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Effects of the Psychedelic Amphetamine MDA (3,4-Methylenedioxyamphetamine) in Healthy Volunteers.

April 9, 2019 / MDMA, Papers, Psychology, Publications / By / , , , , , ,

Abstract

Entactogens such as 3,4-Methylenedioxymethamphetamine (MDMA, “molly”, “ecstasy”) appear to have unusual, potentially therapeutic, emotional effects. Understanding their mechanisms can benefit from clinical experiments with related drugs. Yet the first known drug with such properties, 3,4-Methylenedioxyamphetamine (MDA), remains poorly studied and its pharmacokinetics in humans are unknown. We conducted a within-subjects, double-blind, placebo-controlled study of 1.4 mg/kg oral racemic MDA and compared results to those from our prior similar studies with 1.5 mg/kg oral racemic MDMA. MDA was well-tolerated by participants. MDA induced robust increases in heart rate and blood pressure and increased cortisol and prolactin to a similar degree as MDMA. MDA self-report effects shared features with MDMA as well as with classical psychedelics. MDA self-report effects lasted longer than those of MDMA, with MDA effects remaining elevated at 8 h while MDMA effects resolved by 6 h. Cmax and AUC0-∞ for MDA were 229 ± 39 (mean ± SD) and 3636 ± 958 µg/L for MDA and 92 ± 61 and 1544 ± 741 µg/L for the metabolite 4-hydroxy-3-methoxyamphetamine (HMA). There was considerable between-subject variation in MDA/HMA ratios. The similarity of MDA and MDMA pharmacokinetics suggests that the greater duration of MDA effects is due to pharmacodynamics rather than pharmacokinetics.
Baggott, M. J., Garrison, K. J., Coyle, J. R., Galloway, G. P., Barnes, A. J., Huestis, M. A., & Mendelson, J. E. (2019). Effects of the psychedelic amphetamine MDA (3, 4-methylenedioxyamphetamine) in healthy volunteers. Journal of psychoactive drugs, 1-10., https://doi.org/10.1080/02791072.2019.1593560
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Psychedelic-Assisted Group Therapy: A Systematic Review.

April 5, 2019 / LSD, Mushrooms / Psilocybin, Papers, Psychology, Publications / By / , , , , ,

Abstract

Contemporary research with classic psychedelic drugs (e.g., lysergic acid diethylamide (LSD) and psilocybin) is indebted to the twentieth-century researchers and clinicians who generated valuable clinical knowledge of these substances through experimentation. Several recent reviews that highlight the contributions of this early literature have focused on psychedelic-assisted individual psychotherapy modalities. None have attempted to systematically identify and compile experimental studies of psychedelic-assisted group therapy. In therapeutic settings, psychedelics were often used to enhance group therapy for a variety of populations and clinical indications. We report on the results of a systematic review of the published literature in English and Spanish on psychedelic-assisted group therapies. Publications are characterized by their clinical approach, experimental method, and clinical outcomes. Given the renewed interest in the clinical use of psychedelic medicines, this review aims to stimulate hypotheses to be tested in future research on psychedelic-assisted psychotherapy, group process, and interpersonal functioning.
Trope, A., Anderson, B. T., Hooker, A. R., Glick, G., Stauffer, C., & Woolley, J. D. (2019). Psychedelic-assisted group therapy: a systematic review. Journal of Psychoactive Drugs, 51(2), 174-188., https://doi.org/10.1080/02791072.2019.1593559
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Receptor-Enriched Analysis of functional connectivity by targets (REACT): A novel, multimodal analytical approach informed by PET to study the pharmacodynamic response of the brain under MDMA

April 4, 2019 / MDMA, Neuroscience, Papers, Pharmacology & Chemistry / By / , , , , ,

