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PTSD and MDMA in the ‘picture’

December 6, 2021 / Anxiety Disorders / PTSD, MDMA, Publications / By

a5_ptsd_508With an upcoming fMRI study in the United Kingdom, an attempt is being made to outline the neurobiological mechanisms that are hypothesized to underlie the favorable outcome of MDMA-assisted psychotherapy in posttraumatic stress disorder (PTSD).

Earlier studies found that after just a few treatment sessions with MDMA in addition to psychotherapy, there was a significant short [fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][1] and long [2] term improvement of PTSD symptomatology in patients that were resistant to regular psycho- and/or pharmacotherapy [3]. Up to today, not much is known about the factors that contribute to the success of this form of treatment. Several researchers suggest that MDMA, o.a. by temporarily reducing fear and by easing interpersonal contact, facilitate the therapy on a psychological level [4], but about the neurobiological foundations remains to be speculated.

By using fMRI, dr. Ben Sessa and his research team at Cardiff University will try to image the manifestation of MDMA in PTSD patients. To capture the effects of the compound in isolation, the patients will not receive any psychotherapy during this study.

The research proposal is currently waiting for approval of the Committee of Ethics.

 
[1] Mithoefer, Wagner, Mithoefer, Jerome, & Doblin (2011)
[2] Mithoefer et al. (2012)
[3] A similar study from Oehen, Traber, Widmer, & Schnyder (2013) did not reach significance on the primary measurement (p = .066), a diagnostic tool to assess PTSD symptomatology, though at a subjective level the patients indicated to have some relief from their former complaints. Bouso et al. (2008) couldn’t draw any firm conclusions on their data of the first MDMA-assisted psychotherapy study in PTSD, due to a sudden unexpected cancellation of the study and the consequencing small study sample.
[4] Bouso, Doblin, Farré, Alcázar, & Gómez-Jarabo (2008), Mithoefer et al. (2011), Oehen et al. (2013)
 
References
Bouso, J. C., Doblin, R., Farré, M., Alcázar, M. A., & Gómez-Jarabo, G. (2008). MDMA-assisted psychotherapy using low doses in a small sample of women with chronic posttraumatic stress disorder. Journal of Psychoactive Drugs, 40(3), 225–36. doi:10.1080/02791072.2008.10400637
Mithoefer, M. C. M., Wagner, M. M. T., Mithoefer, A. A. T., Jerome, L., Martin, S. F., Yazar-Klosinski, B., … Doblin, R. (2012). Durability of improvement in posttraumatic stress disorder symptoms and absence of harmful effects or drug dependency after 3,4-methylenedioxymethamphetamine-assisted psychotherapy: a prospective long-term follow-up study. Journal of Psychopharmacology (Oxford, England), 27, 28–39. doi:10.1177/0269881112456611
Mithoefer, M. C., Wagner, M. T., Mithoefer, A. T., Jerome, L., & Doblin, R. (2011). The safety and efficacy of {+/-}3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. Journal of psychopharmacology (Oxford, England) (Vol. 25, pp. 439–452). doi:10.1177/0269881110378371
Oehen, P., Traber, R., Widmer, V., & Schnyder, U. (2013). A randomized, controlled pilot study of MDMA (± 3,4-Methylenedioxymethamphetamine)-assisted psychotherapy for treatment of resistant, chronic Post-Traumatic Stress Disorder (PTSD). Journal of Psychopharmacology (Oxford, England), 27(1), 40–52. doi:10.1177/0269881112464827[/fusion_builder_column][/fusion_builder_row][/fusion_builder_container]

In Memoriam Alexander ‘Sasha’ Shulgin

February 7, 2022 / MDMA, Pharmacology & Chemistry / By

With great sadness, the OPEN foundation would like to acknowledge the death of maverick chemist Alexander “Sasha” Shulgin, who passed away on June 2nd. Dubbed “the godfather of Ecstasy,” Shulgin was credited with introducing MDMA to psychologists in the late 70’s, years before the drug hit the global dance scene.

