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MDMA

The safety and efficacy of ±3,4-methylenedioxymethamphetamineassisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder

July 19, 2010 / Anxiety disorders / PTSD, MDMA, Papers, Psychiatry, Psychology, Psychopharmacology, Psychotherapy, Publications, Safety / By / , , , ,

Abstract

Case reports indicate that psychiatrists administered 3,4-methylenedioxymethamphetamine (MDMA) as a catalyst to psychotherapy before recreational use of MDMA as ‘Ecstasy’ resulted in its criminalization in 1985. Over two decades later, this study is the first completed clinical trial evaluating MDMA as a therapeutic adjunct. Twenty patients with chronic posttraumatic stress disorder, refractory to both psychotherapy and psychopharmacology, were randomly assigned to psychotherapy with concomitant active drug (n¼12) or inactive placebo (n¼8) administered during two 8-h experimental psychotherapy sessions. Both groups received preparatory and follow-up non-drug psychotherapy. The primary outcome measure was the Clinician- Administered PTSD Scale, administered at baseline, 4 days after each experimental session, and 2 months after the second session. Neurocognitive testing, blood pressure, and temperature monitoring were performed. After 2-month follow-up, placebo subjects were offered the option to re-enroll in the experimental procedure with open-label MDMA. Decrease in Clinician-Administered PTSD Scale scores from baseline was significantly greater for the group that received MDMA than for the placebo group at all three time points after baseline. The rate of clinical response was 10/12 (83%) in the active treatment group versus 2/8 (25%) in the placebo group. There were no drug-related serious adverse events, adverse neurocognitive effects or clinically significant blood pressure increases. MDMA-assisted psychotherapy can be administered to posttraumatic stress disorder patients without evidence of harm, and it may be useful in patients refractory to other treatments.

Mithoefer, M. C., Wagner, M. T., Mithoefer, A. T., Jerome, L., & Doblin, R. (2010). The safety and efficacy of ±3,4-methylenedioxymethamphetamineassisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. Journal of Psychopharmacology, 25(4), 439-452. http://dx.doi.org/10.1177/0269881110378371
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Rediscovering MDMA (ecstasy): the role of the American chemist Alexander T. Shulgin

July 9, 2010 / Chemistry, History, MDMA, Other subjects, Papers, Psychotherapy, Publications / By / ,

Abstract

Aims: Alexander T. Shulgin is widely thought of as the ‘father’ of +/-3,4-methylenedioxymethamphetamine (MDMA). This paper re-assesses his role in the modern history of this drug.

Methods: We analysed systematically Shulgin’s original publications on MDMA, his publications on the history of MDMA and his laboratory notebook.

Results: According to Shulgin’s book PIHKAL (1991), he synthesized MDMA in 1965, but did not try it. In the 1960s Shulgin also synthesized MDMA-related compounds such as 3,4-methylenedioxyamphetamine (MDA), 3-methoxy- 4,5-methylenedioxyamphetamine (MMDA) and 3,4-methylenedioxyethylamphetamine (MDE), but this had no impact on his rediscovery of MDMA. In the mid-1970s Shulgin learned of a ‘special effect’ caused by MDMA, whereupon he re-synthesized it and tried it himself in September 1976, as confirmed by his laboratory notebook. In 1977 he gave MDMA to Leo Zeff PhD, who used it as an adjunct to psychotherapy and introduced it to other psychotherapists.

Conclusion: Shulgin was not the first to synthesize MDMA, but he played an important role in its history. It seems plausible that he was so impressed by its effects that he introduced it to psychotherapist Zeff in 1977. This, and the fact that in 1978 he published with David Nichols the first paper on the pharmacological action of MDMA in humans, explains why Shulgin is sometimes (erroneously) called the ‘father’ of MDMA.

Benzenhöfer, U., & Passie, T. (2010). Rediscovering MDMA (ecstasy): the role of the American chemist Alexander T. Shulgin. Addiction, 105(8), 1355–1361. http://dx.doi.org/10.1111/j.1360-0443.2010.02948.x
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The persistence of the subjective in neuropsychopharmacology: observations of contemporary hallucinogen research

February 26, 2010 / Ayahuasca, Cacti / Mescaline, DMT, Iboga / Ibogaine, Ketamine, LSD, MDMA, Mushrooms / Psilocybin, Neuroscience, Other disciplines, Other subjects, Other substances, Papers, Psychology, Psychopharmacology, Publications, Salvia / Salvinorin A / By /

