OPEN Foundation

Toxicology

Evaluating the abuse potential of psychedelic drugs for medical use in humans

February 7, 2018 / Addiction, LSD, MDMA, Medicine, Mushrooms / Psilocybin, Papers, Psychology, Psychotherapy, Publications, Safety, Salvia / Salvinorin A, Toxicology / By / , ,

Abstract

Psychedelics comprise drugs come from various pharmacological classes including 5-HT2A agonists, indirect 5-HT agonists, e.g. MDMA, NMDA antagonists and κ-opioid receptor agonists. There is resurgence in developing psychedelics to treat psychiatric disorders with high unmet clinical need. Many, but not all, psychedelics are schedule 1 controlled drugs (CDs), i.e. no approved medical use. For existing psychedelics in development, regulatory approval will require a move from schedule 1 to a CD schedule for drugs with medical use, i.e. schedules 2-5. Although abuse of the psychedelics is well documented, a systematic preclinical and clinical evaluation of the risks they pose in a medical-use setting does not exist. We describe the non-clinical tests required for a regulatory evaluation of abuse/dependence risks, i.e. drug-discrimination, intravenous self-administration and physical dependence liability. A synopsis of the existing data for the various types of psychedelics is provided and we describe our findings with psychedelic drugs in these models. FDA recently issued its guidance on abuse/dependence evaluation of drug-candidates [59]. We critically review the guidance, discuss the impact this document will have on non-clinical abuse/dependence testing, and offer advice on how non-clinical abuse/dependence experiments can be designed to meet not only the expectations of FDA, but also other regulatory agencies. Finally, we offer views on how these non-clinical tests can be refined to provide more meaningful information to aid the assessment of the risks posed by CNS drug-candidates for abuse and physical dependence.
Heal, D. J., Gosden, J., & Smith, S. L. (2018). Evaluating the abuse potential of psychedelic drugs for medical use in humans. Neuropharmacology. 10.1016/j.neuropharm.2018.01.049
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Is LSD toxic?

February 2, 2018 / LSD, Papers, Psychology, Publications, Safety, Toxicology / By / ,

Abstract

LSD (lysergic acid diethylamide) was discovered almost 75 years ago, and has been the object of episodic controversy since then. While initially explored as an adjunctive psychiatric treatment, its recreational use by the general public has persisted and on occasion has been associated with adverse outcomes, particularly when the drug is taken under suboptimal conditions. LSD’s potential to cause psychological disturbance (bad trips) has been long understood, and has rarely been associated with accidental deaths and suicide. From a physiological perspective, however, LSD is known to be non-toxic and medically safe when taken at standard dosages (50–200 μg). The scientific literature, along with recent media reports, have unfortunately implicated “LSD toxicity” in five cases of sudden death. On close examination, however, two of these fatalities were associated with ingestion of massive overdoses, two were evidently in individuals with psychological agitation after taking standard doses of LSD who were then placed in maximal physical restraint positions (hogtied) by police, following which they suffered fatal cardiovascularcollapse, and one case of extreme hyperthermia leading to death that was likely caused by a drug substituted for LSD with strong effects on central nervous system temperature regulation (e.g. 25i-NBOMe). Given the renewed interest in the therapeutic potential of LSD and other psychedelic drugs, it is important that an accurate understanding be established of the true causes of such fatalities that had been erroneously attributed to LSD toxicity, including massive overdoses, excessive physical restraints, and psychoactive drugs other than LSD.

Nichols, D. E., & Grob, C. S. (2018). Is LSD toxic?. Forensic science international, 284, 141-145. 10.1016/j.forsciint.2018.01.006
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Psychedelic Drugs in Biomedicine

September 22, 2017 / Addiction, Anxiety disorders / PTSD, Cacti / Mescaline, Depression, LSD, Medicine, Mushrooms / Psilocybin, Neuroscience, Papers, Psychiatry, Psychology, Psychopharmacology, Psychotherapy, Safety, Toxicology / By / , , , ,