However MDMA was only one of hundreds of chemicals Shulgin synthesized during his lengthy career. After earning his biochemistry degree from UC Berkeley in 1954, he worked briefly as research director at BioRad Laboratories before becoming a senior research chemist at Dow Chemical Company, where he synthesized the first biodegradable insecticide, Zectran.

Because Shulgin made Dow a sizeable profit, he was granted the freedom to create and patent new drugs. He chose psychedelics. In the late 1950s, Shulgin experimented with mescaline, which he wrote revealed “that our entire universe is contained in the mind and spirit.” But his interest in pharmacology was sparked years earlier. While in the Navy as a teenager, he got a shot of morphine for an injury, making him wonder how drugs altered consciousness. This passion for understanding the human mind and how to unlock its potential—chemically, of course—would mark his career.

In 1966, Shulgin left Dow Chemical to freelance as a consultant and for the following decades worked from his backyard lab in Berkeley, California. In 1976, he heard about MDMA, which was first synthesized at Merck in 1912 as an unimportant precursor in a new synthesis for haemostatic substances and subsequently shelved. He went on to synthesize it, and discovered it was a powerful empathogen, “with emotional and sensual overtones.” He then introduced it to a therapist friend and word spread quickly both inside and outside the therapeutic community. Without MDMA, the dance music scene of the last 30 years would have looked entirely different.

Shulgin was a fixture in the psychedelic subculture that believed in better living through chemistry. He contributed a rational, scientific perspective to the field, coupled with enthusiasm for thorough self-experimentation.

When interviewed about the abuse potential of MDMA, which became a scheduled drug in 1985, Shulgin was quoted as saying it was “as real as the abuse potential of anything that gives pleasure and satisfaction. This applies to MDMA as much as it does to skydiving, mountain climbing and skiing.”

Shulgin died of several health complications after years of poor health, and had recently been diagnosed with terminal liver cancer. He was 88. His wife, Ann Shulgin, with whom he shared thousands of psychedelic experiences, survives him.

The effects of psilocybin and MDMA on between-network resting state functional connectivity in healthy volunteers

May 27, 2014 / MDMA, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications / By / , , , ,

Abstract

Perturbing a system and observing the consequences is a classic scientific strategy for understanding a phenomenon. Psychedelic drugs perturb consciousness in a marked and novel way and thus are powerful tools for studying its mechanisms. In the present analysis, we measured changes in resting-state functional connectivity (RSFC) between a standard template of different independent components analysis (ICA)-derived resting state networks (RSNs) under the influence of two different psychoactive drugs, the stimulant/psychedelic hybrid, MDMA, and the classic psychedelic, psilocybin. Both were given in placebo-controlled designs and produced marked subjective effects, although reports of more profound changes in consciousness were given after psilocybin. Between-network RSFC was generally increased under psilocybin, implying that networks become less differentiated from each other in the psychedelic state. Decreased RSFC between visual and sensorimotor RSNs was also observed. MDMA had a notably less marked effect on between-network RSFC, implying that the extensive changes observed under psilocybin may be exclusive to classic psychedelic drugs and related to their especially profound effects on consciousness. The novel analytical approach applied here may be applied to other altered states of consciousness to improve our characterization of different conscious states and ultimately advance our understanding of the brain mechanisms underlying them.

Roseman, L., Leech, R., Feilding, A., Nutt, D. J., & Carhart-Harris, R. L. (2014). The effects of psilocybin and MDMA on between-network resting state functional connectivity in healthy volunteers. Frontiers in Human Neuroscience, 8, 1-11. http://dx.doi.org/10.3389/fnhum.2014.00204
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Interaction of psychoactive tryptamines with biogenic amine transporters and serotonin receptor subtypes

May 7, 2014 / DMT, LSD, MDMA, Mushrooms / Psilocybin, Papers, Publications / By / , , , , ,

Abstract

Rationale
Synthetic hallucinogenic tryptamines, especially those originally described by Alexander Shulgin, continue to be abused in the USA. The range of subjective experiences produced by different tryptamines suggests that multiple neurochemical mechanisms are involved in their actions, in addition to the established role of agonist activity at serotonin 2A (5-HT2A) receptors.