Abstract

The elimination of subjectivity through brain research and the replacement of so-called ‘folk psychology’ by a neuroscientifically enlightened worldview and self-conception has been both hoped for and feared. But this cultural revolution is still pending. Based on nine months of fieldwork on the revival of hallucinogen research since the ‘Decade of the Brain,’ this paper examines how subjective experience appears as epistemic object and practical problem in a psychopharmacological laboratory. In the quest for neural correlates of (drug-induced altered states of) consciousness, introspective accounts of test subjects play a crucial role in neuroimaging studies. Firsthand knowledge of the drugs’ flamboyant effects provides researchers with a personal knowledge not communicated in scientific publications, but key to the conduct of their experiments. In many cases, the ‘psychedelic experience’ draws scientists into the field and continues to inspire their self-image and way of life. By exploring these domains the paper points to a persistence of the subjective in contemporary neuropsychopharmacology.

Langlitz, N. (2010). The persistence of the subjective in neuropsychopharmacology: observations of contemporary hallucinogen research. History of Human Sciences, 23(1), 37-57. http://dx.doi.org/10.1177/0952695109352413
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Psychedelics and the Human Receptorome

February 2, 2010 / Cacti / Mescaline, Chemistry, DMT, MDMA, Mushrooms / Psilocybin, Other subjects, Other substances, Papers, Psychopharmacology, Publications / By /

Abstract

We currently understand the mental effects of psychedelics to be caused by agonism or partial agonism of 5-HT2A (and possibly 5-HT2C) receptors, and we understand that psychedelic drugs, especially phenylalkylamines, are fairly selective for these two receptors. This manuscript is a reference work on the receptor affinity pharmacology of psychedelic drugs. New data is presented on the affinity of twenty-five psychedelic drugs at fifty-one receptors, transporters, and ion channels, assayed by the National Institute of Mental Health – Psychoactive Drug Screening Program (NIMH-PDSP). In addition, comparable data gathered from the literature on ten additional drugs is also presented (mostly assayed by the NIMH-PDSP). A new method is introduced for normalizing affinity (Ki) data that factors out potency so that the multi-receptor affinity profiles of different drugs can be directly compared and contrasted. The method is then used to compare the thirty-five drugs in graphical and tabular form. It is shown that psychedelic drugs, especially phenylalkylamines, are not as selective as generally believed, interacting with forty-two of forty-nine broadly assayed sites. The thirty-five drugs of the study have very diverse patterns of interaction with different classes of receptors, emphasizing eighteen different receptors. This diversity of receptor interaction may underlie the qualitative diversity of these drugs. It should be possible to use this diverse set of drugs as probes into the roles played by the various receptor systems in the human mind.

Ray, T. S. (2010). Psychedelics and the Human Receptorome. PLoS ONE, 5(2). http://dx.doi.org/10.1371/journal.pone.0009019
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Cannabis and Ecstasy/MDMA: Empirical Measures of Creativity in Recreational Users

December 25, 2009 / Creativity, MDMA, Other substances, Papers, Psychology, Publications / By / , ,

Abstract

This study investigated the associations between chronic cannabis and Ecstasy/MDMA use and one objective and two subjective measure of creativity. Fifteen abstinent Ecstasy users, 15 abstinent cannabis users, and 15 nondnig-user controls, completed three measures of creativity: the Consequences behavioral test of creativity, self-assessed performance on the Consequences test, and Gough’s Trait Self-Report Creative Adjective Checklist. The Consequences test involved five scenarios where possible consequences had to be devised; scoring was conducted by the standard blind rating (by two independent judges) for “remoteness” and “rarity,” and by a frequency and rarity of responses method. Cannabis users had significantly more “rare-creative” responses than controls (Tukey, p < 0.05); this effect remained significant with gender as a covariate. There were no significant differences between the groups on the number of standard scoring “remote-creative” ideas or for fluency of responses. On self-rated creativity, there was a significant ANOVA group difference (p < 0.05), with Ecstasy users tending to rate their answers as more creative than controls (Tukey comparison; p = 0.058, two-tailed). Ecstasy users did not differ from controls on the behavioral measures of creativity, although there was a borderline trend for self-assessment of greater creativity. Cannabis users produced significantly more “rare-creative” responses, but did not rate themselves as more creative.

