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Novel pharmacological targets in drug development for the treatment of anxiety and anxiety-related disorders

August 27, 2019 / Anxiety disorders / PTSD, Ketamine, MDMA, Medicine, Other substances, Papers, Psychopharmacology, Psychotherapy, Publications / By / ,

Abstract

Current medication for anxiety disorders is suboptimal in terms of efficiency and tolerability, highlighting the need for improved drug treatments. In this review an overview of drugs being studied in different phases of clinical trials for their potential in the treatment of fear-, anxiety- and trauma-related disorders is presented. One strategy followed in drug development is refining and improving compounds interacting with existing anxiolytic drug targets, such as serotonergic and prototypical GABAergic benzodiazepines. A more innovative approach involves the search for compounds with novel mechanisms of anxiolytic action using the growing knowledge base concerning the relevant neurocircuitries and neurobiological mechanisms underlying pathological fear and anxiety. The target systems evaluated in clinical trials include glutamate, endocannabinoid and neuropeptide systems, as well as ion channels and targets derived from phytochemicals. Examples of promising novel candidates currently in clinical development for generalised anxiety disorder, social anxiety disorder, panic disorder, obsessive compulsive disorder or post-traumatic stress disorder include ketamine, riluzole, xenon with one common pharmacological action of modulation of glutamatergic neurotransmission, as well as the neurosteroid aloradine. Finally, compounds such as D-cycloserine, MDMA, L-DOPA and cannabinoids have shown efficacy in enhancing fear-extinction learning in humans. They are thus investigated in clinical trials as an augmentative strategy for speeding up and enhancing the long-term effectiveness of exposure-based psychotherapy, which could render chronic anxiolytic drug treatment dispensable for many patients. These efforts are indicative of a rekindled interest and renewed optimism in the anxiety drug discovery field, after decades of relative stagnation.

Sartori, S. B., & Singewald, N. (2019). Novel pharmacological targets in drug development for the treatment of anxiety and anxiety-related disorders. Pharmacology & therapeutics, 107402., 10.1016/j.pharmthera.2019.107402
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Efficacy of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for posttraumatic stress disorder: A systematic review and meta-analysis

February 6, 2022 / Anxiety disorders / PTSD, MDMA, Papers, Psychotherapy / Leave a Comment / By / , , ,

Abstract

Background: Posttraumatic stress disorder (PTSD) is a common psychiatric condition that can develop following a traumatic experience. PTSD is associated with significant disability, a large economic burden, and despite the range of therapies to treat PTSD, response to antidepressants is limited. A growing body of clinical research suggests the efficacy of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in individuals with treatment-refractory PTSD.

Aim: To assess the effectiveness and safety of MDMA-assisted psychotherapy for reducing symptoms of PTSD, a systematic review and meta-analysis was undertaken.

Methods: Six online databases were searched from inception to December 2018. Reference lists of relevant articles were manually searched as well as electronic sources of ongoing trials and conference proceedings. Researchers active in the subject were also contacted. Eligible studies included randomized and quasi-randomized clinical trials using MDMA-assisted psychotherapy for PTSD in comparison with other medications, placebo or no medication (supportive care). We used standard methodological procedures expected by the Cochrane Collaboration. Two authors assessed studies for inclusion and extracted data. Using random-effects meta-analysis with Cochrane’s Review Manager 5.3, we obtained standardized mean differences [SMD] and rate ratios [RR] for reduction in PTSD symptomatology.

Results: A total of 5 trials met inclusion criteria, totaling 106 participants (average age: 35-40 years, 70% female). Studies were rated as moderate in quality. MDMA-assisted psychotherapy demonstrated a high rate of clinical response (RR = 3.47, 95% CI: 1.70, 7.06), remission (RR = 2.63, 95% CI: 1.37, 5.02), with a large effect size at reducing the symptoms of PTSD (SMD = 1.30, 95% CI: 0.66, 1.94). Available evidence indicates that MDMA was well-tolerated, with few serious adverse events reported across studies.

Conclusions: MDMA-assisted psychotherapy appears to be a potentially safe, effective, and durable treatment for individuals with chronic, treatment-refractory PTSD. However, future studies involving larger samples and longer durations of treatment and follow-up are warranted-and underway.

Bahji, A., Forsyth, A., Groll, D., & Hawken, E. R. (2020). Efficacy of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for posttraumatic stress disorder: A systematic review and meta-analysis. Progress in neuro-psychopharmacology & biological psychiatry, 96, 109735. https://doi.org/10.1016/j.pnpbp.2019.109735

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Efficacy of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for posttraumatic stress disorder: A systematic review and meta-analysis.