Objectives
This study evaluated the interaction of a series of synthetic tryptamines with biogenic amine neurotransmitter transporters and with serotonin (5-HT) receptor subtypes implicated in psychedelic effects.

Methods
Neurotransmitter transporter activity was determined in rat brain synaptosomes. Receptor activity was determined using calcium mobilization and DiscoveRx PathHunter® assays in HEK293, Gα16-CHO, and CHOk1 cells transfected with human receptors.

Results
Twenty-one tryptamines were analyzed in transporter uptake and release assays, and 5-HT2A, serotonin 1A (5-HT1A), and 5-HT2A β-arrestin functional assays. Eight of the compounds were found to have 5-HT-releasing activity. Thirteen compounds were found to be 5-HT uptake inhibitors or were inactive. All tryptamines were 5-HT2A agonists with a range of potencies and efficacies, but only a few compounds were 5-HT1A agonists. Most tryptamines recruited β-arrestin through 5-HT2A activation.

Conclusions
All psychoactive tryptamines are 5-HT2A agonists, but 5-HT transporter (SERT) activity may contribute significantly to the pharmacology of certain compounds. The in vitro transporter data confirm structure-activity trends for releasers and uptake inhibitors whereby releasers tend to be structurally smaller compounds. Interestingly, two tertiary amines were found to be selective substrates at SERT, which dispels the notion that 5-HT-releasing activity is limited only to primary or secondary amines.

Blough, B. E., Landavazo, A., Decker, A. M., Partilla, J. S., Baumann, M. H., & Rothman, R. B. (2014). Interaction of psychoactive tryptamines with biogenic amine transporters and serotonin receptor subtypes. Psychopharmacology, 231(21), 4135-4144. http://dx.doi.org/10.1007/s00213-014-3557-7
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A window into the intoxicated mind? Speech as an index of psychoactive drug effects.

April 3, 2014 / MDMA, Papers, Psychology, Publications / By / , , , , ,

Abstract

Abused drugs can profoundly alter mental states in ways that may motivate drug use. These effects are usually assessed with self-report, an approach that is vulnerable to biases. Analyzing speech during intoxication may present a more direct, objective measure, offering a unique ‘window’ into the mind. Here, we employed computational analyses of speech semantic and topological structure after ±3,4-methylenedioxymethamphetamine (MDMA; ‘ecstasy’) and methamphetamine in 13 ecstasy users. In 4 sessions, participants completed a 10-min speech task after MDMA (0.75 and 1.5 mg/kg), methamphetamine (20 mg), or placebo. Latent Semantic Analyses identified the semantic proximity between speech content and concepts relevant to drug effects. Graph-based analyses identified topological speech characteristics. Group-level drug effects on semantic distances and topology were assessed. Machine-learning analyses (with leave-one-out cross-validation) assessed whether speech characteristics could predict drug condition in the individual subject. Speech after MDMA (1.5 mg/kg) had greater semantic proximity than placebo to the concepts friend, support, intimacy, and rapport. Speech on MDMA (0.75 mg/kg) had greater proximity to empathy than placebo. Conversely, speech on methamphetamine was further from compassion than placebo. Classifiers discriminated between MDMA (1.5 mg/kg) and placebo with 88% accuracy, and MDMA (1.5 mg/kg) and methamphetamine with 84% accuracy. For the two MDMA doses, the classifier performed at chance. These data suggest that automated semantic speech analyses can capture subtle alterations in mental state, accurately discriminating between drugs. The findings also illustrate the potential for automated speech-based approaches to characterize clinically relevant alterations to mental state, including those occurring in psychiatric illness.

