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Novel psychopharmacological therapies for psychiatric disorders: psilocybin and MDMA

April 5, 2016 / Anxiety Disorders / PTSD, MDMA, Mushrooms / Psilocybin, Papers, Psychology, Publications, Substance Use Disorder / By / , ,

Abstract

4-phosphorloxy-N,N-dimethyltryptamine (psilocybin) and methylenedioxymethamfetamine (MDMA), best known for their illegal use as psychedelic drugs, are showing promise as therapeutics in a resurgence of clinical research during the past 10 years. Psilocybin is being tested for alcoholism, smoking cessation, and in patients with advanced cancer with anxiety. MDMA is showing encouraging results as a treatment for refractory post-traumatic stress disorder, social anxiety in autistic adults, and anxiety associated with a life-threatening illness. Both drugs are studied as adjuncts or catalysts to psychotherapy, rather than as stand-alone drug treatments. This model of drug-assisted psychotherapy is a possible alternative to existing pharmacological and psychological treatments in psychiatry. Further research is needed to fully assess the potential of these compounds in the management of these common disorders that are difficult to treat with existing methods.

Mithoefer, M. C., Grob, C. S., & Brewerton, T. D. (2016). Novel psychopharmacological therapies for psychiatric disorders: psilocybin and MDMA. The Lancet Psychiatry. http://dx.doi.org/10.1016/S2215-0366(15)00576-3
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Can ecstasy treat the agony of PTSD?

April 1, 2016 / Anxiety Disorders / PTSD, MDMA, Papers, Psychology, Publications / By /

Abstract

Two serotonin reuptake inhibitors (SSRIs) have received FDA indication for treatment of PTSD, however the effectiveness of pharmacotherapy for PTSD is limited. Psychotherapy, including several well established evidence based methods, is the mainstay of PTSD treatment. Despite advances in this area, a significant percentage of PTSD patients are refractory to existing treatments. Recent research has explored the possibility that certain drugs could increase the effectiveness of psychotherapy when administered intermittently in conjunction with psychotherapy sessions. The most robust published. Results to date using this approach have been in early clinical trials of±3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy. These studies primarily involved civilians with treatment-resistant, crime-related PTSD. A more recent phase 2 trial, completed in 2015 yielded equally promising. Results in a cohort of military veterans, police officers and firefighters, mostly veterans from the wars in Iraq and Afghanistan.In these double blind controlled trials subjects with PTSD refractory to prior treatment are randomized to an active dose of MDMA or an active or inactive placebo administered to each individual on only two or three occasions during eight-hour psychotherapy sessions one month apart, in conjunction with preparatory and follow-up psychotherapy sessions. Outcome measures are repeated one or two months after the second MDMA-assisted session before the blind is broken. Subjects who were randomized to full dose MDMA are then eligible for one additional, open label, MDMA-assisted session. Those randomized to placebo or a lower dose of MDMA are eligible for three open-label full dose sessions. Outcome measures are repeated two months following the third MDMA-assisted session. The primary outcome measure is the Clinician Administered PTSD Scale (CAPS). Additional measures include the Beck Depression Inventory-II (BDI-II), Global Assessment of Functioning (GAF), Pittsburgh Sleep Quality Index (PSQI) and Posttraumatic Growth Inventory (PTGI).In the original study comparing MDMA with inactive placebo along with the same psychotherapy PTSD was resolved in 83% of the MDMA group vs. 25% of the placebo group receiving the same therapy. Improvement was maintained for at least 74% of subjects at long-term follow-up a mean of 45 months later. In a more recent, unpublished, study both the high dose and the medium dose of MDMA showed large effect sizes in reducing CAPS scores, and improvements in secondary measures: and BDI-II, PSQI, GAF and PTGI.Evidence in phase II trials suggest that MDMA-assisted psychotherapy is effective in treating PTSD in both civilians and veterans who have not responded to established treatments. Phase III trials are necessary to definitively establish safety and efficacy of MDMA-assisted psychotherapy for PTSD.

