptoms, improved insight, reduced substance use, improved relationships, and decreased vegetative symptoms. Commonly reported adverse effects were psychological, neurological, physical, and gastrointestinal in nature. Serious adverse events (homicide and suicide) were reported in published studies of LSD. In conclusion, there is only low-level evidence to support the safety and efficacy of non-psilocybin serotonergic psychedelics in individuals with mental and substance use disorders.

Mescaline, lysergic acid diethylamide (LSD), and psilocybin are classic serotonergic psychedelics. A valid, direct comparison of the effects of these substances is lacking. The main goal of the present study was to investigate potential pharmacological, physiological and phenomenological differences at psychoactive-equivalent doses of mescaline, LSD, and psilocybin. The present study used a randomized, double-blind, placebo-controlled, cross-over design to compare the acute subjective effects, autonomic effects, and pharmacokinetics of typically used, moderate to high doses of mescaline (300 and 500 mg), LSD (100 µg), and psilocybin (20 mg) in 32 healthy participants. A mescaline dose of 300 mg was used in the first 16 participants and 500 mg was used in the subsequent 16 participants. Acute subjective effects of 500 mg mescaline, LSD, and psilocybin were comparable across various psychometric scales. Autonomic effects of 500 mg mescaline, LSD, and psilocybin were moderate, with psilocybin causing a higher increase in diastolic blood pressure compared with LSD, and LSD showing a trend toward an increase in heart rate compared with psilocybin. The tolerability of mescaline, LSD, and psilocybin was comparable, with mescaline at both doses inducing slightly more subacute adverse effects (12-24 h) than LSD and psilocybin. Clear distinctions were seen in the duration of action between the three substances. Mescaline had the longest effect duration (mean: 11.1 h), followed by LSD (mean: 8.2 h), and psilocybin (mean: 4.9 h). Plasma elimination half-lives of mescaline and LSD were similar (approximately 3.5 h). The longer effect duration of mescaline compared with LSD was due to the longer time to reach maximal plasma concentrations and related peak effects. Mescaline and LSD, but not psilocybin, enhanced circulating oxytocin. None of the substances altered plasma brain-derived neurotrophic factor concentrations. In conclusion, the present study found no evidence of qualitative differences in altered states of consciousness that were induced by equally strong doses of mescaline, LSD, and psilocybin. The results indicate that any differences in the pharmacological profiles of mescaline, LSD, and psilocybin do not translate into relevant differences in the subjective experience. ClinicalTrials.gov identifier: NCT04227756., (© 2023. The Author(s).)

Background: The classical serotonergic psychedelics LSD, psilocybin, mescaline are not known to cause brain damage and are regarded as non-addictive. Clinical studies do not suggest that psychedelics cause long-term mental health problems. Psychedelics have been used in the Americas for thousands of years. Over 30 million people currently living in the US have used LSD, psilocybin, or mescaline., Objective: To evaluate the association between the lifetime use of psychedelics and current mental health in the adult population., Method: Data drawn from years 2001 to 2004 of the National Survey on Drug Use and Health consisted of 130,152 respondents, randomly selected to be representative of the adult population in the United States. Standardized screening measures for past year mental health included serious psychological distress (K6 scale), mental health treatment (inpatient, outpatient, medication, needed but did not receive), symptoms of eight psychiatric disorders (panic disorder, major depressive episode, mania, social phobia, general anxiety disorder, agoraphobia, posttraumatic stress disorder, and non-affective psychosis), and seven specific symptoms of non-affective psychosis. We calculated weighted odds ratios by multivariate logistic regression controlling for a range of sociodemographic variables, use of illicit drugs, risk taking behavior, and exposure to traumatic events., Results: 21,967 respondents (13.4% weighted) reported lifetime psychedelic use. There were no significant associations between lifetime use of any psychedelics, lifetime use of specific psychedelics (LSD, psilocybin, mescaline, peyote), or past year use of LSD and increased rate of any of the mental health outcomes. Rather, in several cases psychedelic use was associated with lower rate of mental health problems., Conclusion: We did not find use of psychedelics to be an independent risk factor for mental health problems.

The hypothesis that the action of hallucinogenic drugs is mediated by a depression of the activity of brain serotonergic (raphe) neurons was tested by examining the behavioral effects of several hallucinogenic drugs while concurrently monitoring the activity of raphe neurons in freely moving cats. LSD produced a dose-dependent decrease in raphe unit activity and a dose-dependent increase in certain behaviors (e.g. limb flick and abortive groom), and the peak of the behavioral and unit changes were temporally correlated. However, there were three important dissociations between the behavioral and electrophysiological effects of LSD. Firstly, low doses of LSD produced only small decreases in raphe unit activity but significant behavioral changes. Secondly, the duration of LSD-induced behavioral changes significantly outlasted the depression of raphe unit activity. And thirdly, raphe neurons were at least as responsive to LSD during tolerance as they were in the nontolerant condition. Psilocin produced a dose-dependent decrease in raphe unit activity, while the behavioral changes were not dose-related. However, the peak behavioral changes corresponded to the maximal depression of raphe unit activity. The phenylethylamine hallucinogens, DOM and mescaline, both produced large behavioral changes but no overall effect on raphe neurons. Following administration of DOM or mescaline, some raphe units showed a significant increase, while some showed a significant decrease, and others showed no change in activity. Therefore, the phenylethylamine hallucinogens may exert a depressant effect upon a subset of serotonin-containing neurons, and an amphetamine-like excitatory effect upon another subset of these neurons. Consistent with previous studies, all hallucinogens produced a high concentration of slow waves in the cortical EEG. Following administration of LSD or psilocin, the appearance of slow waves in the EEG was often associated with a transitory decrease in unit activity, while this was not observed for the phenylethylamine hallucinogens. The present data, in conjunction with recent data from other laboratories, suggest that the serotonin hypothesis of hallucinogenic drug action should be re-evaluated.

Fifteen rats were trained to discriminate between the tryptamine hallucinogen psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine; 1.0 mg/kg) and saline in a two-lever choice task. Dose-response and time-response curves were obtained. The psilocybin cue generalized to psilocin (the dephosphorylated congener of psilocybin) and to the prototypical indoleamine hallucinogen LSD, but not to the phenylethylamine hallucinogen mescaline. These results indicate that the hallucinogenic effects of these drugs in humans may not be identical with their discriminative stimulus functions in animals, and that these four compounds may not be members of a single drug class. The term 'hallucinogen' may thus be a misnomer in the context of drug discrimination studies in nonhumans.