Abstract

One of the main limitations of pharmacological fMRI is its inability to provide a molecular insight into the main effect of compounds, leaving an open question about the relationship between drug effects and haemodynamic response. The aim of this study is to investigate the acute effects of 3,4-methylenedioxymethamphetamine (MDMA) on functional connectivity (FC) using a novel multimodal method (Receptor-Enriched Analysis of functional Connectivity by Targets – REACT). This approach enriches the resting state (rs-)fMRI analysis with the molecular information about the distribution density of serotonin receptors in the brain, given the serotonergic action of MDMA. Twenty healthy subjects participated in this double-blind, placebo-controlled, crossover study. A high-resolution in vivo atlas of four serotonin receptors (5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4) and its transporter (5-HTT) was used as a template in a two-step multivariate regression analysis to estimate the spatial maps reflecting the whole-brain connectivity behaviour related to each target under placebo and MDMA. Results showed that the networks exhibiting significant changes after MDMA administration are the ones informed by the 5-HTT and 5-HT1Adistribution density maps, which are the main targets of this compound. Changes in the 5-HT1A-enriched functional maps were also associated with the pharmacokinetic levels of MDMA and MDMA-induced FC changes in the 5-HT2A-enriched maps correlated with the spiritual experience subscale of the Altered States of Consciousness Questionnaire. By enriching the rs-fMRI analysis with molecular data of voxel-wise distribution of the serotonin receptors across the brain, we showed that MDMA effects on FC can be understood through the distribution of its main targets. This result supports the ability of this method to characterise the specificity of the functional response of the brain to MDMA binding to serotonergic receptors, paving the way to the definition of a new fingerprint in the characterization of new compounds and potentially to a further understanding to the response to treatment.

Dipasquale, O., Selvaggi, P., Veronese, M., Gabay, A. S., Turkheimer, F., & Mehta, M. A. (2019). Receptor-Enriched Analysis of functional connectivity by targets (REACT): A novel, multimodal analytical approach informed by PET to study the pharmacodynamic response of the brain under MDMA. NeuroImage, 195, 252-260., 10.1016/j.neuroimage.2019.04.007

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Oxytocin-dependent reopening of a social reward learning critical period with MDMA

April 3, 2019 / Depressive Disorders, MDMA, Neuroscience, Papers, Publications / By / , , , , , ,

Abstract

A critical period is a developmental epoch during which the nervous system is expressly sensitive to specific environmental stimuli that are required for proper circuit organization and learning. Mechanistic characterization of critical periods has revealed an important role for exuberant brain plasticity during early development, and for constraints that are imposed on these mechanisms as the brain matures. In disease states, closure of critical periods limits the ability of the brain to adapt even when optimal conditions are restored. Thus, identification of manipulations that reopen critical periods has been a priority for translational neuroscience. Here we provide evidence that developmental regulation of oxytocin-mediated synaptic plasticity (long-term depression) in the nucleus accumbens establishes a critical period for social reward learning. Furthermore, we show that a single dose of (+/-)-3,4-methylendioxymethamphetamine (MDMA) reopens the critical period for social reward learning and leads to a metaplastic upregulation of oxytocin-dependent long-term depression. MDMA-induced reopening of this critical period requires activation of oxytocin receptors in the nucleus accumbens, and is recapitulated by stimulation of oxytocin terminals in the nucleus accumbens. These findings have important implications for understanding the pathogenesis of neurodevelopmental diseases that are characterized by social impairments and of disorders that respond to social influence or are the result of social injury.

Nardou, R., Lewis, E. M., Rothhaas, R., Xu, R., Yang, A., Boyden, E., & Dölen, G. (2019). Oxytocin-dependent reopening of a social reward learning critical period with MDMA. Nature, 569(7754), 116., 10.1038/s41586-019-1075-9
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Classic psychedelics: the special role of the visual system

April 2, 2019 / Ayahuasca, DMT, Iboga / Ibogaine, Ketamine, LSD, MDMA, Mescaline / Cacti, Mushrooms / Psilocybin, Papers, Psychology, Psychotic Disorders, Publications, Salvia / Salvinorin A / By / , ,

Abstract

Here, we briefly overview the various aspects of classic serotonergic hallucinogens reported by a number of studies. One of the key hypotheses of our paper is that the visual effects of psychedelics might play a key role in resetting fears. Namely, we especially focus on visual processes because they are among the most prominent features of hallucinogen-induced hallucinations. We hypothesize that our brain has an ancient visual-based (preverbal) intrinsic cognitive process that, during the transient inhibition of top-down convergent and abstract thinking (mediated by the prefrontal cortex) by psychedelics, can neutralize emotional fears of unconscious and conscious life experiences from the past. In these processes, the decreased functional integrity of the self-referencing processes of the default mode network, the modified multisensory integration (linked to bodily self-consciousness and self-awareness), and the modified amygdala activity may also play key roles. Moreover, the emotional reset (elimination of stress-related emotions) by psychedelics may induce psychological changes and overwrite the stress-related neuroepigenetic information of past unconscious and conscious emotional fears.

