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Dose-response study of N,N-dimethyltryptamine in humans. II. Subjective effects and preliminary results of a new rating scale

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Validation of animal models of hallucinogenic drugs' subjective effects requires human data. Previous human studies used varied groups of subjects and assessment methods. Rating scales for hallucinogen effects emphasized psychodynamic principles or the drugs' dysphoric properties. We describe the subjective effects of graded doses of N,N-dimethyltryptamine (DMT), an endogenous hallucinogen and drug of abuse, in a group of experienced hallucinogen users. We also present preliminary data from a new rating scale for these effects. Twelve highly motivated volunteers received two doses (0.04 and 0.4 mg/kg) of intravenous (IV) dimethyltryptamine fumarate "nonblind," before entering a double-blind, saline placebo-controlled, randomized study using four doses of IV DMT. Subjects were carefully interviewed after resolution of drug effects, providing thorough and systematic descriptions of DMT's effects. They also were administered a new instrument, the Hallucinogen Rating Scale (HRS). The HRS was drafted from interviews obtained from an independent sample of 19 experienced DMT users, and modified during early stages of the study. Psychological effects of IV DMT began almost immediately after administration, peaked at 90 to 120 seconds, and were almost completely resolved by 30 minutes. This time course paralleled DMT blood levels previously described. Hallucinogenic effects were seen after 0.2 and 0.4 mg/kg of dimethyltryptamine fumarate, and included a rapidly moving, brightly colored visual display of images. Auditory effects were less common. "Loss of control," associated with a brief, but overwhelming "rush," led to a dissociated state, where euphoria alternated or coexisted with anxiety. These effects completely replaced subjects' previously ongoing mental experience and were more vivid and compelling than dreams or waking awareness. Lower doses, 0.1 and 0.05 mg/kg, were primarily affective and somaesthetic, while 0.1 mg/kg elicited the least desirable effects. Clustering of HRS items, using either a clinical, mental status method or principal components factor analysis provided better resolution of dose effects than did the biological variables described previously. These clinical and preliminary quantitative data provide bases for further psychopharmacologic characterization of DMT's properties in humans. They also may be used to compare the effects of other agents affecting relevant brain receptors in volunteer and psychiatric populations.
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... Alternatively, DMT can be administered parenterally, thereby avoiding hepatic first-pass metabolism. Modern clinical trials that examined DMT for the treatment of various psychiatric and neurodegenerative disorders mainly used the intravenous or inhalative route [5][6][7][8][9][10][11]. Historically, the first trials with intravenous DMT used bolus injections [12,13]. Recently, we tested a regimen that combined initial intravenous DMT bolus doses of 15 and 25 mg, administered within 45 s, followed by continuous infusions that were administered at dose rates of 0.6 and 1 mg/min over 90 min [5]. ...
... mg/min of DMT fumarate [6]. The bolus doses produced rapidly increasing subjective effects that were often overwhelming and short-lived [5,12,13]. Conversely, continuous infusions at dose rates of 0.6 and 1.0 mg/min DMT without a bolus induced mild to moderate psychedelic effects that gradually reached a plateau within 20-30 min [5]. Infusions of DMT without a bolus or with a slowly administered loading dose resulted in less anxiety compared with a bolus injection and was better tolerated [5,7,9]. ...
... Previous research on intravenous DMT examined the combination of an initial bolus dose with a continuous infusion [5,6]. However such high bolus doses were less well tolerated [5,12,13] than continuous infusions [5,7] likely because of greater negative drug effects, including fear and physical discomfort, that are associated with the rapid and immediate onset of acute effects of bolus doses [5]. Inhalation of high doses of DMT, which exhibits kinetics similar to that of intravenous bolus doses, may be associated with similar tolerability issues [11]. ...
