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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, Papers, Psychology / 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, Papers, Psychology / 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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The 21st century psychedelic renaissance: heroic steps forward on the back of an elephant

August 23, 2017 / LSD, MDMA, Mushrooms / Psilocybin, Papers, Psychology / By /

Abstract

Given the plethora of new studies and published papers in the scientific press and the increasingly emerging presence of articles about positive psychedelic experiences appearing in the popular media, there is little doubt that we are in the midst of a Psychedelic Renaissance. The classical psychedelic drugs LSD and psilocybin and the entactogen MDMA are showing promise as tools to assist psychotherapy for a wide range of mental disorders, with multiple pilot studies demonstrating their safety and efficacy. In this article, the author describes how MDMA in particular has inherent characteristics that make it well suited for assisting trauma-focused psychotherapy in a population of patients who have experienced child abuse. But despite these advances, there remain many obstacles ahead of the widespread mainstream acceptance of psychedelic medicines. The author argues that the Misuse of Drugs Act 1971 is one such obstacle. Other impediments include a prevailing attitude of pseudoscience and rigidity from within the non-scientific psychedelic community itself. Resolution of these conflicts must be sought if medicine and society are to see psychedelics gaining a place in mainstream culture and science.
Sessa, B. (2017). The 21st century psychedelic renaissance: heroic steps forward on the back of an elephant. Psychopharmacology, 1-10. 10.1007/s00213-017-4713-7
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MDMA Impairs Both the Encoding and Retrieval of Emotional Recollections

August 21, 2017 / MDMA, Papers, Psychology, Publications / By / , , ,

Abstract

The psychoactive drug ±3,4-methylenedioxymethamphetamine (MDMA) is increasingly used for its perceived emotional effects (eg, prosociality, empathy, psychotherapy), but surprisingly little research has been aimed at identifying the effect of the drug on emotional episodic memory in humans. Here, we report the first double-blind placebo-controlled study to examine the effects of MDMA on emotional memory separately during encoding and retrieval in healthy participants. Participants viewed emotionally negative, neutral, and positive pictures and their labels. Forty-eight hours later, they were given cued recollection and recognition memory tests designed to assess recollection and familiarity for the studied pictures. Participants were randomly assigned to one of three groups who received MDMA (1 mg/kg) either during encoding (Encoding group; N=20), retrieval (Retrieval group; N=20), or neither (Placebo group; N=20). Although MDMA administered at either phase did not affect overall memory accuracy, it did alter the recollection of details associated specifically with emotional memories as estimated using a dual process signal detection analysis of confidence judgments and subjective ‘remember’ judgments. In the Encoding group, MDMA reduced recollection estimates for negative and positive pictures but had little to no effect on neutral items or familiarity estimates. There was evidence for similar trends in the Retrieval group. These findings indicate that MDMA attenuates the encoding and retrieval of salient details from emotional events, consistent with the idea that its potential therapeutic effects for treating posttraumatic stress disorder are related to altering emotional memory.
Doss, M. K., Weafer, J., Gallo, D. A., & de Wit, H. (2017). MDMA Impairs Both the Encoding and Retrieval of Emotional Recollections. Neuropsychopharmacology. 10.1038/npp.2017.171
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The Non-Peptide Arginine-Vasopressin v1a Selective Receptor Antagonist, SR49059, Blocks the Rewarding, Prosocial, and Anxiolytic Effects of 3,4-Methylenedioxymethamphetamine and Its Derivatives in Zebra Fish

August 14, 2017 / MDMA, Neuroscience, Papers, Psychology, Publications / By / , , ,