Bedi, G., Cecchi, G. A., Slezak, D. F., Carrillo, F., Sigman, M., & de Wit, H. (2014). A window into the intoxicated mind? speech as an index of psychoactive drug effects. Neuropsychopharmacology. https://dx.doi.org/10.1038/npp.2014.80

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Why Psychiatry Needs Psychedelics and Psychedelics Need Psychiatry

March 11, 2014 / Anxiety Disorders / PTSD, Depressive Disorders, LSD, MDMA, Mushrooms / Psilocybin, Papers, Psychology, Publications, Substance Use Disorder / By /

Abstract

Without researching psychedelic drugs for medical therapy, psychiatry is turning its back on a group of compounds that could have great potential. Without the validation of the medical profession, the psychedelic drugs, and those who take them off-license, remain archaic sentiments of the past, with the users maligned as recreational drug abusers and subject to continued negative opinion. These two disparate groups—psychiatrists and recreational psychedelic drug users—are united by their shared recognition of the healing potential of these compounds. A resolution of this conflict is essential for the future of psychiatric medicine and psychedelic culture alike. Progression will come from professionals working in the field adapting to fit a conservative paradigm. In this way, they can provide the public with important treatments and also raise the profile of expanded consciousness in mainstream society.

Sessa, B. (2014). Why Psychiatry Needs Psychedelics and Psychedelics Need Psychiatry. Journal of Psychoactive Drugs, 46(1), 57–62. http://dx.doi.org/10.1080/02791072.2014.877322
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MDMA and the “Ecstasy Paradigm”

March 11, 2014 / MDMA, Neuroscience, Papers, Psychology, Publications / By /

Abstract

For nearly 30 years, there has been a steady flow of research papers highlighting the dangers of MDMA and the implications for ecstasy users. After such a long time, it would be reasonable to expect that these dangers would be obvious due to the large number of ecstasy users. The available evidence does not indicate that there are millions of ecstasy users experiencing any problems linked to their ecstasy use. The “precautionary principle” suggests that, in the absence of knowing for certain, “experts” should argue that MDMA be avoided. However, this may have been taken too far, as the dire warnings do not seem to be reducing with the lack of epidemiological evidence of clinically relevant problems. The “ecstasy paradigm” is one way of articulating this situation, in that the needs of research funders and publication bias lead to a specific set of subcultural norms around what information is acceptable in the public domain. By digging a little deeper, it is easy to find problems with the evidence base that informs the public debate around MDMA. The key question is whether it is acceptable to maintain this status quo given the therapeutic potential of MDMA.

Cole, J. C. (2014). MDMA and the “Ecstasy Paradigm”. Journal of Psychoactive Drugs, 46(1), 44–56. http://dx.doi.org/10.1080/02791072.2014.878148
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The Potential Dangers of Using MDMA for Psychotherapy

March 11, 2014 / Anxiety Disorders / PTSD, MDMA, Neuroscience, Papers, Psychology, Publications / By /

Abstract

MDMA has properties that may make it attractive for psychotherapy, although many of its effects are potentially problematic. These contrasting effects will be critically reviewed in order to assess whether MDMA could be safe for clinical usage. Early studies from the 1980s noted that MDMA was an entactogen, engendering feelings of love and warmth. However, negative experiences can also occur with MDMA since it is not selective in the thoughts or emotions it releases. This unpredictability in the psychological material released is similar to another serotonergic drug, LSD. Acute MDMA has powerful neurohormonal effects, increasing cortisol, oxytocin, testosterone, and other hormone levels. The release of oxytocin may facilitate psychotherapy, whereas cortisol may increase stress and be counterproductive. MDMA administration is followed by a period of neurochemical recovery, when low serotonin levels are often accompanied by lethargy and depression. Regular usage can also lead to serotonergic neurotoxicity, memory problems, and other psychobiological problems. Proponents of MDMA-assisted therapy state that it should only be used for reactive disorders (such as PTSD) since it can exacerbate distress in those with a prior psychiatric history. Overall, many issues need to be considered when debating the relative benefits and dangers of using MDMA for psychotherapy.