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N,N -dimethyltryptamine (DMT) is a serotonergic psychedelic that is known for its short-lasting effects when administered intravenously. Several studies have investigated the administration of intravenous boluses or combinations of a bolus and a subsequent continuous infusion. However, data on dose-dependent acute effects and pharmacokinetics of continuous DMT infusions are lacking. We used a double-blind, randomized, placebo-controlled, crossover design in 22 healthy participants (11 women, 11 men) who received placebo and DMT (0.6, 1.2, 1.8, and 2.4 mg/min) over an infusion duration of 120 min. We also tested a self-guided titration scheme that allowed participants to adjust the DMT dose rate at prespecified time points to achieve their desired level of subjective effects. Outcome measures included subjective effects, autonomic effects, adverse effects, plasma hormone concentrations, and pharmacokinetics up to 3 h after starting the infusion. DMT infusions exhibited dose-proportional pharmacokinetics and rapidly induced dose-dependent subjective effects that reached a plateau after 30 min. A ceiling effect was observed for “good drug effect” at 1.8 mg/min. The 2.4 mg/min dose of DMT induced greater anxious ego dissolution than the 1.8 mg/min dose and induced significant anxiety compared with placebo. We observed moderate acute tolerance to acute effects of DMT. In the self-guided titration session, the participants opted for moderate to strong psychedelic effects, comparable in intensity to the 1.8 mg/min DMT dose rate in the randomized dosing sessions. These results may assist with dose finding for future DMT research and demonstrate that acute subjective effects of DMT can be rapidly adjusted through dose titration.
... DMT has been found to be inactive orally in doses as high as 1 g, but it has been found to be psychoactive after intramuscular administration (0.25-2.00 mg/kg), when inhaled as vaporized freebase (0.2-0.7 mg/kg), and after intravenous administration (0.2-0.4 mg/kg). [8][9][10] The intramuscular route produces an experience that initiates around 3-5 minutes and ends after 1 hour. 8 With intravenous administration or with vaporized/smoked DMT, the subjective effects initiate almost instantaneously (around 30 seconds) and end after 20-30 minutes. ...
... 8 With intravenous administration or with vaporized/smoked DMT, the subjective effects initiate almost instantaneously (around 30 seconds) and end after 20-30 minutes. 9,10 Peak concentrations of DMT (100 ng/ml) were reached after 10-15 min following an intramuscular injection of a 0.7 mg/kg dose, and then fell rapidly to baseline levels. After about 45-120 min, DMT levels were undetectable. ...
... Subjective effects are similar in quality to those of intravenous DMT, but with ayahuasca they are milder and last longer. 10,49,55,56 Effects include intricate eyes-closed visual imagery, complex thought processes, and a general state of heightened awareness. Overall perceptual, cognitive, and affective processes are significantly modified, in the presence of a clear sensorium. ...
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Ayahuasca is a botanical hallucinogen traditionally used for therapeutic and ritual purposes by indigenous groups from Northwestern Amazonian countries such as Brazil, Peru, Colombia, and Ecuador. Ayahuasca is made by the decoction of two plants, which are rich in the 5-HT1A/2A partial agonist dimethyltryptamine or DMT (from the leaves of the Psychotria viridis bush) and β-carbolines such as harmine, from the stalks of the Banisteriopsis caapi vine. There is an increasing interest in the possible therapeutic effects of ayahuasca, especially for psychiatric disorders (major depression, posttraumatic stress disorder, and substance use disorder). This review summarizes information on the pharmacology, safety, and therapeutic potentials of ayahuasca. Although human experimental and naturalist studies published until now suggest a good safety and tolerability profile, often associated with improvements in depressive and anxious symptoms, there are few controlled studies, with small sample sizes, using only single doses, and with short follow-ups. Potential benefits of ayahuasca should be evaluated in larger samples in both experimental and observational studies and using different doses in controlled trials.
... The 105-item HRS was originally based on detailed phenomenological interviews with experienced psychedelics users and then refined in subsequent studies of intravenous DMT (24,25). This led to straightforward item formulations assessing fundamental components of experience, and the authors avoided basing questions on spiritual, theological, or other higher-order interpretations of psychedelic effects. ...
