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M. Torrens

Therapeutic Use of LSD in Psychiatry: A Systematic Review of Randomized-Controlled Clinical Trials.

January 21, 2020 / Depressive Disorders, LSD, Papers, Psychology, Publications, Substance Use Disorder / By / , , , ,

Abstract

Lysergic acid diethylamide (LSD) was studied from the 1950s to the 1970s to evaluate behavioral and personality changes, as well as remission of psychiatric symptoms in various disorders. LSD was used in the treatment of anxiety, depression, psychosomatic diseases and addiction. However, most of the studies were not performed under contemporary standards, and it has taken several decades for a resurgence of interest in LSD research and its therapeutic potential for psychiatry. The aim of this review is to identify controlled and randomized clinical trials that assess the potential use of LSD in psychiatry. PRISMA guidelines for systematic review were followed. A literature search of PubMed and Psychedelic bibliography from Multidisciplinary Association for Psychedelic Studies (MAPS) databases was performed as well as a manual search of references from evaluated studies. Only randomized-controlled clinical trials were included. Study quality was systematically calculated by using the Cochrane Collaboration Tool for assessing risk of bias. A final selection of 11 articles was made after considering inclusion and exclusion criteria. LSD was administered to 567 patients in a dose ranging from 20 to 800 mcg. Despite the design heterogeneity of clinical trials, positive results were observed, thus revealing the therapeutic potential of LSD to reduce psychiatric symptomatology, mainly in alcoholism. The vast majority of authors describe significant and positive short-term changes in patients, despite the fact that in some studies an important homogenization was observed between the LSD treatment group and control group at long-term follow-up. Multiple variables regarding LSD treatment therapeutic approach and quality of experience were revealed and related to therapeutic outcomes. LSD is revealed as a potential therapeutic agent in psychiatry; the evidence to date is strongest for the use of LSD in the treatment of alcoholism. Despite the difficulty of designing proper double blind clinical trials with this substance, new studies that conform to modern standards are necessary in order to strengthen our knowledge on its use and open new doors in the future.
Fuentes, J. J., Fonseca, F., Elices, M., Farre, M., & Torrens, M. (2019). Therapeutic use of LSD in psychiatry: A systematic review of randomized-controlled clinical trials. Frontiers in Psychiatry, 10, 943., https://doi.org/10.3389/fpsyt.2019.00943
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Monoamine biosynthesis via a noncanonical calcium-activatable aromatic amino acid decarboxylase in psilocybin mushroom

November 28, 2018 / Mushrooms / Psilocybin, Papers, Pharmacology & Chemistry, Publications / By / , , , ,

Abstract

Aromatic l-amino acid decarboxylases (AAADs) are a phylogenetically diverse group of enzymes responsible for the decarboxylation of aromatic amino acid substrates into their corresponding aromatic arylalkylamines. AAADs have been extensively studied in mammals and plants as they catalyze the first step in the production of neurotransmitters and bioactive phytochemicals, respectively. Unlike mammals and plants, the hallucinogenic psilocybin mushroom Psilocybe cubensis reportedly employs an unrelated phosphatidylserine-decarboxylase-like enzyme to catalyze l-tryptophan decarboxylation, the first step in psilocybin biosynthesis. To explore the origin of this chemistry in psilocybin mushroom, we generated the first de novo transcriptomes of P. cubensis and investigated several putative l-tryptophan-decarboxylase-like enzymes. We report the biochemical characterization of a noncanonical AAAD from P. cubensis (PcncAAAD) that exhibits substrate permissiveness toward l-phenylalanine, l-tyrosine, and l-tryptophan, as well as chloro-tryptophan derivatives. The crystal structure of PcncAAAD revealed the presence of a unique C-terminal appendage domain featuring a novel double-β-barrel fold. This domain is required for PcncAAAD activity and regulates catalytic rate and thermal stability through calcium binding. PcncAAAD likely plays a role in psilocybin production in P. cubensis and offers a new tool for metabolic engineering of aromatic-amino-acid-derived natural products.