Abstract

Psychedelic drugs, such as lysergic acid diethylamide (LSD), mescaline, and psilocybin, exert profound effects on brain and behavior. After decades of difficulties in studying these compounds, psychedelics are again being tested as potential treatments for intractable biomedical disorders. Preclinical research of psychedelics complements human neuroimaging studies and pilot clinical trials, suggesting these compounds as promising treatments for addiction, depression, anxiety, and other conditions. However, many questions regarding the mechanisms of action, safety, and efficacy of psychedelics remain. Here, we summarize recent preclinical and clinical data in this field, discuss their pharmacological mechanisms of action, and outline critical areas for future studies of psychedelic drugs, with the goal of maximizing the potential benefits of translational psychedelic biomedicine to patients.
Kyzar, E. J., Nichols, C. D., Gainetdinov, R. R., Nichols, D. E., & Kalueff, A. V. (2017). Psychedelic Drugs in Biomedicine. Trends in Pharmacological Sciences. 10.1016/j.tips.2017.08.003
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First Time View on Human Metabolome Changes after a Single Intake of 3,4-Methylenedioxymethamphetamine in Healthy Placebo-Controlled Subjects

September 1, 2017 / MDMA, Medicine, Other subjects, Papers, Publications, Safety, Toxicology / By / , , , ,

Abstract

3,4-Methylenedioxymethamphetamine (MDMA; “ecstasy”) is widely consumed recreationally. Little is known about its effects on the human metabolome. Mapping biochemical changes after drug exposure can complement traditional approaches by revealing potential biomarkers of organ toxicity or discovering new metabolomic features in a time- and dose-dependent manner. We aimed to analyze for the first time plasma samples from a randomized, double-blind, placebo-controlled crossover study in healthy adults to explore changes in endogenous plasma metabolites following a single intake of MDMA. Plasma samples from 15 subjects taken at four different time points were analyzed with the commercially available AbsoluteIDQ kit (Biocrates). Time series analysis revealed a total of nine metabolites, which showed a significant concentration change after MDMA administration compared with placebo. Paired t tests of the single time points showed statistically significant concentration changes mainly of glycerophospholipids and the metabolic ratio of methionine-sulfoxide over methionine. Changes of this metabolic ratio may be indicative for changes in systemic oxidative stress levels, and the increased amount of glycerophospholipids could be interpreted as an upregulation of energy production. Baseline samples within the experimental study design were crucial for evaluation of metabolomics data as interday individuality within subjects was high otherwise resulting in overestimations of the findings.
Boxler, M. I., Liechti, M. E., Schmid, Y., Kraemer, T., & Steuer, A. E. (2017). First Time View on Human Metabolome Changes after a Single Intake of 3, 4-Methylenedioxymethamphetamine in Healthy Placebo-Controlled Subjects. Journal of proteome research, 16(9), 3310-3320. 10.1021/acs.jproteome.7b00294
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MDA, MDMA and other mescaline-like substances in the US military's search for a truth drug (1940s to 1960s)

August 29, 2017 / MDMA, New substances, Other subjects, Other substances, Papers, Psychology, Toxicology / By / ,

Abstract

This article describes the broader context in which 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA) and other mescaline-like compounds were explored as hallucinogens for military and intelligence purposes during the 1940s to the 1960s. Germans first tested mescaline as a “truth drug” in a military context. Since the 1940s, the United States military tested hallucinogenic drugs as “truth drugs” for the purpose of interrogation and behavior manipulation. After tests carried out using mescaline and other drugs in 1950, some derivatives of mescaline were synthesized by the Army for the exploration of possible „speech-inducing“ effects. After insufficient animal testing, the substances were given to patients at the New York State Psychiatric Institute (NYSPI). 3,4-Methylenedioxy-N-ethylamphetamine (MDE), a compound almost identical to MDMA, was among the mescaline derivatives delivered for testing at the NYSPI. During tests with other derivatives (3,4-dimethoxyphenethylamine (DMA), 3,4-methylenedioxyphenethylamine (MDPEA), MDA) in 1952-53, an unwitting patient died in these tests, which was kept secret from the public. Research was interrupted and toxicological animal testing procedures were initiated. The secret animal studies run in 1953/54 revealed that some of the “mescaline derivatives” tested (e.g. MDA, MDE, DMA, 3,4,5-trimethoxyamphetamine (TMA), MDMA) were considered for further testing in humans. Since 1955, the military changed focus to LSD, but some interest in mescaline-like compounds remained for their ability to change mood and habit without interefing with cognition and sensory perception. Based on the known documents, it remains unclear (but probable) wether any of the mescaline derivatives tested were being used operationally.
Passie, T., & Benzenhöfer, U. (2017). MDA, MDMA and other mescaline‐like substances in the US military’s search for a truth drug (1940s to 1960s). Drug testing and analysis. 10.1002/dta.2292
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MDA, MDMA and other mescaline-like substances in the US military’s search for a truth drug (1940s to 1960s)

