Reactivations after 5-methoxy-N,N-dimethyltryptamine use in naturalistic settings: An initial exploratory analysis of the phenomenon's predictors and its emotional valence.

Background: The psychedelic 5-MeO-DMT has shown clinical potential due to its short duration and ability to induce mystical experiences. However, a phenomenon known as "reactivations" (similar to "flashbacks") is a poorly understood and frequently reported phenomenon which appears associated with 5-MeO-DMT use and warranted further investigation. Aims: This study examined whether differences in age, gender, education, lifetime use, use location, and preparation strategies predict reactivations (primary outcome). Additionally, we explored how reactivations were perceived by survey respondents and whether demographic data predicted emotional valence (secondary outcome) of reported reactivations. Materials and methods: This study used secondary quantitative data from a survey assessing epidemiological and behavioral associations of 5-MeO-DMT use in non-clinical settings (N = 513). Descriptive statistics, chi-square tests, t-tests, and logistic regressions were utilized to explore aims. Results: Being female, older at the time of first 5-MeO-DMT dose, having higher educational attainment, and dosing in a structured group setting were associated with increased odds of reporting a reactivation event. Higher mystical experience scores, greater personal wellbeing and having had a non-dual awareness experience that was not substance-induced were associated with higher likelihood of reporting a neutral or positive emotional valence of a reactivation event. Conclusion: These findings suggest that reactivation phenomena, in this particular sample may most often represent a neutral or positive byproduct of the acute 5-MeO-DMT experience. More information is needed to best identify individuals most likely to experience a reactivation as a negative event to prevent such potential challenging outcomes.

The clinical pharmacology and potential therapeutic applications of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT).

5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a naturally occurring tryptamine that primarily acts as an agonist at the 5-HT1A and 5-HT2A receptors, whereby affinity for the 5-HT1A subtype is highest. Subjective effects following 5-MeO-DMT administration include distortions in auditory and time perception, amplification of emotional states, and feelings of ego dissolution that usually are short-lasting, depending on the route of administration. Individual dose escalation of 5-MeO-DMT reliably induces a "peak" experience, a state thought to be a core predictor of the therapeutic efficacy of psychedelics. Observational studies and surveys have suggested that single exposure to 5-MeO-DMT can cause rapid and sustained reductions in symptoms of depression, anxiety, and stress. 5-MeO-DMT also stimulates neuroendocrine function, immunoregulation, and anti-inflammatory processes, which may contribute to changes in mental health outcomes. To date, only one clinical trial has been published on 5-MeO-DMT, demonstrating the safety of vaporized dosing up to 18 mg. Importantly, the rapid onset and short duration of the 5-MeO-DMT experience may render it more suitable for individual dose-finding strategies compared with longer-acting psychedelics. A range of biotech companies has shown an interest in the development of 5-MeO-DMT formulations for a range of medical indications, most notably depression. Commercial development will therefore be the most important resource for bringing 5-MeO-DMT to the clinic. However, fundamental research will also be needed to increase understanding of the neurophysiological and neural mechanisms that contribute to the potential clinical effects of 5-MeO-DMT and its sustainability and dissemination over time. Such studies are less likely to be conducted as part of drug development programs and are more likely to rely on independent, academic initiatives.

The epidemiology of mescaline use: Pattern of use, motivations for consumption, and perceived consequences, benefits, and acute and enduring subjective effects.