Császár-Nagy, N., Kapócs, G., & Bókkon, I. (2019). Classic psychedelics: the special role of the visual system. Reviews in the neurosciences.,  10.1515/revneuro-2018-0092
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Might Microdosing Psychedelics Be Safe and Beneficial? An Initial Exploration.

March 29, 2019 / LSD, Papers, Psychology, Publications / By / ,

Abstract

Albert Hoffman suggested that low doses of LSD might be an appropriate alternative to Ritalin. Following this possibility, a systematic exploration of the effects of “microdoses,” comprising hundreds of lengthy descriptive reports, was undertaken. Based on these reports, using a psychedelic in the microdose range (10 micrograms) every three days was determined to be safe across a wide variety of individuals and conditions. Over 18 months, more than a thousand individuals from 59 countries did a daily evaluation of negative and positive emotional state using the PANAS checklist plus written reports for between one week and four months. Participant reports suggested that spaced but repeated microdoses were followed by improvements in negative moods, especially depression, and increases in positive moods. Increased energy, improved work effectiveness, and improved health habits were observed in clinical and non-clinical populations. Smaller samples described alleviation of symptoms in migraine headaches, pre-menstrual syndromes, traumatic brain injury, shingles, and other conditions not previously associated with psychedelic use.
Fadiman, J., & Korb, S. (2019). Might Microdosing Psychedelics Be Safe and Beneficial? An Initial Exploration. Journal of psychoactive drugs, 1-5., https://doi.org/10.1080/02791072.2019.1593561
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Sensitization to the prosocial effects of 3,4-methylenedioxymethamphetamine (MDMA).

March 25, 2019 / Anxiety Disorders / PTSD, MDMA, Neuroscience, Papers, Psychology, Publications / By / , , , , ,

Abstract

The recreational drug 3,4-methylenedioxymethamphetamine (MDMA) has well documented prosocial effects and is currently under clinical investigation as a treatment for patients with PTSD, autism, and other conditions. Early clinical trials have found that MDMA-assisted therapy may have robust long-lasting therapeutic effects, yet the mechanism by which acute treatments produce these long-term effects is unclear. Sensitization to certain behavioral drug effects is a common rodent model used to assess long-lasting neurobiological adaptations induced by acute drug treatments. Nine independent experiments were undertaken to investigate if and how mice sensitize to the prosocial effects of MDMA. When treated with 7.8 mg/kg MDMA and paired every other day for a week, MDMA-induced social interaction increased precipitously across treatment sessions. This previously unreported phenomenon was investigated and found to be heavily influenced by a social context and 5-HT2AR activation. Social sensitization did not appear to develop if mice were administered MDMA in isolation, and pretreatment with MDL100907, a selective 5-HT2AR antagonist, inhibited the development of social sensitization. However, when MDL100907 was administered to mice that had already been sensitized, it did not attenuate social interaction, suggesting that 5-HT2AR activity may be necessary for the development of social sensitization but not the expression of MDMA-induced social behavior. Additional investigation is warranted to further explore the phenomenon of social sensitization and to determine the underlying neurobiological mechanisms.
Curry, D. W., Berro, L. F., Belkoff, A. R., Sulima, A., Rice, K. C., & Howell, L. L. (2019). Sensitization to the prosocial effects of 3, 4-methylenedioxymethamphetamine (MDMA). Neuropharmacology, 151, 13-20., https://doi.org/10.1016/j.neuropharm.2019.03.017
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Embracing Neurodiversity in Psychedelic Science: A Mixed-Methods Inquiry into the MDMA Experiences of Autistic Adults