Jones, K. A., Blagrove, M., & Parrott, A. C. Cannabis and Ecstasy/MDMA: Empirical Measures of Creativity in Recreational Users. Journal of Psychoactive Drugs, 41(4), 323-329. http://dx.doi.org/10.1080/02791072.2009.10399769
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How could MDMA (ecstasy) help anxiety disorders? A neurobiological rationale

March 9, 2009 / Anxiety disorders / PTSD, MDMA, Neuroscience, Papers, Psychiatry, Psychology, Psychopharmacology, Psychotherapy, Publications / By / ,

Abstract

Exposure therapy is known to be an effective treatment for anxiety disorders. Nevertheless, exposure is not used as much as it should be, and instead patients are often given supportive medications such as serotonin reuptake inhibitors (SSRIs) and benzodiazepines, which may even interfere with the extinction learning that is the aim of treatment. Given that randomized controlled trials are now investigating a few doses of ±3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) in combination with psychotherapy for treatment-resistant anxiety disorders, we would like to suggest the following three mechanisms for this potentially important new approach: 1) MDMA increases oxytocin levels, which may strengthen the therapeutic alliance; 2) MDMA increases ventromedial prefrontal activity and decreases amygdala activity, which may improve emotional regulation and decrease avoidance and 3) MDMA increases norepinephrine release and circulating cortisol levels, which may facilitate emotional engagement and enhance extinction of learned fear associations. Thus, MDMA has a combination of pharmacological effects that, in a therapeutic setting, could provide a balance of activating emotions while feeling safe and in control, as described in case reports of MDMA-augmented psychotherapy. Further clinical and preclinical studies of the therapeutic value of MDMA are indicated.

Johansen, P. Ø., & Krebs, T. S. (2009). How could MDMA (ecstasy) help anxiety disorders? A neurobiological rationale. Journal of Psychopharmacology, 23(4), 389-391. http://dx.doi.org/10.1177/0269881109102787
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Human hallucinogen research: guidelines for safety

July 1, 2008 / Ayahuasca, Cacti / Mescaline, DMT, Iboga / Ibogaine, Ketamine, LSD, MDMA, Medicine, Mushrooms / Psilocybin, Neuroscience, Other substances, Papers, Psychiatry, Psychology, Psychopharmacology, Publications, Safety, Salvia / Salvinorin A / By / , ,

Abstract

There has recently been a renewal of human research with classical hallucinogens (psychedelics). This paper first briefly discusses the unique history of human hallucinogen research, and then reviews the risks of hallucinogen administration and safeguards for minimizing these risks. Although hallucinogens are relatively safe physiologically and are not considered drugs of dependence, their administration involves unique psychological risks. The most likely risk is overwhelming distress during drug action (‘bad trip’), which could lead to potentially dangerous behaviour such as leaving the study site. Less common are prolonged psychoses triggered by hallucinogens. Safeguards against these risks include the exclusion of volunteers with personal or family history of psychotic disorders or other severe psychiatric disorders, establishing trust and rapport between session monitors and volunteer before the session, careful volunteer preparation, a safe physical session environment and interpersonal support from at least two study monitors during the session. Investigators should probe for the relatively rare hallucinogen persisting perception disorder in follow-up contact. Persisting adverse reactions are rare when research is conducted along these guidelines. Incautious research may jeopardize participant safety and future research. However, carefully conducted research may inform the treatment of psychiatric disorders, and may lead to advances in basic science.

Johnson, M. W., Richards, W. A., & Griffiths, R. R. (2008). Human hallucinogen research: guidelines for safety.  Journal of Psychopharmacology, 22(6), 603–620. http://dx.doi.org/10.1177/0269881108093587
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The behavioral pharmacology of hallucinogens

January 1, 2008 / Cacti / Mescaline, Chemistry, DMT, LSD, MDMA, Mushrooms / Psilocybin, Other subjects, Papers, Psychopharmacology, Publications / By / , ,

Abstract

Until very recently, comparatively few scientists were studying hallucinogenic drugs. Nevertheless, selective antagonists are available for relevant serotonergic receptors, the majority of which have now been cloned, allowing for reasonably thorough pharmacological investigation. Animal models sensitive to the behavioral effects of the hallucinogens have been established and exploited. Sophisticated genetic techniques have enabled the development of mutant mice, which have proven useful in the study of hallucinogens. The capacity to study post-receptor signaling events has lead to the proposal of a plausible mechanism of action for these compounds. The tools currently available to study the hallucinogens are thus more plentiful and scientifically advanced than were those accessible to earlier researchers studying the opioids, benzodiazepines, cholinergics, or other centrally active compounds. The behavioral pharmacology of phenethylamine, tryptamine, and ergoline hallucinogens are described in this review, paying particular attention to important structure activity relationships which have emerged, receptors involved in their various actions, effects on conditioned and unconditioned behaviors, and in some cases, human psychopharmacology. As clinical interest in the therapeutic potential of these compounds is once again beginning to emerge, it is important to recognize the wealth of data derived from controlled preclinical studies on these compounds.