... Using the other half of our dataset, we used CFA to test the validity of the new 8-factor model and compare it with the original clinical clusters (25), as well as to a subsequent factor model from an ayahuasca study (26). All models showed good to excellent internal consistency, with the new model having the highest consistency (Table S2). ...
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Background The Hallucinogen Rating Scale (HRS) has been widely used to measure the subjective effects of psychedelics and other psychoactive substances. Its advantages include a basis in phenomenological interviews and clinical studies, straightforward items, and broad coverage of psychedelic effects. Previous studies have attempted to resolve its factor structure but were limited by small samples of participants who took only one substance. Methods We obtained 991 HRS questionnaires from the authors of 18 publications involving 13 psychoactive substances. Exploratory factor analysis was used to analyze its factor structure, and mixed-effects analyses of variance were used to compare HRS scores between drugs. Results The HRS resolved into 8 factors with good to excellent internal consistency and that intuitively map onto the effects of psychedelics. The factor model also showed good measures of fit that were superior to previous proposed models. Model factors were able to show dose responses for most drugs. Additionally, patterns of responses on the 8 factors significantly differentiated classic psychedelics, such as psilocybin and DMT, from other substance classes, including dissociatives such as ketamine and salvinorin A, empathogens such as MDMA, stimulants such as methylphenidate and amphetamine, and Δ⁹-tetrahydrocannabinol. The factor of meaningfulness also uniquely differentiated psychedelics from all other substances. Conclusions These data show that the HRS is an intuitive and psychometrically sound tool for measuring the effects of psychedelic drugs, and it may also have utility for measuring the effects of other drugs and altered states of consciousness.
... amerykański psychiatra Rick Strassman uzyskał pozwolenie na wskrzeszenie badań nad psychodelikami z udziałem ludzi, sprawdzając efekty wywoływane przez dimetylotryptaminę i psylocybinę u zdrowych ochotników (Strassman i współat. 1994, Strassman i Qualls 1994, Strassman 1996. Jego projekty pomogły ustanowić precedens dla innych naukowców i otworzyć furtkę do eksperymentów nad terapeutycznym użyciem tej grupy substancji (Strassman 1991). ...
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In the past decade, there has been a surge of interest in the therapeutic use of psychedelics, especially in the treatment of depression and addiction, resulting in many new research projects on their properties. This publication outlines the history of scientific experiments conducted with psychedelics in the 1950s and 1960s, as well as their subsequent international outlawing in the 1970s and the resurgence of research into their medical potential with the onset of the 21st century. Additionally, it discusses the potential mechanisms responsible for their therapeutic impact, the dangers accompanying their use, and changes in their legal status in some countries. The text also makes predictions about the development of a new branch of medicine based on the use of classic psychedelics and their new analogs.
... The study of mystical experiences has historically been conducted in conjunction with the broader field of psychedelic phenomena and represents a significant area of research within this field. Pioneers like William James (James 1902) and Aldous Huxley (Huxley 1945(Huxley , 1954(Huxley , 1956 made significant contributions to their phenomenological description and an intense discourse contributed to developing basic terminology and conceptual frameworks (Stace 1960;Pahnke 1963;Stoeber 2015). ...
Chapter
The range of phenomena that can be induced by psychedelic substances is broad and variable, including effects on perception, cognition, and emotion. The umbrella term “psychedelic phenomenology” is used to refer to a combination of altered experiential features, such as hallucinations or ego dissolution, which together constitute a psychedelic experience. However, there is no consensus on the set of alterations of consciousness that qualifies an altered state to be a “psychedelic state.” In this chapter we summarize the most commonly discussed changes in subjective experiences which could be seen as “core features” of psychedelic experiences. While acknowledging the rich history of pioneering phenomenological work of the last century, this chapter focuses on more recent developments in the quantitative work on the assessment of these phenomena. We also address the under-researched phenomenology of distressing effects, often referred to as “challenging experiences” or “bad trips,” and point to their importance in understanding the therapeutic potential and risks associated with psychedelic phenomenology. Historically, one can find many links between psychedelic phenomenology and the phenomenology of psychopathology. We stress the importance to refine the assessment and description also of distressing effects, to identify factors that promote acute experiences which are beneficial and limit those which can have potentially harmful long-term effects.