BACKGROUND: Mescaline is a naturally occurring psychoactive phenethylamine found in several cacti and historically used ceremonially by Indigenous and Latin American populations. Broader recognition of its possible therapeutic value in Western science began in the 1950s; however, knowledge of the safety profile of mescaline and the extent of its use remains limited. The primary aim of this study is to examine the epidemiology of mescaline use among English-speaking adults. METHODS: About 452 respondents completed a web-based survey designed to assess their previous experience with mescaline (subjective effects, outcome measures, and mescaline type used). RESULTS: Most respondents reported that they had consumed mescaline infrequently (⩽once/year), for spiritual exploration or to connect with nature (74%). A small number of respondents reported drug craving/desire (9%), whereas very few reported legal (1%), or psychological problems (1%) related to its use, and none reported seeking any medical attention. Overall, respondents rated the acute mystical-type effects as "moderate," ego-dissolution and psychological insight effects as "slight," and challenging effects as "very slight." Most respondents reported that they used Peyote and San Pedro in their most memorable mescaline experience. Overall, the intensity of acute mescaline effects did not differ between mescaline types. About 50% of the sample reported having a psychiatric condition (i.e. depression, anxiety, etc.), and most (>67%) reported improvements in these conditions following their most memorable experience with mescaline. CONCLUSION: Findings indicate that the mescaline in any form may produce a psychedelic experience that is associated with the spiritual significance and improvements in the mental health with low potential for abuse.

Naturalistic Use of Mescaline Is Associated with Self-Reported Psychiatric Improvements and Enduring Positive Life Changes.

Mescaline is a naturally occurring psychoactive alkaloid that has been used as a sacrament by Indigenous populations in spiritual ritual and healing ceremonies for millennia. Despite promising early preliminary research and favorable anecdotal reports, there is limited research investigating mescaline's psychotherapeutic potential. We administered an anonymous online questionnaire to adults (N = 452) reporting use of mescaline in naturalistic settings about mental health benefits attributed to mescaline. We assessed respondents' self-reported improvements in depression, anxiety, post-traumatic stress disorder (PTSD), and alcohol and drug use disorders (AUD and DUD). Of the respondents reporting histories of these clinical conditions, most (68-86%) reported subjective improvement following their most memorable mescaline experience. Respondents who reported an improvement in their psychiatric conditions reported significantly higher ratings of acute psychological factors including mystical-type, psychological insight, and ego dissolution effects compared to those who did not report improvements (Cohen's d range 0.7 - 1.5). Many respondents (35-50%) rated the mescaline experience as the single or top five most spiritually significant or meaningful experience(s) of their lives. Acute experiences of psychological insight during their mescaline experience were associated with increased odds of reporting improvement in depression, anxiety, AUD and DUD. Additional research is needed to corroborate these preliminary findings and to rigorously examine the efficacy of mescaline for psychiatric treatment in controlled, longitudinal clinical trials.

Synthesis and Characterization of 5-MeO-DMT Succinate for Clinical Use.

To support clinical use, a multigram-scale process has been developed to provide 5-MeO-DMT, a psychedelic natural product found in the parotid gland secretions of the toad, Incilius alvarius. Several synthetic routes were initially explored, and the selected process featured an optimized Fischer indole reaction to 5-MeO-DMT freebase in high-yield, from which the 1:1 succinate salt was produced to provide 136 g of crystalline active pharmaceutical ingredient (API) with 99.86% peak area by high-performance liquid chromatography (HPLC) and a net yield of 49%. The report provides in-process monitoring, validated analytical methods, impurity formation and removal, and solid-state characterization of the API essential for subsequent clinical development.

A Meta-Analysis of Placebo-Controlled Trials of Psychedelic-Assisted Therapy.

After a two-decade hiatus in which research on psychedelics was essentially halted, placebo-controlled clinical trials of psychedelic-assisted therapy for mental health conditions have begun to be published. We identified nine randomized, placebo-controlled clinical trials of psychedelic-assisted therapy published since 1994. Studies examined psilocybin, LSD (lysergic acid diethylamide), ayahuasca (which contains a combination of N,N-dimethyltryptamine and harmala monoamine oxidase inhibitor alkaloids), and MDMA (3,4-methylenedioxymethamphetamine). We compared the standardized mean difference between the experimental and placebo control group at the primary endpoint. Results indicated a significant mean between-groups effect size of 1.21 (Hedges g), which is larger than the typical effect size found in trials of psychopharmacological or psychotherapy interventions. For the three studies that maintained a placebo control through a follow-up assessment, effects were generally maintained at follow-up. Overall, analyses support the efficacy of psychedelic-assisted therapy across four mental health conditions - post-traumatic stress disorder, anxiety/depression associated with a life-threatening illness, unipolar depression, and social anxiety among autistic adults. While study quality was high, we identify several areas for improvement regarding the conduct and reporting of trials. Larger trials with more diverse samples are needed to examine possible moderators and mediators of effects, and to establish whether effects are maintained over time.