Abstract

3,4-Methylenedioxymethamphetamine (MDMA) and its derivatives, 2,5-dimethoxy-4-bromo-amphetamine hydrobromide (DOB) and para-methoxyamphetamine (PMA), are recreational drugs whose pharmacological effects have recently been attributed to serotonin 5HT2A/C receptors. However, there is growing evidence that the oxytocin (OT)/vasopressin system can modulate some the effects of MDMA. In this study, MDMA (2.5–10 mg/kg), DOB (0.5 mg/kg), or PMA (0.005, 0.1, or 0.25 mg/kg) were administered intramuscularly to adult zebra fish, alone or in combination with the V1a vasopressin antagonist, SR49059 (0.01–1 ng/kg), before carrying out conditioned place preference (CPP), social preference, novel tank diving, and light–dark tests in order to evaluate subsequent rewarding, social, and emotional-like behavior. The combination of SR49059 and each drug progressively blocked: (1) rewarding behavior as measured by CPP in terms of time spent in drug-paired compartment; (2) prosocial effects measured on the basis of the time spent in the proximity of a nacre fish picture; and (3) anxiolytic effects in terms of the time spent in the upper half of the novel tank and in the white compartment of the tank used for the light–dark test. Antagonism was obtained at SR49059 doses which, when given alone, did not change motor function. In comparison with a control group, receiving vehicle alone, there was a three to five times increase in the brain release of isotocin (the analog of OT in fish) after treatment with the most active doses of MDMA (10 mg/kg), DOB (0.5 mg/kg), and PMA (0.1 mg/kg) as evaluated by means of bioanalytical reversed-phase high-performance liquid chromatography. Taken together, these findings show that the OT/vasopressin system is involved in the rewarding, prosocial, and anxiolytic effects of MDMA, DOB, and PMA in zebra fish and underline the association between this system and the behavioral alterations associated with disorders related to substance abuse.
Ponzoni, L., Braida, D., Bondiolotti, G., & Sala, M. (2017). The Non-Peptide Arginine-Vasopressin v1a Selective Receptor Antagonist, SR49059, Blocks the Rewarding, Prosocial, and Anxiolytic Effects of 3, 4-Methylenedioxymethamphetamine and Its Derivatives in Zebra Fish. Frontiers in psychiatry, 8, 146. 10.3389/fpsyt.2017.00146
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MDMA and brain activity during neurocognitive performance: An overview of neuroimaging studies with abstinent ‘Ecstasy’ users

August 8, 2017 / MDMA, Papers, Psychology, Publications / By / , , ,

Abstract

MDMA/Ecstasy has had a resurgence in popularity, with recent supplies comprising higher strength MDMA, potentially leading to increased drug-related harm. Neurocognitive problems have been widely reported in ecstasy users, equally some studies report null findings, and it remains unclear which factors underlie the development of neurocognitive impairments. This review covers the empirical research into brain activity during neurocognitive performance, using fMRI, fNIRS, and EEG. Our main conclusion is that chronic repeated use of recreational ecstasy can result in haemodynamic and electrophysiological changes that reflect recruitment of additional resources to perform cognitive tasks.

Findings are consistent with serotonergic system changes, although whether this reflects neurotoxicity or neuroadaptation, cannot be answered from these data. There is a degree of heterogeneity in the methodologies and findings, limiting the strengths of current conclusions. Future research with functional neuroimaging paired with molecular imaging, genetics or pharmacological challenges of the serotonin system may help to decipher the link between serotonergic and cognitive changes in ecstasy users.

Roberts, C. A., Quednow, B. B., Montgomery, C., & Parrott, A. C. (2017). MDMA and brain activity during neurocognitive performance: An overview of neuroimaging studies with abstinent ‘Ecstasy’users. Neuroscience & Biobehavioral Reviews. 10.1016/j.neubiorev.2017.07.015
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Psychotherapy with Adjuvant use of Serotonergic Psychoactive Substances: Possibilities and Challenges

August 2, 2017 / Anxiety Disorders / PTSD, Depressive Disorders, LSD, MDMA, Mushrooms / Psilocybin, Papers, Psychology, Substance Use Disorder / By / , , , , ,

Abstract

Background Recently, scientific interest in the therapeutic potential of serotonergic and psilocybin hallucinogens (psychedelics) such as lysergic acid diethylamide (LSD) and entactogens like 3,4-methylendioxymethamphetamine (MDMA) within the framework of psychotherapy has resumed. The present article provides an overview on the current evidence on substance-assisted psychotherapy with these substances.
Method A selective search was carried out in the PubMed and Cochrane Library including studies investigating the clinical use of serotonergic psychoactive substances since 2000.
Results Studies were found investigating the following indications: alcohol (LSD and psilocybin) and tobacco addiction (psilocybin), anxiety and depression in patients suffering from life-threatening somatic illness (LSD and psilocybin), obsessive-compulsive disorder (OCD) (psilocybin), treatment-resistant major depression (psilocybin), and posttraumatic stress disorder (PTSD) (MDMA).
Discussion Substance use disorders, PTSD and anxiety and depression in patients suffering from life-threatening somatic illness belong to the indications with the best evidence for substance-assisted psychotherapy with serotonergic psychoactive agents. To date, studies indicate efficacy and relatively good tolerability. Further studies are needed to determine whether these substances may represent suitable and effective treatment options for some treatment-resistant psychiatric disorders in the future.
Majić, T., Jungaberle, H., Schmidt, T. T., Zeuch, A., Hermle, L., & Gallinat, J. (2017). Psychotherapy with Adjuvant use of Serotonergic Psychoactive Substances: Possibilities and Challenges. Fortschritte der Neurologie-Psychiatrie, 85(7), 383. 10.1055/s-0043-103085
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Inhibition of serotonin transporters disrupts the enhancement of fear memory extinction by 3,4-methylenedioxymethamphetamine (MDMA)

