Science
February 13, 2009
Dominique Fontanilla, Molly Johannessen, Abdol R. Hajipour et al.
528 citations
The sigma-1 receptor, once mistaken for an opioid receptor, binds many synthetic compounds but not opioid peptides and is now considered an orphan receptor. Its pharmacophore includes an alkylamine core also found in the endogenous compound N,N-dimethyltryptamine (DMT). DMT bound to sigma-1 receptors and inhibited voltage-gated sodium ion channels in both native cardiac myocytes and heterologous cells expressing sigma-1 receptors. DMT induced hypermobility in wild-type mice but not in sigma-1 receptor knockout mice. These experiments indicate that DMT is an endogenous agonist for the sigma-1 receptor.
Clinical Pharmacokinetics
March 28, 2017
Randall Brown, Christopher R. Nicholas, Nicholas V. Cozzi et al.
189 citations
Psilocybin, a naturally occurring hallucinogen, has shown promise as a therapeutic agent in pharmacology. In a study involving 100 participants, 70% reported significant mood improvements after psilocybin administration. The pharmacokinetics revealed that the active metabolite was detectable in urine for up to 24 hours post-ingestion. This highlights psilocybin's potential in medicine, emphasizing its unique chemical synthesis and alkaloid profile. As interest grows in psychedelics within drug studies and forensic toxicology, understanding these dynamics becomes increasingly vital for future applications.
Journal of Psychopharmacology
June 27, 2018
Christopher R. Nicholas, Kelsey M. Henriquez, Michele Gassman et al.
85 citations
Healthy participants given escalating doses of psilocybin (0.3, 0.45, and 0.6 mg/kg) showed a significant linear dose-related increase in Mystical Experience Questionnaire total score and the transcendence of time and space subscale, but not in the rate of complete mystical experiences. Dose 3 produced significantly higher transcendence of time and space scores than dose 1, while no dose-related differences emerged for total scores or mystical experience rate. Positive persisting effects 30 days after the last dose were significantly higher than negative ones, and a moderate increase in well-being or life satisfaction was associated with the maximum mystical experience score. Pharmacokinetic measures correlated with dose but not with mystical experience scores or rate, indicating that a complete mystical experience was not necessary for positive outcomes.
Headache The Journal of Head and Face Pain
November 1, 2022
Christina Luddy, Yutong Zhu, Hayley Lindsey et al.
75 citations
In an exploratory randomized, double-blind, placebo-controlled trial, a pulse regimen of three doses of psilocybin (0.143 mg/kg) given about five days apart did not significantly reduce cluster headache attack frequency compared to placebo. Over three weeks, attack frequency changed by −3.2 attacks per week with psilocybin (baseline 9.6) and 0.03 attacks per week with placebo (baseline 8.9), a difference that was not statistically significant. The overall effect size was moderate (d = 0.69), but large in chronic participants (d = 1.25) and small in episodic participants (d = 0.35). Changes in attack frequency were not linked to the intensity of acute psychedelic effects. Psilocybin was well-tolerated with no serious adverse events.
ACS Omega
July 1, 2020
Jessica Sable, Tura Patterson, Gary Tarpley et al.
41 citations
A new chemical process produces over one kilogram of high-purity psilocybin, the active compound in psychedelic mushrooms, using a second-generation synthesis designed for large-scale manufacturing. The method improves on earlier procedures by optimizing the Speeter-Anthony tryptamine synthesis to create the intermediate psilocin with better control and impurity removal. It then directly phosphorylates psilocin with phosphorous oxychloride, avoiding a complex benzyl-protecting group strategy used in previous methods. This approach addresses challenges in yield, purity, atom economy, and suitability for pilot plant-scale reactors, providing a more efficient and consistent route for producing psilocybin under current Good Manufacturing Practices.
Bioorganic & medicinal chemistry letters
February 1, 2016
Nicholas V. Cozzi, Paul F. Daley
24 citations
N,N-Diallyltryptamine (DALT) and its 5-methoxy derivative (5-MeO-DALT) are tryptamines originally synthesized by Alexander Shulgin, with 5-MeO-DALT reported psychoactive at 12-20 mg and DALT showing few effects at 42-80 mg. This study synthesized additional 5-substituted-DALTs and measured their binding affinities at 45 cloned receptors and transporters. Five DALT compounds had affinities of 10-80 nM for serotonin 5-HT1A and 5-HT2B receptors, while DALT itself had 100 nM affinity at 5-HT1A. Affinities at 5-HT2A receptors were weakest (250-730 nM). Five compounds showed 50-400 nM affinity for 5-HT1D, 5-HT6, and 5-HT7 receptors. Binding also occurred at adrenergic, sigma, histamine, and transporter sites. Quantitative structure-affinity relationships revealed correlations with steric, electronic, and hydrophobic parameters, aiding future drug development.
Drug Testing and Analysis
July 1, 2020
Nicholas V. Cozzi, Paul F. Daley
12 citations
A slightly modified Speeter–Anthony synthesis produced DMT hemifumarate with over 99.9% purity, meeting regulatory standards for human intravenous administration. Aluminum hydride generated in situ from lithium aluminum hydride was used for the first time to reduce an intermediate to DMT, and a quench protocol yielded exceptionally pure free base DMT. The final salt was analyzed by multiple techniques including X-ray powder diffraction, NMR, GC–MS, and HPLC. No significant impurities or residual solvents were detected. The work supports planned clinical trials of DMT for major depressive disorder.
Acta Crystallographica Section C Structural Chemistry
December 20, 2021
Alexander M. Sherwood, Robert B. Kargbo, Kristi W. Kaylo et al.
10 citations
Psilocybin, a natural product from psychoactive fungi, exists in three distinct crystal forms: Hydrate A, Polymorph A, and Polymorph B. This article presents newly solved crystal structures for the two anhydrate forms using X-ray diffraction and computational methods. Analysis of psilocybin samples produced between 1963 and 2021 shows that all contain one or more of these three forms, with no additional forms needed to explain their diffraction patterns. The composition correlates with process methods, sample age, and storage conditions. The authors also identify that a recently granted patent incorrectly described a mixture of about 81% Polymorph A and 19% Polymorph B as a single-phase variant, recommending revision of such characterizations.
Naunyn-Schmiedeberg's archives of pharmacology
June 18, 2026
Nicholas V. Cozzi
Deuterium substitution at the ring methoxy positions of the psychedelic drug 2C-B slightly increased its binding affinity at human 5-HT2A receptors, likely due to kinetic isotope effects that dampen molecular vibrations and rotations. However, deuteration did not alter the drug's ability to stimulate intracellular calcium release or recruit β-arrestin 2; all compounds showed similar low nanomolar potency and efficacy in these functional assays. No appreciable metabolism by human liver microsomes was observed for any compound during the experiment.