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Studying transitions in and out of the altered state of consciousness caused by intravenous (IV) N,N-Dimethyltryptamine (DMT - a fast-acting tryptamine psychedelic) offers a safe and powerful means of advancing knowledge on the neurobiology of conscious states. Here we sought to investigate the effects of IV DMT on the power spectrum and signal diversity of human brain activity (6 female, 7 male) recorded via multivariate EEG, and plot relationships between subjective experience, brain activity and drug plasma concentrations across time. Compared with placebo, DMT markedly reduced oscillatory power in the alpha and beta bands and robustly increased spontaneous signal diversity. Time-referenced and neurophenomenological analyses revealed close relationships between changes in various aspects of subjective experience and changes in brain activity. Importantly, the emergence of oscillatory activity within the delta and theta frequency bands was found to correlate with the peak of the experience - particularly its eyes-closed visual component. These findings highlight marked changes in oscillatory activity and signal diversity with DMT that parallel broad and specific components of the subjective experience, thus advancing our understanding of the neurobiological underpinnings of immersive states of consciousness.

Psychedelic drugs are potent modulators of conscious states and therefore powerful tools for investigating their neurobiology. N,N, Dimethyltryptamine (DMT) can rapidly induce an extremely immersive state of consciousness characterized by vivid and elaborate visual imagery. Here, we investigated the electrophysiological correlates of the DMT-induced altered state from a pool of participants receiving DMT and (separately) placebo (saline) while instructed to keep their eyes closed. Consistent with our hypotheses, results revealed a spatio-temporal pattern of cortical activation (i.e. travelling waves) similar to that elicited by visual stimulation. Moreover, the typical top-down alpha-band rhythms of closed-eyes rest were significantly decreased, while the bottom-up forward wave was significantly increased. These results support a recent model proposing that psychedelics reduce the ‘precision-weighting of priors’, thus altering the balance of top-down versus bottom-up information passing. The robust hypothesis-confirming nature of these findings imply the discovery of an important mechanistic principle underpinning psychedelic-induced altered states.

Harmine, a major alkaloid in ayahuasca (hoasca), is a selective and reversible inhibitor of the enzyme monoamine oxidase-A (MAO-A). It is also a selective inhibitor of the human cytochrome P450 isozyme 2D6 (CYP 2D6), which metabolizes harmine to a more hydrophilic derivative for eventual excretion. CYP 2D6 exhibits a wide range of polymorphisms in human populations, and variations in this enzymatic activity could account for differences in effects between individuals who use hoasca. This report broadly describes two subgroups of CYP 2D6 phenotypes-i.e., fast and slow metabolizers of harmine-in 14 experienced male members of the Uniāo do Vegetal (UDV) who received a standardized dosage of hoasca. To compensate for metabolic variations in their normal religious practice, the administered dose of hoasca is always determined by the presiding mestre, who is responsible for deciding the actual amount for each individual. This age-old method compensates for metabolic variations between individuals and variations in both the alkaloid profile and strength of the hoasca.

Rationale Ayahuasca is an Amazonian tea containing the natural psychedelic 5-HT 2A/2C/1A agonist N , N -dimethyltryptamine (DMT). It is used in ceremonial contexts for its visionary properties. The human pharmacology of ayahuasca has been well characterized following its administration in single doses. Objectives To evaluate the human pharmacology of ayahuasca in repeated doses and assess the potential occurrence of acute tolerance or sensitization. Methods In a double-blind, crossover, placebo-controlled clinical trial, nine experienced psychedelic drug users received PO the two following treatment combinations at least 1 week apart: (a) a lactose placebo and then, 4 h later, an ayahuasca dose; and (b) two ayahuasca doses 4 h apart. All ayahuasca doses were freeze-dried Amazonian-sourced tea encapsulated to a standardized 0.75 mg DMT/kg bodyweight. Subjective, neurophysiological, cardiovascular, autonomic, neuroendocrine, and cell immunity measures were obtained before and at regular time intervals until 12 h after first dose administration. Results DMT plasma concentrations, scores in subjective and neurophysiological variables, and serum prolactin and cortisol were significantly higher after two consecutive doses. When effects were standardized by plasma DMT concentrations, no differences were observed for subjective, neurophysiological, autonomic, or immunological effects. However, we observed a trend to reduced systolic blood pressure and heart rate, and a significant decrease for growth hormone (GH) after the second ayahuasca dose. Conclusions Whereas there was no clear-cut tolerance or sensitization in the psychological sphere or most physiological variables, a trend to lower cardiovascular activation was observed, together with significant tolerance to GH secretion.