Mithoefer, M. (2016). Can ecstasy treat the agony of PTSD?. European Psychiatry, (33), S10. http://dx.doi.org/10.1016%2Fj.eurpsy.2016.01.798
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Effects of 3,4-Methylenedioxymethamphetamine on Patient Utterances in a Psychotherapeutic Setting

March 17, 2016 / Anxiety Disorders / PTSD, MDMA, Papers, Psychology, Publications / By / , ,

Abstract

3,4-Methylenedioxymethamphetamine (MDMA) administered as an adjunct to talk therapy influences patient speech content and increases improvement in treatment-resistant posttraumatic stress disorder (PTSD). Data came from the recordings of Mithoefer et al. (2011). In the third therapeutic session studied, patients were assigned, double blind, to an MDMA or a placebo group. Condition-blind scorers listened to therapy recordings and scored utterances where patients initiated topics that were empathic (regarding others’ emotions), entactic (requesting or appreciating physical touch), or ensuic (describing a change in their sense of themselves). Patients who received MDMA produced high levels of ensuic, empathic, and entactic utterances compared with those who received the placebo. Interrater discourse scoring was reliable. The relationship between the number of scored utterances and the Clinician Administered PTSD Scale scores measuring PTSD severity after the treatment was significant, and reanalysis grouped bimodally into “many” or “few” such utterances remained significant. MDMA assisted these patients in having meaningful and disorder-resolving thoughts and discourse in talk therapy.

Corey, V. R., Pisano, V. D., & Halpern, J. H. (2016). Effects of 3, 4-Methylenedioxymethamphetamine on Patient Utterances in a Psychotherapeutic Setting. The Journal of Nervous and Mental Disease. http://dx.doi.org/10.1097/NMD.0000000000000499

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Meta-analysis of executive functioning in ecstasy/polydrug users

March 11, 2016 / MDMA, Neuroscience, Papers, Psychology, Publications / By / , ,

Abstract

Ecstasy/3,4-methylenedioxymethamphetamine (MDMA) use is proposed to cause damage to serotonergic (5-HT) axons in humans. Therefore, users should show deficits in cognitive processes that rely on serotonin-rich, prefrontal areas of the brain. However, there is inconsistency in findings to support this hypothesis. The aim of the current study was to examine deficits in executive functioning in ecstasy users compared with controls using meta-analysis. We identified k = 39 studies, contributing 89 effect sizes, investigating executive functioning in ecstasy users and polydrug-using controls. We compared function-specific task performance in 1221 current ecstasy users and 1242 drug-using controls, from tasks tapping the executive functions – updating, switching, inhibition and access to long-term memory. The significant main effect demonstrated overall executive dysfunction in ecstasy users [standardized mean difference (SMD) = -0.18, 95% confidence interval (CI) -0.26 to -0.11, Z = 5.05, p < 0.001, I 2 = 82%], with a significant subgroup effect (χ 2 = 22.06, degrees of freedom = 3, p < 0.001, I 2 = 86.4%) demonstrating differential effects across executive functions. Ecstasy users showed significant performance deficits in access (SMD = -0.33, 95% CI -0.46 to -0.19, Z = 4.72, p < 0.001, I 2 = 74%), switching (SMD = -0.19, 95% CI -0.36 to -0.02, Z = 2.16, p < 0.05, I 2 = 85%) and updating (SMD = -0.26, 95% CI -0.37 to -0.15, Z = 4.49, p < 0.001, I 2 = 82%). No differences were observed in inhibitory control. We conclude that this is the most comprehensive analysis of executive function in ecstasy users to date and provides a behavioural correlate of potential serotonergic neurotoxicity.

Roberts, C. A., Jones, A., & Montgomery, C. (2016). Meta-analysis of executive functioning in ecstasy/polydrug users. Psychological medicine, 1-16. http://dx.doi.org/10.1017/S0033291716000258

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The History of MDMA as an Underground Drug in the United States, 1960-1979