Torrens-Spence, M. P., Liu, C. T., Pluskal, T., Chung, Y. K., & Weng, J. K. (2018). Monoamine Biosynthesis via a Noncanonical Calcium-Activatable Aromatic Amino Acid Decarboxylase in Psilocybin Mushroom. ACS chemical biology, 13(12), 3343-3353., 10.1021/acschembio.8b00821
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Acute pharmacological effects of 2C-B in humans: An observational study

March 13, 2018 / Papers, Psychology, Publications / By / , , , , , ,

Abstract

2,5-dimethoxy-4-bromophenethylamine (2C-B) is a psychedelic phenylethylamine derivative, structurally similar to mescaline. It is a serotonin 5-hydroxytryptamine-2A (5-HT2A), 5-hydroxytryptamine-2B (5-HT2B), and 5-hydroxytryptamine-2C (5-HT2C) receptor partial agonist used recreationally as a new psychoactive substance. It has been reported that 2C-B induces mild psychedelic effects, although its acute pharmacological effects and pharmacokinetics have not yet been fully studied in humans. An observational study was conducted to assess the acute subjective and physiological effects, as well as pharmacokinetics of 2C-B. Sixteen healthy, experienced drug users self-administered an oral dose of 2C-B (10, 15, or 20 mg). Vital signs (blood pressure and heart rate) were measured at baseline 1, 2, 3, 4, and 6 hours (h). Each participant completed subjective effects using three rating scales: the visual analog scale (VAS), the Addiction Research Centre Inventory (ARCI), and the Evaluation of the Subjective Effects of Substances with Abuse Potential (VESSPA-SSE) at baseline, 2–3 and 6 h after self-administration (maximum effects along 6 h), and the Hallucinogenic Rating Scale (maximum effects along 6 h). Oral fluid (saliva) was collected to assess 2C-B and cortisol concentrations during 24 h. Acute administration of 2C-B increased blood pressure and heart rate. Scores of scales related to euphoria increased (high, liking, and stimulated), and changes in perceptions (distances, colors, shapes, and lights) and different body feelings/surrounding were produced. Mild hallucinating effects were described in five subjects. Maximum concentrations of 2C-B and cortisol were reached at 1 and 3 h after self-administration, respectively. Oral 2C-B at recreational doses induces a constellation of psychedelic/psychostimulant-like effects similar to those associated with serotonin-acting drugs.
Papaseit, E., Farré, M., Perez-Maña, C., Torrens, M., Ventura, M., Pujadas, M., … & González, D. (2018). Acute pharmacological effects of 2C-B in humans: An observational study. Frontiers in Pharmacology, 9, 206. 10.3389/fphar.2018.00206
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Key interindividual determinants in MDMA pharmacodynamics

February 14, 2018 / MDMA, Papers, Psychology, Publications / By / , , , ,

Abstract

MDMA, 3,4-methylenedioxymethamphetamine, is a synthetic phenethylamine derivative with structural and pharmacological similarities to both amphetamines and mescaline. MDMA produces characteristic amphetamine-like actions (euphoria, well-being), increases empathy, and induces pro-social effects that seem to motivate its recreational consumption and provide a basis for its potential therapeutic use. Areas covered: The aim of this review is to present the main interindividual determinants in MDMA pharmacodynamics. The principal sources of pharmacodynamic variability are reviewed, with special emphasis on sex-gender, race-ethnicity, genetic differences, interactions, and MDMA acute toxicity, as well as possible therapeutic use. Expert opinion: Acute MDMA effects are more pronounced in women than they are in men. Very limited data on the relationship between race-ethnicity and MDMA effects are available. MDMA metabolism includes some polymorphic enzymes that can slightly modify plasma concentrations and effects. Although a considerable number of studies exist about the acute effects of MDMA, the small number of subjects in each trial limits evaluation of the different interindividual factors and does not permit a clear conclusion about their influence. These issues should be considered when studying possible MDMA therapeutic use.
Papaseit, E., Torrens, M., Pérez-Mañá, C., Muga, R., & Farré, M. (2018). Key interindividual determinants in MDMA pharmacodynamics. Expert opinion on drug metabolism & toxicology, (just-accepted). 10.1080/17425255.2018.1424832
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Key interindividual determinants in MDMA pharmacodynamics.