There is considerable interest in the therapeutic potential of psychedelic drugs. Dimethyltryptamine (DMT) is a potent, rapid-onset, and short-acting psychedelic drug that has not yet been independently tested for the treatment of depression. The safety, tolerability, and efficacy of intravenous DMT were investigated in treatment-resistant individuals with major depressive disorder (MDD) and healthy controls (HC) in an open-label, fixed-order, dose-escalation (0.1 mg/kg followed by 0.3 mg/kg) exploratory phase 1 study that was conducted in a typical hospital setting with strategic psychoeducation/support, but minimal psychotherapy. Tolerability, safety, cardiovascular function, abuse liability, psychedelic, and psychotomimetic effects, mood, and anxiety were assessed at each dosing session. In addition, depression was measured using the HAMD-17 in MDD participants 1 day after each dosing session. DMT was tolerated by both HC (n = 3) and MDD participants (n = 7) studied; there were no dropouts. HAMD-17 scores decreased significantly (p = 0.017) compared to baseline in MDD participants the day after receiving 0.3 mg/kg DMT (mean difference −4.5 points, 95% CI: −7.80 to −1.20, Hedge’s g = 0.75). Adverse events were mostly mild with one self-limited serious event. DMT increased blood pressure, heart rate, anxiety, psychedelic effects, and psychotomimetic effects, which resolved within 20–30 min of injection. There were no dose-related differences in measures of drug reinforcement and abuse liability. In this small exploratory pilot study, intravenous DMT at doses of 0.1 and 0.3 mg/kg was mostly safe and tolerated and may have next-day (rapid) antidepressant effects in patients with treatment-resistant MDD. Further rigorous trials are warranted to replicate these findings and to determine the durability of antidepressant effects.

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 orphan receptor sigma-1 (sigmar-1) is a transmembrane chaperone protein expressed in both the central nervous system and in immune cells. It has been shown to regulate neuronal differentiation and cell survival, and mediates anti-inflammatory responses and immunosuppression in murine in vivo models. Since the details of these findings have not been elucidated so far, we studied the effects of the endogenous sigmar-1 ligands N,N-dimethyltryptamine (NN-DMT), its derivative 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and the synthetic high affinity sigmar-1 agonist PRE-084 hydrochloride on human primary monocyte-derived dendritic cell (moDCs) activation provoked by LPS, polyI:C or pathogen-derived stimuli to induce inflammatory responses. Co-treatment of moDC with these activators and sigma-1 receptor ligands inhibited the production of pro-inflammatory cytokines IL-1β, IL-6, TNFα and the chemokine IL-8, while increased the secretion of the anti-inflammatory cytokine IL-10. The T-cell activating capacity of moDCs was also inhibited, and dimethyltryptamines used in combination with E. coli or influenza virus as stimulators decreased the differentiation of moDC-induced Th1 and Th17 inflammatory effector T-cells in a sigmar-1 specific manner as confirmed by gene silencing. Here we demonstrate for the first time the immunomodulatory potential of NN-DMT and 5-MeO-DMT on human moDC functions via sigmar-1 that could be harnessed for the pharmacological treatment of autoimmune diseases and chronic inflammatory conditions of the CNS or peripheral tissues. Our findings also point out a new biological role for dimethyltryptamines, which may act as systemic endogenous regulators of inflammation and immune homeostasis through the sigma-1 receptor.

Ayahuasca is a South American psychoactive beverage that contains the naturally occurring psychedelic agent N,N-dimethyltryptamine (DMT). This \"tea\" has been used for centuries in religious and medicinal contexts in the rain forest areas of South America and is presently gaining the attention of psychedelic users in North America and Europe. In the present study, the psychological effects and tolerability of ayvahuasca were assessed. Three increasing doses of encapsulated freeze-dried ayahuasca (0.5, 0.75, and 1.0 mg DMT/kg body weight) were administered to six healthy male volunteers with prior experience in the use of this tea, in a single-blind crossover placebo-controlled clinical trial. Ayahuasca produced significant dose-dependent increases in five of the six subscales of the Hallucinogen Rating Scale, in the LSD, MBG, and A scales of the Addiction Research Center Inventory, and in the \"liking\", \"good effects\" and \"high\" visual analogue scales. Psychological effects were first noted after 30-60 min, peaked between 60-120 min, and were resolved by 240 min. The tea was well tolerated from a cardiovascular point of view, with a trend toward increase for systolic blood pressure. Modified physical sensations and nausea were the most frequently reported somatic-dysphoric effects. The overall experience was regarded as pleasant and satisfactory by five of the six volunteers, while one volunteer experienced an intensely dysphoric reaction with transient disorientation and anxiety at the medium dose and voluntarily withdrew from the study. Ayahuasca can be described as inducing changes in the perceptual, affective, cognitive, and somatic spheres, with a combination of stimulatory and visual psychoactive effects of longer duration and milder intensity than those previously reported for intravenously administered DMT.