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Acute dose-dependent effects and self-guided titration of continuous N,N-dimethyltryptamine infusions in a double-blind placebo-controlled study in healthy participants
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.
Journal Article
Dead straight guide to Guns n' Roses
Guns N' Roses, or GNR as they're known, is one of the biggest-selling rock bands of the past 30 years. Formed in 1985 their first album, Appetite for Destruction, followed two years later. With many star performers including Slash, Axl Rose, Izzy Stradlin and later drummer Matt Sorum, the band has always been high-profile. Use Your Illusion I and Use Your Illusion II, recorded simultaneously and released in 1991, debuted at number two and number one on the Billboard 200 respectively and have sold a combined 35 million copies worldwide.
Book
Structure, function and regulation of the hsp90 machinery
Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone which is essential in eukaryotes. It is required for the activation and stabilization of a wide variety of client proteins and many of them are involved in important cellular pathways. Since Hsp90 affects numerous physiological processes such as signal transduction, intracellular transport, and protein degradation, it became an interesting target for cancer therapy. Structurally, Hsp90 is a flexible dimeric protein composed of three different domains which adopt structurally distinct conformations. ATP binding triggers directionality in these conformational changes and leads to a more compact state. To achieve its function, Hsp90 works together with a large group of cofactors, termed co-chaperones. Co-chaperones form defined binary or ternary complexes with Hsp90, which facilitate the maturation of client proteins. In addition, posttranslational modifications of Hsp90, such as phosphorylation and acetylation, provide another level of regulation. They influence the conformational cycle, co-chaperone interaction, and inter-domain communications. In this review, we discuss the recent progress made in understanding the Hsp90 machinery.
Journal Article
Neural correlates of the DMT experience assessed with multivariate EEG
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.
Journal Article
فن الحياة : الفيسنا : تقنية التأمل والتصبر، كما يعلمة س. ن. غونكا /
الفيسنا (Vipassanā) هي إحدى أقدم تق نيات الهند في التأم أعيد كتشافها منذ 2500 عام من قبل غوتاما بودا، الذي درسها كعلاج عالمي لأمراض العالم. فيسنا هو مصطلح باللغة الپالية يعني التبصر، أي رؤية الأشياء كما هي في الحقيق هي ليست إيمانا أعمى أو فلسفة، ولا علاقة لها بالطوائف الدينية، بل هي طريقة عملية يمكن تطبيقها من قبل أي شخص ذي ذكاء متوسط، والهدف منها هو تنقية العقل، والقضاء على التوترات والسلبيات التي تجعلنا بؤساء.تعتبر الپ سنا تقليد من أجل تحويل الذات عن طريق مراقبتها والتأمل فيها، حيث يشار إلى هذا النوع من التأمل في الكثير من الأحيان باسم \"التأمل الداخلي. أعد هذا الكتاب بالاستناد إلى محاضرات وكتابات س. ن. غونكا، يظهر فيه وليميليام هارت كيف يمكن استخدام الفيسنا لحل المشاكل وتطوير الإمكانات غير العادية، وكيف يمكن للمرء أن يقود حياة سلمية ومنتجة. كما يتضمن الكتاب قصصا لـ س. ن. غونكا صعد تهدف إلى إيصال الحكمة إلى القارئ بسهولة، تنقل شعور لتعاليمه. وتتجلى في هذا الكتاب بوضوح فوائد الفيسنا على صعد متنوعة، متمثلة بقدرتها على شفاءات عجز الطب عنها، مستندة إلى تعزيز قدرة الإنسان الذاتية وطاقاته. هذه هي أول دراسة منهجية لتعاليمه لتظهر باللغة العربية
Book
Safety, Pharmacokinetics, and Pharmacodynamics of a 6‐h N,N‐Dimethyltryptamine (DMT) Infusion in Healthy Volunteers: A Randomized, Double‐Blind, Placebo‐Controlled Trial
The serotonergic psychedelic N,N‐dimethyltryptamine (DMT) presumably stimulates neuroplasticity in vitro and in vivo, by which it may exert neuroprotective effects during acute ischemic stroke. Since neuroplasticity has been implicated in the mechanism of action of rehabilitative therapy in stroke recovery, a pharmacological augmentation strategy facilitating neuroplasticity could be beneficial. To optimize this treatment strategy, a detailed understanding of the safety, pharmacokinetics, and pharmacodynamics of prolonged DMT administration is required. This randomized, double‐blind, placebo‐controlled, single ascending dose study administered three intravenous doses of DMT as a 30‐s bolus followed by a 6‐h infusion: 1.5 mg + 0.105 mg/min, 7.5 mg + 0.525 mg/min, and 5.0 mg + 0.7875 mg/min. Twelve female and seventeen male psychedelic‐experienced and naïve healthy participants, with a mean age of 27.3 (SD 10.2, range 19–57) years, were included. No serious adverse events occurred, and all adverse events were mild in intensity and self‐limiting. No significant abnormalities in vital signs or 12‐lead electrocardiography, and no suicidality or treatment‐emergent psychopathology occurred. Moderate interindividual pharmacokinetic variability was observed. Mild psychedelic effects were accompanied by decreases in sustained attention, postural stability, and occipital alpha electroencephalographic power at the highest dose, which peaked rapidly after bolus administration and remained relatively stable or decreased over time. Together, DMT administered intravenously as a 30‐s bolus followed by a 6‐h infusion and reaching maximal exposures of approximately 35 ng/mL in healthy volunteers was safe and demonstrated rapidly occurring but mild psychedelic effects, providing the basis for future proof‐of‐mechanism studies in patient populations. Trial Registration: ClinicalTrial.gov identifier: NCT05559931
Journal Article
DMT alters cortical travelling waves
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.
Journal Article