Use of Benefit Enhancement Strategies among 5-Methoxy-N,N-Dimethyltryptamine (5-MeO-DMT) Users: Associations with Mystical, Challenging, and Enduring Effects.

5-Methoxy-N,N-Dimethyltryptamine (5-MeO-DMT) is a potent, fast-acting psychedelic. Anecdotal reports from 5-MeO-DMT users suggest that they employ a variety of benefit enhancement (BE) strategies aimed to increase positive effects and decrease any potential challenging effects of the substance, but no empirical study has investigated this claim. We examined the prevalence of BE strategy use using secondary data from a survey of 5-MeO-DMT users (n = 515; Mage = 35.4, SD = 11.7; Male = 79%; White/Caucasian = 86%). Results indicated that BE strategy use was common in this sample. As a secondary aim, we assessed whether the use of BE strategies was associated with acute subjective (i.e., mystical-type, challenging) and persisting effects of 5-MeO-DMT among a subset of respondents who reported using 5-MeO-DMT once in their lifetime (n = 116). Results showed that the use of several BE strategies were associated with significantly more intense mystical-type effects and enduring beliefs about the personal meaning and spiritual significance of their experience, and some BE strategies were associated with less intense or challenging experiences. Data suggests that BE strategies are commonly used, and that the use of BE strategies may be associated with increases in positive mystical-type and enduring effects. The causal influence of BE strategies on acute/persisting effects of 5-MeO-DMT should be examined in longitudinal research.

Prospective examination of synthetic 5-methoxy-N,N-dimethyltryptamine inhalation: effects on salivary IL-6, cortisol levels, affect, and non-judgment.

RATIONALE: 5-methoxy-N,N-dimethyltryptamine is a psychotropic substance found in various plant and animal species and is synthetically produced. 5-methoxy-N,N-dimethyltryptamine is used in naturalistic settings for spiritual exploration, recreation, or to address negative affect and mood problems. However, scientific knowledge on the effects of 5-methoxy-N,N-dimethyltryptamine in humans is scarce. OBJECTIVES: The first objective was to assess the effects of inhalation of vaporized synthetic 5-methoxy-N,N-dimethyltryptamine on neuroendocrine markers. The second objective was to assess effects of the substance on affect and mindfulness. In addition, we assessed whether ratings of subjective measures were associated with changes in stress biomarkers (i.e., cortisol) and immune response (i.e., IL-6, CRP, IL-1ß), as well as the acute psychedelic experience. METHODS: Assessments (baseline, immediately post-session, and 7-day follow-up) were made in 11 participants. Salivary samples were collected at baseline and post-session and analyzed by high-sensitivity enzyme-linked immunosorbent assay (ELISA). RESULTS: 5-methoxy-N,N-dimethyltryptamine significantly increased cortisol levels and decreased IL-6 concentrations in saliva immediately post-session. These changes were not correlated to ratings of mental health or the psychedelic experience. Relative to baseline, ratings of non-judgment significantly increased, and ratings of depression decreased immediately post-session and at follow-up. Ratings of anxiety and stress decreased from baseline to 7-day follow-up. Participant ratings of the psychedelic experience correlated negatively with ratings of affect and positively with ratings of non-judgment. CONCLUSION: Inhalation of vaporized synthetic 5-methoxy-N,N-dimethyltryptamine produced significant changes in inflammatory markers, improved affect, and non-judgment in volunteers. Future research should examine the effect of 5-methoxy-N,N-dimethyltryptamineamine with healthy volunteers in a controlled laboratory setting.

5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) used in a naturalistic group setting is associated with unintended improvements in depression and anxiety.