July 24, 2017 / Anxiety Disorders / PTSD, MDMA, Neuroscience, Papers, Psychology / By / , , , , , ,

Abstract

Rationale

3,4-Methylenedioxymethamphetamine (MDMA) persistently improves symptoms of post-traumatic stress disorder (PTSD) when combined with psychotherapy. Studies in rodents suggest that these effects can be attributed to enhancement of fear memory extinction. Therefore, MDMA may improve the effects of exposure-based therapy for PTSD, particularly in treatment-resistant patients. However, given MDMA’s broad pharmacological profile, further investigation is warranted before moving to a complex clinical population.

Objectives

We aimed to inform clinical research by providing a translational model of MDMA’s effect, and elucidating monoaminergic mechanisms through which MDMA enhances fear extinction.

Methods

We explored the importance of monoamine transporters targeted by MDMA to fear memory extinction, as measured by reductions in conditioned freezing and fear-potentiated startle (FPS) in mice. Mice were treated with selective inhibitors of individual monoamine transporters prior to combined MDMA treatment and fear extinction training.

Results

MDMA enhanced the lasting extinction of FPS. Acute and chronic treatment with a 5-HT transporter (5-HTT) inhibitor blocked MDMA’s effect on fear memory extinction. Acute inhibition of dopamine (DA) and norepinephrine (NE) transporters had no effect. 5-HT release alone did not enhance extinction. Blockade of MDMA’s effect by 5-HTT inhibition also downregulated 5-HT2A-mediated behavior, and 5-HT2A antagonism disrupted MDMA’s effect on extinction.

Conclusions

We validate enhancement of fear memory extinction by MDMA in a translational behavioral model, and reveal the importance of 5-HTT and 5-HT2A receptors to this effect. These observations support future clinical research of MDMA as an adjunct to exposure therapy, and provide important pharmacological considerations for clinical use in a population frequently treated with 5-HTT inhibitors.

Young, M. B., Norrholm, S. D., Khoury, L. M., Jovanovic, T., Rauch, S. A., Reiff, C. M., … & Howell, L. L. (2017). Inhibition of serotonin transporters disrupts the enhancement of fear memory extinction by 3, 4-methylenedioxymethamphetamine (MDMA). Psychopharmacology, 234(19), 2883-2895. 10.1007/s00213-017-4684-8
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MDMA-induced indifference to negative sounds is mediated by the 5-HT2A receptor

July 22, 2017 / MDMA, Papers, Psychology / By / , , , ,

Abstract

BACKGROUND:
MDMA has been shown to induce feelings of sociability, a positive emotional bias and enhanced empathy. While previous research has used only visual emotional stimuli, communication entails more than that single dimension and it is known that auditory information is also crucial in this process. In addition, it is, however, unclear what the neurobiological mechanism underlying these MDMA effects on social behaviour is. Previously, studies have shown that MDMA-induced emotional excitability and positive mood are linked to the action on the serotonin (5-HT) 2A receptor.
AIM:
The present study aimed at investigating the effect of MDMA on processing of sounds (Processing of Affective Sounds Task (PAST)) and cognitive biases (Approach-Avoidance Task (AAT)) towards emotional and social stimuli and the role of 5-HT2A receptor in these effects.
METHODS:
Twenty healthy recreational users entered a 2 × 2, placebo-controlled, within-subject study with ketanserin (40 mg) as pre-treatment and MDMA (75 mg) as treatment. Behavioural (PAST, AAT) measures were conducted 90 min after treatment with MDMA, respectively, 120 min after ketanserin. Self-report mood measures and oxytocin concentrations were taken at baseline and before and after behavioural tests.
RESULTS:
Findings showed that MDMA reduced arousal elicited by negative sounds. This effect was counteracted by ketanserin pre-treatment, indicating involvement of the 5-HT2 receptor in this process. MDMA did not seem to induce a bias towards emotional and social stimuli. It increased positive and negative mood ratings and elevated oxytocin plasma concentrations. The reduction in arousal levels when listening to negative sounds was not related to the elevated subjective arousal.
CONCLUSION:
It is suggested that this decrease in arousal to negative stimuli reflects potentially a lowering of defences, a process that might play a role in the therapeutic process.
Kuypers, K. P. C., de la Torre, R., Pizarro, N., Xicota, L., & Ramaekers, J. G. MDMA-induced indifference to negative sounds is mediated by the 5-HT2A receptor. Psychopharmacology, 1-10. 10.1007/s00213-017-4699-1
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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, Papers, Psychiatry & Medicine / 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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