August 29, 2017 / MDMA, New substances, Other subjects, Other substances, Papers, Psychology, Toxicology / By / ,

Abstract

This article describes the broader context in which 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA) and other mescaline-like compounds were explored as hallucinogens for military and intelligence purposes during the 1940s to the 1960s. Germans first tested mescaline as a “truth drug” in a military context. Since the 1940s, the United States military tested hallucinogenic drugs as “truth drugs” for the purpose of interrogation and behavior manipulation. After tests carried out using mescaline and other drugs in 1950, some derivatives of mescaline were synthesized by the Army for the exploration of possible „speech-inducing“ effects. After insufficient animal testing, the substances were given to patients at the New York State Psychiatric Institute (NYSPI). 3,4-Methylenedioxy-N-ethylamphetamine (MDE), a compound almost identical to MDMA, was among the mescaline derivatives delivered for testing at the NYSPI. During tests with other derivatives (3,4-dimethoxyphenethylamine (DMA), 3,4-methylenedioxyphenethylamine (MDPEA), MDA) in 1952-53, an unwitting patient died in these tests, which was kept secret from the public. Research was interrupted and toxicological animal testing procedures were initiated. The secret animal studies run in 1953/54 revealed that some of the “mescaline derivatives” tested (e.g. MDA, MDE, DMA, 3,4,5-trimethoxyamphetamine (TMA), MDMA) were considered for further testing in humans. Since 1955, the military changed focus to LSD, but some interest in mescaline-like compounds remained for their ability to change mood and habit without interefing with cognition and sensory perception. Based on the known documents, it remains unclear (but probable) wether any of the mescaline derivatives tested were being used operationally.
Passie, T., & Benzenhöfer, U. (2017). MDA, MDMA and other mescaline‐like substances in the US military’s search for a truth drug (1940s to 1960s). Drug testing and analysis. 10.1002/dta.2292
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Novel Psychoactive Substances—Recent Progress on Neuropharmacological Mechanisms of Action for Selected Drugs

August 18, 2017 / DMT, Ketamine, New substances, Other substances, Papers, Psychopharmacology, Publications, Toxicology / By / , , , , , ,

Abstract

A feature of human culture is that we can learn to consume chemical compounds, derived from natural plants or synthetic fabrication, for their psychoactive effects. These drugs change the mental state and/or the behavioral performance of an individual and can be instrumentalized for various purposes. After the emergence of a novel psychoactive substance (NPS) and a period of experimental consumption, personal and medical benefits and harm potential of the NPS can be estimated on evidence base. This may lead to a legal classification of the NPS, which may range from limited medical use, controlled availability up to a complete ban of the drug form publically accepted use. With these measures, however, a drug does not disappear, but frequently continues to be used, which eventually allows an even better estimate of the drug’s properties. Thus, only in rare cases, there is a final verdict that is no more questioned. Instead, the view on a drug can change from tolerable to harmful but may also involve the new establishment of a desired medical application to a previously harmful drug. Here, we provide a summary review on a number of NPS for which the neuropharmacological evaluation has made important progress in recent years. They include mitragynine (“Kratom”), synthetic cannabinoids (e.g., “Spice”), dimethyltryptamine and novel serotonergic hallucinogens, the cathinones mephedrone and methylone, ketamine and novel dissociative drugs, γ-hydroxybutyrate, γ-butyrolactone, and 1,4-butanediol. This review shows not only emerging harm potentials but also some potential medical applications.
Hassan, Z., Bosch, O. G., Singh, D., Narayanan, S., Kasinather, B. V., Seifritz, E., … & Müller, C. P. (2017). Novel Psychoactive Substances—Recent Progress on Neuropharmacological Mechanisms of Action for Selected Drugs. Frontiers in psychiatry, 8, 152. 10.3389/fpsyt.2017.00152
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Mushroom-Derived Indole Alkaloids