March 25, 2019 / Anthropology & Sociology, Anxiety Disorders / PTSD, Depressive Disorders, MDMA, Papers, Psychology, Publications / By /

Abstract

This exploratory inquiry analyzed subjective experiences autistic adults reported after they took the drug 3,4-methylenedioxymethamphetamine (MDMA), also known as ecstasy, in nonclinical settings. Using a secure, globally available website, this study collected data from participants in 13 countries who were experienced with MDMA (n = 100). A subset of survey respondents (n = 24) were then invited to participate in qualitative interviews. The researcher applied thematic content analysis of interview transcripts to create a comprehensive account of emergent themes. MDMA has well-documented acute effects that promote pro-social attitudes such as caring and trust in neurotypical, or typically developing, populations. Findings from this study suggested that MDMA-assisted therapy may be an effective catalyst in autistic adults for intra- and interpersonal change. In addition, participants reported accounts of lasting transformation and healing from conditions such as trauma and social anxiety that are common in autistic populations. No participants reported long-term adverse outcomes as a result of using MDMA/ecstasy. Qualitative findings support a case for future clinical trials of MDMA-assisted therapy with autistic adults who present with social adaptability challenges.

Danforth, A. L. (2019). Embracing neurodiversity in psychedelic science: A mixed-methods inquiry into the MDMA experiences of autistic adults. Journal of psychoactive drugs, 51(2), 146-154., 10.1080/02791072.2019.1587116
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Salvia divinorum: from recreational hallucinogenic use to analgesic and anti-inflammatory action

March 22, 2019 / Biology & Ethnobotany, Neuroscience, Papers, Pharmacology & Chemistry, Psychiatry & Medicine, Publications, Salvia / Salvinorin A / By / ,

Abstract

Salvia divinorum is a herbal plant native to the southwest region of Mexico. Traditional preparations of this plant have been used in illness treatments that converge with inflammatory conditions and pain. Currently, S. divinorum extracts have become popular in several countries as a recreational drug due to its hallucinogenic effects. Its main active component is a diterpene named salvinorin A (SA), a potent naturally occurring hallucinogen with a great affinity to the κ opioid receptors and with allosteric modulation of cannabinoid type 1 receptors. Recent biochemical research has revealed the mechanism of action of the anti-inflammatory and analgesic effect of SA at the cellular and molecular level. Nevertheless, because of their short-lasting and hallucinogenic effect, the research has focused on discovering a new analogue of SA that is able to induce analgesia and reduce inflammation with a long-lasting effect but without the hallucinatory component. In this review, we explore the role of S. divinorum, SA and its analogues. We focus mainly on their analgesic and anti-inflammatory roles but also mention their psychoactive properties.

Coffeen, U., & Pellicer, F. (2019). Salvia divinorum: from recreational hallucinogenic use to analgesic and anti-inflammatory action. Journal of pain research, 12, 1069., 10.2147/JPR.S188619

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A Review of 3,4-methylenedioxymethamphetamine (MDMA)-Assisted Psychotherapy.

March 20, 2019 / Anxiety Disorders / PTSD, MDMA, Papers, Psychology, Publications, Substance Use Disorder / By / , ,

Abstract

This paper provides a brief review of the history, proposed pharmacological mechanisms, safety issues, and clinical applications of the medicine 3,4-methylenedioxymethamphetamine (MDMA). Most clinical MDMA research in patients to date has focused on MDMA-assisted psychotherapy to treat posttraumatic stress disorder (PTSD). In this review paper other potential therapeutic applications for MDMA therapy are described, including contemporary studies treating anxiety associated with autism and the authors’ ongoing study exploring the potential role for MDMA-assisted psychotherapy to treat alcohol use disorder. MDMA therapy for PTSD is now entering the final Phase 3 stage of drug development, with a target set for licensing by the FDA and EMA in 2021. This means that if clinical efficacy criteria are achieved, MDMA would become a medicine.
Sessa, B., Higbed, L., & Nutt, D. (2019). A Review of 3, 4-methylenedioxymethamphetamine (MDMA)-Assisted Psychotherapy. Frontiers in Psychiatry, 10, 138., https://doi.org/10.3389/fpsyt.2019.00138
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