BACKGROUND: A recent epidemiological study suggested that 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) used for spiritual and recreational reasons is associated with subjective improvement in depression and anxiety. Further exploration of the potential psychotherapeutic effects of 5-MeO-DMT could inform future clinical trials. OBJECTIVES: We examined self-reported improvement in depression and anxiety among people who use 5-MeO-DMT in a group setting with structured procedures guiding dose and administration of 5-MeO-DMT. Such procedures also include activities for the preparation of, and support during/following sessions, which are similar to procedures used in clinical trials of hallucinogen administration. Next, we examined whether depression or anxiety were improved following use, and whether the acute subjective effects (mystical/challenging) or beliefs about the 5-MeO-DMT experience were associated with improvements in these conditions. METHODS: Respondents (n = 362; Mage = 47.7; Male = 55%; White/Caucasian = 84%) completed an anonymous web-based survey. RESULTS: Of those reporting having been diagnosed with depression (41%) or anxiety (48%), most reported these conditions were improved (depression = 80%; anxiety = 79%) following 5-MeO-DMT use, and fewer reported they were unchanged (depression = 17%; anxiety = 19%) or worsened (depression = 3%; anxiety = 2%). Improvement in depression/anxiety conditions were associated with greater intensity of mystical experiences and higher ratings of the spiritual significance and personal meaning of the 5-MeO-DMT experience. There were no associations between depression or anxiety improvement and the intensity of acute challenging physical/psychological effects during the 5-MeO-DMT experience. CONCLUSIONS: Future prospective controlled clinical pharmacology studies should examine the safety and efficacy of 5-MeO-DMT administration for relieving depression and anxiety.

Intensity of Mystical Experiences Occasioned by 5-MeO-DMT and Comparison With a Prior Psilocybin Study.

5-MeO-DMT is a psychoactive substance found in high concentrations in the bufotoxin of the Colorado River Toad (Bufo alvarius). Emerging evidence suggests that vaporized 5-MeO-DMT may occasion mystical experiences of comparable intensity to those occasioned by more widely studied psychedelics such as psilocybin, but no empirical study has tested this hypothesis. Data was obtained from 20 individuals (M age = 38.9, ± 10.7; male = 55%, Caucasian = 85%) who were administered 5-MeO-DMT as part of a psychospiritual retreat program in Mexico. All participants received 50 mg of inhaled vaporized toad bufotoxin which contains 5-MeO-DMT and completed the Mystical Experience Questionnaire (MEQ30) approximately 4-6 h after their session. Administration of 5-MeO-DMT occasioned strong mystical experiences (MEQ30 Overall M intensity = 4.17, ± 0.64, range 0-5) and the majority (n = 15, 75%) had "a complete mystical experience" (≥60% on all MEQ30 subscales). Compared to a prior laboratory-based psilocybin study, there were no differences in the intensity of mystical effects between 5-MeO-DMT and a high dose (30 mg/70 kg) of psilocybin, but the intensity of mystical effects was significantly higher in the 5-MeO-DMT sample compared to moderate/high dose (20 mg/70 kg) of psilocybin (MEQ30 Total Score: p = 0.02, d = 0.81). Administration of vaporized 5-MeO-DMT reliably occasioned complete mystical experiences in 75% of individuals and was similar in intensity to high dose psilocybin administered in a laboratory setting. The short duration of action may be advantageous for clinical interventions and for studying mystical-type experiences.

The epidemiology of 5-methoxy- N, N-dimethyltryptamine (5-MeO-DMT) use: Benefits, consequences, patterns of use, subjective effects, and reasons for consumption.

BACKGROUND/AIM: 5-Methoxy- N,N-dimethyltryptamine (5-MeO-DMT) is a psychoactive compound found in several plants and in high concentrations in Bufo alvarius toad venom. Synthetic, toad, and plant-sourced 5-MeO-DMT are used for spiritual and recreational purposes and may have psychotherapeutic effects. However, the use of 5-MeO-DMT is not well understood. Therefore, we examined patterns of use, motivations for consumption, subjective effects, and potential benefits and consequences associated with 5-MeO-DMT use. METHODS: Using internet-based advertisements, 515 respondents ( Mage=35.4. SD=11.7; male=79%; White/Caucasian=86%; United States resident=42%) completed a web-based survey. RESULTS: Most respondents consumed 5-MeO-DMT infrequently (