July 19, 2017 / Ethnobotany, Mushrooms / Psilocybin, Other subjects, Papers, Toxicology / By / ,

Abstract

Mushrooms are known to produce over 140 natural products bearing an indole heterocycle. In this review, the isolation of these mushroom-derived indole alkaloids is discussed, along with their associated biological activities.
Homer, J. A., & Sperry, J. (2017). Mushroom-Derived Indole Alkaloids. Journal of Natural Products, 80(7), 2178-2187. 10.1021/acs.jnatprod.7b00390
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First time view on human metabolome changes after a single intake of 3,4 methylenedioxymethamphetamine (MDMA) in healthy placebo-controlled subjects

July 19, 2017 / MDMA, Medicine, Papers, Safety, Toxicology / By / , , , ,

Abstract

3,4-Methylenedioxymethamphetamine (MDMA; “ecstasy”) is widely consumed recreationally. Little is known about its effects on the human metabolome. Mapping biochemical changes after drug exposure can complement traditional approaches by revealing potential biomarkers of organ toxicity or discovering new metabolomic features in a time- and dose-dependent manner. We aimed to analyze for the first time plasma samples from a randomized, double-blind, placebo-controlled crossover study in healthy adults to explore changes in endogenous plasma metabolites following a single intake of MDMA. Plasma samples from 15 subjects taken at four different time points were analyzed with the commercially available AbsoluteIDQ kit (Biocrates). Time series analysis revealed a total of nine metabolites, which showed a significant concentration change after MDMA administration compared with placebo. Paired t tests of the single time points showed statistically significant concentration changes mainly of glycerophospholipids and the metabolic ratio of methionine-sulfoxide over methionine. Changes of this metabolic ratio may be indicative for changes in systemic oxidative stress levels, and the increased amount of glycerophospholipids could be interpreted as an upregulation of energy production. Baseline samples within the experimental study design were crucial for evaluation of metabolomics data as interday individuality within subjects was high otherwise resulting in overestimations of the findings.
Boxler, M. I., Liechti, M. E., Schmid, Y., Kraemer, T., & Steuer, A. E. (2017). First Time View on Human Metabolome Changes after a Single Intake of 3, 4-Methylenedioxymethamphetamine in Healthy Placebo-Controlled Subjects. Journal of Proteome Research, 16(9), 3310-3320. 10.1021/acs.jproteome.7b00294
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Isolated non-cardiogenic pulmonary edema – A rare complication of MDMA toxicity

June 27, 2017 / MDMA, Medicine, Papers, Publications, Safety, Toxicology / By / , , , ,

Abstract

This is a case of a 19-year-old male who presented to the medical tent at an outdoor electronic dance music festival (EDMF) due to an altered mental state in the setting of acute 3,4-methylenedioxymethamphetamine (MDMA) intoxication. He was noted to be in severe respiratory distress, required endotracheal intubation in the field and subsequently developed Acute Respiratory Distress Syndrome (ARDS) without other acute organ dysfunction. He was hospitalized for 5days requiring endotracheal intubation and mechanical ventilation. By presenting this case, we will explore and discuss the cardiopulmonary effects of MDMA intoxication that can lead to a rare, deleterious complication of MDMA intoxication other than previously reported adverse outcomes.
Haaland, A., Warman, E., Pushkar, I., Likourezos, A., & Friedman, M. S. (2017). Isolated non-cardiogenic pulmonary edema—A rare complication of MDMA toxicity. The American journal of emergency medicine, 35(9), 1385-e3. 10.1016/j.ajem.2017.06.040
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7 May - Psychedelics, Nature & Mental Health with Sam Gandy

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