January 16, 2018 / MDMA, Papers, Psychiatry & Medicine, Psychology, Publications / By / , , , ,

Abstract

MDMA, 3,4-methylenedioxymethamphetamine, is a synthetic phenethylamine derivative with structural and pharmacological similarities to both amphetamines and mescaline. MDMA produces characteristic amphetamine-like actions (euphoria, well-being), increases empathy, and induces pro-social effects that seem to motivate its recreational consumption and provide a basis for its potential therapeutic use. Areas covered: The aim of this review is to present the main interindividual determinants in MDMA pharmacodynamics. The principal sources of pharmacodynamic variability are reviewed, with special emphasis on sex-gender, race-ethnicity, genetic differences, interactions, and MDMA acute toxicity, as well as possible therapeutic use. Expert opinion: Acute MDMA effects are more pronounced in women than they are in men. Very limited data on the relationship between race-ethnicity and MDMA effects are available. MDMA metabolism includes some polymorphic enzymes that can slightly modify plasma concentrations and effects. Although a considerable number of studies exist about the acute effects of MDMA, the small number of subjects in each trial limits evaluation of the different interindividual factors and does not permit a clear conclusion about their influence. These issues should be considered when studying possible MDMA therapeutic use.
Papaseit, E., Torrens, M., Pérez-Mañá, C., Muga, R., & Farré, M. (2018). Key interindividual determinants in MDMA pharmacodynamics. Expert opinion on drug metabolism & toxicology, (just-accepted). 10.1080/17425255.2018.1424832
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Human Pharmacology of Mephedrone in Comparison to MDMA

May 20, 2016 / Neuroscience, Papers, Publications / By / , , , , , ,

Abstract

Mephedrone (4-methylmethcathinone) is a novel psychoactive substance popular among drug users because it displays similar effects to MDMA (3,4-metylenedioxymethamphetamine, ecstasy). Mephedrone consumption has been associated with undesirable effects and fatal intoxications. At present, there is no research available on its pharmacological effects in humans under controlled and experimental administration. This study aims to evaluate the clinical pharmacology of mephedrone, and its relative abuse liability, compared to MDMA. Twelve male volunteers participated in a randomized, double-blind, crossover, and placebo-controlled trial. The single oral dose conditions were: mephedrone 200 mg, MDMA 100 mg, and placebo. Outcome variables included physiological, subjective, and psychomotor effects, and pharmacokinetic parameters. The protocol was registered in ClinicalTrials.gov (NCT02232789). Mephedrone produced a significant increase in systolic and diastolic blood pressure, heart rate, and pupillary diameter. It elicited stimulant-like effects, euphoria, and well-being, and induced mild changes in perceptions with similar ratings to those observed after MDMA administration although effects peaked earlier and were shorter in duration. Maximal plasma concentrations values for mephedrone and MDMA peaked at 1.25 and 2.00 h, respectively. The elimination half-life for mephedrone was 2.15 and 7.89 h for MDMA. In a similar manner to MDMA, mephedrone exhibits high abuse liability. Its earlier onset and shorter duration of effects, probably related to its short elimination half-life, could explain a more compulsive pattern of use as described by users.

Papaseit, E., Pérez-Mañá, C., Mateus, J. A., Pujadas, M., Fonseca, F., Torrens, M., … & Farré, M. (2016). Human Pharmacology of Mephedrone in Comparison to MDMA. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology. http://dx.doi.org/10.1038/npp.2016.75
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