Parrott, A. C. (2014). The Potential Dangers of Using MDMA for Psychotherapy. Journal of Psychoactive Drugs, 46(1) , 37–43. http://dx.doi.org/10.1080/02791072.2014.873690
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History and Future of the Multidisciplinary Association for Psychedelic Studies (MAPS)

March 11, 2014 / Anxiety Disorders / PTSD, LSD, MDMA, Papers, Publications / By / , , ,

Abstract

This article describes the teenage vision of the founder of the Multidisciplinary Association for Psychedelic Studies (MAPS) that humanity’s future would be aided by the therapeutic and spiritual potential of psychedelic substances. The article traces the trajectory of MAPS from inception in 1986 to its present, noting future goals with respect to research, outreach, and harm reduction. MAPS was created as a non-profit psychedelic pharmaceutical company in response to the 1985 scheduling of 3,4-methylenedioxymethamphetamine (MDMA). Overcoming many hurdles, MAPS developed the first double-blind, placebo-controlled trial of MDMA-assisted psychotherapy for posttraumatic stress disorder (PTSD) and plans for FDA prescription approval in 2021. MAPS’ program of research expanded to include a trial of lysergic acid diethylamide (LSD)-assisted psychotherapy for anxiety when facing life-threatening illness, observational studies of ibogaine in the treatment of addiction, and studies of MDMA for social anxiety in people with autism spectrum disorders. MAPS meets the challenges of drug development through a clinical research team led by a former Novartis drug development professional experienced in the conduct, monitoring, and analysis of clinical trials. MAPS’ harm-reduction efforts are intended to avoid backlash and build a post-prohibition world by assisting non-medical users to transform difficult psychedelic experiences into opportunities for growth.

Emerson, A., Ponté, L., Jerome, L., & Doblin, R. (2014). History and Future of the Multidisciplinary Association for Psychedelic Studies (MAPS). Journal of Psychoactive Drugs, 46(1), 27–36. http://dx.doi.org/10.1080/02791072.2014.877321
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MDMA decreases the effects of simulated social rejection

February 8, 2014 / Anxiety Disorders / PTSD, MDMA, Papers, Psychology, Publications / By / , , ,

Abstract

3-4-Methylenedioxymethamphetamine (MDMA) increases self-reported positive social feelings and decreases the ability to detect social threat in faces, but its effects on experiences of social acceptance and rejection have not been determined. We examined how an acute dose of MDMA affects subjective and autonomic responses to simulated social acceptance and rejection. We predicted that MDMA would decrease subjective responses to rejection. On an exploratory basis, we also examined the effect of MDMA on respiratory sinus arrhythmia (RSA), a measure of parasympathetic cardiac control often thought to index social engagement and emotional regulation. Over three sessions, healthy adult volunteers with previous MDMA experience (N = 36) received capsules containing placebo, 0.75 or 1.5 mg/kg of MDMA under counter-balanced double-blind conditions. During expected peak drug effect, participants played two rounds of a virtual social simulation task called “Cyberball” during which they experienced acceptance in one round and rejection in the other. During the task we also obtained electrocardiograms (ECGs), from which we calculated RSA. After each round, participants answered questionnaires about their mood and self-esteem. As predicted, MDMA decreased the effect of simulated social rejection on self-reported mood and self-esteem and decreased perceived intensity of rejection, measured as the percent of ball tosses participants reported receiving. Consistent with its sympathomimetic properties, MDMA decreased RSA as compared to placebo. Our finding that MDMA decreases perceptions of rejection in simulated social situations extends previous results indicating that MDMA reduces perception of social threat in faces. Together these findings suggest a cognitive mechanism by which MDMA might produce pro-social behavior and feelings and how the drug might function as an adjunct to psychotherapy. These phenomena merit further study in non-simulated social environments.

Frye, C. G., Wardle, M. C., Norman, G. J., & de Wit, H. (2014). MDMA decreases the effects of simulated social rejection. Pharmacology Biochemistry and Behavior, 117, 1-6. https://dx.doi.org/10.1016/j.pbb.2013.11.030

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