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Introduction Meditation practice and psychedelic use have attracted increasing attention in the public sphere and scientific research. Both methods induce non-ordinary states of consciousness that may have significant therapeutic benefits. Thus, there is growing scientific interest in potential synergies between psychedelic use and meditation practice with some research suggesting that psychedelics may benefit meditation practice. The present study examined individual, psychedelic-related, and meditation-related factors to determine under what conditions meditators perceive psychedelic use as beneficial for their meditation practice. Method Participants (N = 863) who had reported psychedelic use and a regular meditation practice (at least 3 times per week during the last 12 months) were included in the study. To accommodate a large number of variables, machine learning (i.e., elastic net, random forest) was used to analyze the data. Results Most participants (n = 634, 73.5%) found psychedelic use to have a positive influence on their quality of meditation. Twenty-eight variables showed significant zero-order associations with perceived benefits even following a correction. Elastic net had the best performance (R² = .266) and was used to identify the most important features. Across 53 variables, the model found that greater use of psychedelics, intention setting during psychedelic use, agreeableness, and exposure to N,N-Dimethyltryptamine (N,N-DMT) were most likely to be associated with the perception that psychedelics benefit meditation practice. The results were consistent across several different approaches used to identify the most important variables (i.e., Shapley values, feature ablation). Discussion Results suggest that most meditators found psychedelic use to have a positive influence on their meditation practice, with: 1) regularity of psychedelic use, 2) the setting of intentions for psychedelic use, 3) having an agreeable personality, and 4) reported use of N,N-DMT being the most likely predictors of perceiving psychedelic use as beneficial. Longitudinal designs and randomized trials manipulating psychedelic use are needed to establish causality.
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Background Recent interest in the clinical use of psychedelics has highlighted plant-derived medicines like ayahuasca showing rapid-acting and sustainable therapeutic effects in various psychiatric conditions. This traditional Amazonian plant decoction contains N,N-dimethyltryptamine (DMT) and β-carboline alkaloids such as harmine. However, its use is often accompanied by distressing effects like nausea, vomiting, and intense hallucinations, possibly due to complex pharmacokinetic/pharmacodynamic (PK-PD) interactions and lack of dose standardization. Methods This study addresses these limitations by testing a novel pharmaceutical formulation containing pure forms of DMT and harmine in a double-blind, randomized, placebo-controlled trial with 31 healthy male volunteers. We evaluated PK-PD by monitoring drug and metabolite plasma levels, subjective effects, adverse events, and cardiovascular parameters. Each participant received 3 randomized treatments: (1) 100 mg buccal harmine with 100 mg intranasal DMT, (2) 100 mg buccal harmine with intranasal placebo, and (3) full placebo, using a repeated-intermittent dosing scheme, such that 10 mg of DMT (or placebo) was administered every 15 minutes. Results N,N-dimethyltryptamine produced consistent PK profiles with Cmax values of 22.1 ng/mL and acute drug effects resembling the psychological effects of ayahuasca with a duration of 2–3 hours. Likewise, buccal harmine produced sustained-release PK profiles with Cmax values of 32.5 ng/mL but lacked distinguishable subjective effects compared to placebo. All drug conditions were safe and well tolerated, indicating the formulation’s suitability for clinical applications. Conclusions This study underscores the potential of a patient-oriented pharmaceutical formulation of DMT and harmine to reduce risks and improve therapeutic outcomes in treating mental health disorders. Clinical trial registration number Neurodynamics of prosocial emotional processing following serotonergic stimulation with N,N-dimethyltryptamine (DMT) and harmine in healthy subjects (NCT04716335) https://clinicaltrials.gov/ct2/show/NCT04716335
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CITATION Chaves C, dos Santos RG, Dursun SM, Tusconi M, Carta MG, Brietzke E and Hallak JEC (2024) Why N,N-dimethyltryptamine matters: unique features and therapeutic potential beyond classical psychedelics.
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