Fantegrossi, W. E.,  Murnane, K. S., & Reissig, C. J. (2008). The behavioral pharmacology of hallucinogens. Biochemical Pharmacology 75(1), 17–33. http://dx.doi.org/10.1016/j.bcp.2007.07.018
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Comparative potencies of MDMA analogues as inhibitors of [3H]noradrenaline and [3H]5-HT transport in mammalian cell lines

December 1, 2007 / Chemistry, MDMA, New substances, Other subjects, Other substances, Papers, Psychopharmacology, Publications / By / , , , , ,

Abstract

Background and purpose:Illegal ‘ecstasy’ tablets frequently contain 3,4-methylenedioxymethamphetamine (MDMA)-like compounds of unknown pharmacological activity. Since monoamine transporters are one of the primary targets of MDMA action in the brain, a number of MDMA analogues have been tested for their ability to inhibit [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”][3H]noradrenaline uptake into rat PC12 cells expressing the noradrenaline transporter (NET) and [3H]5-HT uptake into HEK293 cells stably transfected with the 5-HT transporter (SERT).

Experimental approach:Concentration–response curves for the following compounds at both NET and SERT were determined under saturating substrate conditions: 4-hydroxy-3-methoxyamphetamine (HMA), 4-hydroxy 3-methoxymethamphetamine (HMMA), 3,4-methylenedioxy-N-hydroxyamphetamine (MDOH), 2,5-dimethoxy-4-bromophenylethylamine (2CB), 3,4-dimethoxymethamphetamine (DMMA), 3,4-methylenedioxyphenyl-2-butanamine (BDB), 3,4-methylenedioxyphenyl- N-methyl-2-butanamine (MBDB) and 2,3-methylenedioxymethamphetamine (2,3-MDMA).

Key results: 2,3-MDMA was significantly less potent than MDMA at SERT, but equipotent with MDMA at NET. 2CB and BDB were both significantly less potent than MDMA at NET, but equipotent with MDMA at SERT. MBDB, DMMA, MDOH and the MDMA metabolites HMA and HMMA, were all significantly less potent than MDMA at both NET and SERT.

Conclusions and implications: This study provides an important insight into the structural requirements of MDMA analogue affinity at both NET and SERT. It is anticipated that these results will facilitate understanding of the likely pharmacological actions of structural analogues of MDMA.

Montgomery, T., Buon, C., Eibauer, S., Guiry, P. J., Keenan, A.K., & McBean, G. J. (2007). Comparative potencies of MDMA analogues as inhibitors of [3H]noradrenaline and [3H]5-HT transport in mammalian cell lines. British Journal of Pharmacology, 152(7), 1121–1130. http://dx.doi.org/10.1038/sj.bjp.0707473
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Acute dose of MDMA (75 mg) impairs spatial memory for location but leaves contextual processing of visuospatial information unaffected

March 1, 2006 / MDMA, Other subjects, Papers, Psychiatry, Psychology, Publications / By / ,

Abstract

Rationale: Research concerning spatial memory in 3,4-methylenedioxymethamphetamine (MDMA) users has presented conflicting results showing either the presence or absence of spatial memory deficits. Two factors may have confounded results in abstinent users: memory task characteristics and polydrug use.

Objectives: The present study aims to assess whether a single dose of MDMA affects spatial memory performance during intoxication and withdrawal phase and whether spatial memory performance after MDMA is task dependent.

Materials and methods: Eighteen recreational MDMA users participated in a double-blind, placebo-controlled, three-way crossover design. They were treated with placebo, MDMA 75 mg, and methylphenidate 20 mg. Memory tests were conducted between 1.5 and 2 h (intoxication phase) and between 25.5 and 26 h (withdrawal phase) post-dosing. Two spatial memory tasks of varying complexity were used that required either storage of stimulus location alone (spatial memory task) or memory for location as well as processing of content or contextual information (change blindness task).

Results: After a single dose of MDMA, the subjects made larger localization errors and responded faster compared to placebo in the simple spatial memory task during intoxication phase. Inaccuracy was not due to increased response speed, as determined by regression analysis. Performance in the change blindness task was not affected by MDMA. Methylphenidate did not affect performance on any of the tasks.

Conclusion: It is concluded that a single dose of MDMA impairs spatial memory for location but leaves processing of contextual information intact.

Kuypers, K. P., & Ramaekers, J. G. (2007). Acute dose of MDMA (75 mg) impairs spatial memory for location but leaves contextual processing of visuospatial information unaffected. Psychopharmacology, 189(4), 557-563. 10.1007/s00213-006-0321-7

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30 April - Q&A with Rick Strassman

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