March 3, 2016 / Humanities & Art, MDMA, Papers, Publications / By / ,

Abstract

MDMA (3,4-methylenedioxy-methylamphetamine, a.k.a. “ecstasy”) was first synthesized in 1912 and resynthesized more than once for pharmaceutical reasons before it became a popular recreational drug. Partially based on previously overlooked U.S. government documentation, this article reconstructs the early history of MDMA as a recreational drug in the U.S. from 1960 to 1979. According to the literature, MDMA was introduced as a street drug at the end of the 1960s. The first forensic detection of MDMA “on the street” was reported in 1970 in Chicago. It appears that MDMA was first synthesized by underground chemists in search of “legal alternatives” for the closely related and highly sought-after drug MDA, which was scheduled under the Controlled Substances Act (CSA) in 1970. Until 1974, nearly all MDMA street samples seized came from the U.S. Midwest, the first “hot region” of MDMA use. In Canada, MDMA was first detected in 1974 and scheduled in 1976. From 1975 to 1979, MDMA was found in street samples in more than 10 U.S. states, the West Coast becoming the major “hot region” of MDMA use. Recreational use of MDMA spread across the U.S. in the early 1980s, and in 1985 it was scheduled under the CSA.

Passie, T., & Benzenhöfer, U. (2016). The history of MDMA as an underground drug in the United States, 1960–1979. Journal of psychoactive drugs, 48(2), 67-75., 10.1080/02791072.2015.1128580

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Verbal Memory Impairment in Polydrug Ecstasy Users: A Clinical Perspective

February 23, 2016 / MDMA, Papers, Psychology, Publications / By / , , , , , ,

Abstract

BACKGROUND:

Ecstasy use has been associated with short-term and long-term memory deficits on a standard Word Learning Task (WLT). The clinical relevance of this has been debated and is currently unknown. The present study aimed at evaluating the clinical relevance of verbal memory impairment in Ecstasy users. To that end, clinical memory impairment was defined as decrement in memory performance that exceeded the cut-off value of 1.5 times the standard deviation of the average score in the healthy control sample. The primary question was whether being an Ecstasy user (E-user) was predictive of having clinically deficient memory performance compared to a healthy control group.

METHODS:

WLT data were pooled from four experimental MDMA studies that compared memory performance during placebo and MDMA intoxication. Control data were taken from healthy volunteers with no drug use history who completed the WLT as part of a placebo-controlled clinical trial. This resulted in a sample size of 65 E-users and 65 age- and gender-matched healthy drug-naïve controls. All participants were recruited by similar means and were tested at the same testing facilities using identical standard operating procedures. Data were analyzed using linear mixed-effects models, Bayes factor, and logistic regressions.

RESULTS:

Findings were that verbal memory performance of placebo-treated E-users did not differ from that of controls, and there was substantial evidence in favor of the null hypothesis. History of use was not predictive of memory impairment. During MDMA intoxication of E-users, verbal memory was impaired.

CONCLUSION:

The combination of the acute and long-term findings demonstrates that, while clinically relevant memory impairment is present during intoxication, it is absent during abstinence. This suggests that use of Ecstasy/MDMA does not lead to clinically deficient memory performance in the long term. Additionally, it has to be investigated whether the current findings apply to more complex cognitive measures in diverse ‘user categories’ using a combination of genetics, imaging techniques and neuropsychological assessments.

Kuypers, K. P., Theunissen, E. L., van Wel, J. H., Perna, E. B. D. S. F., Linssen, A., Sambeth, A., … & Ramaekers, J. G. (2016). Verbal Memory Impairment in Polydrug Ecstasy Users: A Clinical Perspective. PloS one, 11(2), e0149438. http://dx.doi.org/10.1371/journal.pone.0149438

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Effects of 3,4-methylenedioxymethamphetamine on socioemotional feelings, authenticity, and autobiographical disclosure in healthy volunteers in a controlled setting

February 15, 2016 / MDMA, Papers, Psychology, Publications / By / , , , , ,

Abstract

The drug 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”, “molly”) is a widely used illicit drug and experimental adjunct to psychotherapy. MDMA has unusual, poorly understood socioemotional effects, including feelings of interpersonal closeness and sociability. To better understand these effects, we conducted a small (n=12) within-subjects double-blind placebo controlled study of the effects of 1.5 mg/kg oral MDMA on social emotions and autobiographical disclosure in a controlled setting. MDMA displayed both sedative- and stimulant-like effects, including increased self-report anxiety. At the same time, MDMA positively altered evaluation of the self (i.e. increasing feelings of authenticity) while decreasing concerns about negative evaluation by others (i.e. decreasing social anxiety). Consistent with these feelings, MDMA increased how comfortable participants felt describing emotional memories. Overall, MDMA produced a prosocial syndrome that seemed to facilitate emotional disclosure and that appears consistent with the suggestion that it represents a novel pharmacological class.

Baggott, M. J., Coyle, J. R., Siegrist, J. D., Garrison, K. J., Galloway, G. P., & Mendelson, J. E. (2016). Effects of 3, 4-methylenedioxymethamphetamine on socioemotional feelings, authenticity, and autobiographical disclosure in healthy volunteers in a controlled setting. Journal of psychopharmacology (Oxford, England). dx.doi.org/10.1177/0269881115626348

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Effects of MDMA Injections on the Behavior of Socially-Housed Long-Tailed Macaques (Macaca fascicularis)

February 3, 2016 / MDMA, Papers, Psychology, Publications / By / , , ,

Abstract

3,4-methylenedioxy-N-methyl amphetamine (MDMA) is one of the few known molecules to increase human and rodent prosocial behaviors. However, this effect has never been assessed on the social behavior of non-human primates. In our study, we subcutaneously injected three different doses of MDMA (1.0, 1.5 or 2.0mg/kg) to a group of three, socially housed, young male long-tailed macaques. More than 200 hours of behavioral data were recorded, during 68 behavioral sessions, by an automatic color-based video device that tracked the 3D positions of each animal and of a toy. This data was then categorized into 5 exclusive behaviors (resting, locomotion, foraging, social contact and object play). In addition, received and given social grooming was manually scored. Results show several significant dose-dependent behavioral effects. At 1.5mg/kg only, MDMA induces a significant increase in social grooming behavior, thus confirming the prosocial effect of MDMA in macaques. Additionally, at 1.5 and 2.0 mg/kg MDMA injection substantially decreases foraging behavior, which is consistent with the known anorexigenic effect of this compound. Furthermore, at 2.0 mg/kg MDMA injection induces an increase in locomotor behavior, which is also in accordance with its known stimulant property. Interestingly, MDMA injected at 1.0mg/kg increases the rate of object play, which might be interpreted as a decrease of the inhibition to manipulate a unique object in presence of others, or, as an increase of the intrinsic motivation to manipulate this object. Together, our results support the effectiveness of MDMA to study the complex neurobiology of primates’ social behaviors.

Ballesta, S., Reymond, G., Pozzobon, M., & Duhamel, J. R. (2016). Effects of MDMA Injections on the Behavior of Socially-Housed Long-Tailed Macaques (Macaca fascicularis). PloS one, 11(2), e0147136. http://dx.doi.org/10.1371/journal.pone.0147136
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Oxytocin receptor gene variation predicts subjective responses to MDMA

January 20, 2016 / MDMA, Neuroscience, Papers, Psychology, Publications / By / , , , , ,

Abstract

3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) enhances desire to socialize and feelings of empathy, which are thought to be related to increased oxytocin levels. Thus, variation in the oxytocin receptor gene (OXTR) may influence responses to the drug. Here we examined the influence of a single OXTR nucleotide polymorphism (SNP) on responses to MDMA in humans. Based on findings that carriers of the A allele at rs53576 exhibit reduced sensitivity to oxytocin-induced social behavior, we hypothesized that these individuals would show reduced subjective responses to MDMA, including sociability. In this 3-session, double blind, within-subjects study, healthy volunteers with past MDMA experience (N = 68) received a MDMA (0, 0.75 mg/kg and 1.5 mg/kg) and provided self-report ratings of sociability, anxiety, and drug effects. These responses were examined in relation to rs53576. MDMA (1.5 mg/kg) did not increase sociability in individuals with the A/A genotype as it did in G allele carriers. The genotypic groups did not differ in responses at the lower MDMA dose, or in cardiovascular or other subjective responses. These findings are consistent with the idea that MDMA-induced sociability is mediated by oxytocin, and that variation in the oxytocin receptor gene may influence responses to the drug.

Bershad, A. K., Weafer, J. J., Kirkpatrick, M. G., Wardle, M. C., Miller, M. A., & de Wit, H. (2016). Oxytocin receptor gene variation predicts subjective responses to MDMA. Social neuroscience. http://dx.doi.org/10.1080/17470919.2016.1143026

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