August 19, 2019 / Anxiety disorders / PTSD, MDMA, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By / , , ,

Abstract

BACKGROUND:
Posttraumatic stress disorder (PTSD) is a common psychiatric condition that can develop following a traumatic experience. PTSD is associated with significant disability, a large economic burden, and despite the range of therapies to treat PTSD, response to antidepressants is limited. A growing body of clinical research suggests the efficacy of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in individuals with treatment-refractory PTSD.
AIM:
To assess the effectiveness and safety of MDMA-assisted psychotherapy for reducing symptoms of PTSD, a systematic review and meta-analysis was undertaken.
METHODS:
Six online databases were searched from inception to December 2018. Reference lists of relevant articles were manually searched as well as electronic sources of ongoing trials and conference proceedings. Researchers active in the subject were also contacted. Eligible studies included randomized and quasi-randomized clinical trials using MDMA-assisted psychotherapy for PTSD in comparison with other medications, placebo or no medication (supportive care). We used standard methodological procedures expected by the Cochrane Collaboration. Two authors assessed studies for inclusion and extracted data. Using random-effects meta-analysis with Cochrane’s Review Manager 5.3, we obtained standardized mean differences [SMD] and rate ratios [RR] for reduction in PTSD symptomatology.
RESULTS:
A total of 5 trials met inclusion criteria, totaling 106 participants (average age: 35-40 years, 70% female). Studies were rated as moderate in quality. MDMA-assisted psychotherapy demonstrated a high rate of clinical response (RR = 3.47, 95% CI: 1.70, 7.06), remission (RR = 2.63, 95% CI: 1.37, 5.02), with a large effect size at reducing the symptoms of PTSD (SMD = 1.30, 95% CI: 0.66, 1.94). Available evidence indicates that MDMA was well-tolerated, with few serious adverse events reported across studies.
CONCLUSIONS:
MDMA-assisted psychotherapy appears to be a potentially safe, effective, and durable treatment for individuals with chronic, treatment-refractory PTSD. However, future studies involving larger samples and longer durations of treatment and follow-up are warranted-and underway.
Bahji, A., Forsyth, A., Groll, D., & Hawken, E. R. (2019). Efficacy of 3, 4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for posttraumatic stress disorder: A systematic review and meta-analysis. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 109735., https://doi.org/10.1016/j.pnpbp.2019.109735
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Emotional breakthrough and psychedelics: Validation of the Emotional Breakthrough Inventory

July 11, 2019 / Ayahuasca, Cacti / Mescaline, DMT, Iboga / Ibogaine, Ketamine, LSD, MDMA, Mushrooms / Psilocybin, Mystical experiences, Papers, Psychiatry, Psychology, Psychopharmacology, Publications, Salvia / Salvinorin A / By

Abstract

Background: Psychedelic therapy is gaining recognition and the nature of the psychedelic experience itself has been found to mediate subsequent long-term psychological changes. Much emphasis has been placed on the occurrence of mystical-type experiences in determining long-term responses to psychedelics yet here we demonstrate the importance of another component, namely: emotional breakthrough.
Methods: Three hundred and seventy-nine participants completed online surveys before and after a planned psychedelic experience. Items pertaining to emotional breakthrough were completed one day after the psychedelic experience, as were items comprising the already validated Mystical Experience Questionnaire and the Challenging Experience Questionnaire. Emotional breakthrough, Mystical Experience Questionnaire and Challenging Experience Questionnaire scores were used to predict changes in well-being (Warwick-Edinburgh Mental Wellbeing Scale) in a subsample of 75 participants with low well-being baseline scores (⩽45).
Results: Factor analyses revealed six emotional breakthrough items with high internal consistency (Cronbach’s alpha=0.932) and supported our prior hypothesis that emotional breakthrough is a distinct component of the psychedelic experience. Emotional breakthrough scores behaved dose-dependently, and were higher if the psychedelic was taken with therapeutic planning and intent. Emotional breakthrough, Mystical Experience Questionnaire and Challenging Experience Questionnaire scores combined, significantly predicted subsequent changes in well-being (r=0.45, p=0.0005, n=75), with each scale contributing significant predictive value. Emotional breakthrough and Mystical Experience Questionnaire scores predicted increases in well-being and Challenging Experience Questionnaire scores predicted less increases.
Conclusions: Here we validate a six-item ‘Emotional Breakthrough Inventory’. Emotional breakthrough is an important and distinct component of the acute psychedelic experience that appears to be a key mediator of subsequent longer-term psychological changes. Implications for psychedelic therapy are discussed.

Keywords: Psychedelics; catharsis; emotion; therapy.
Roseman, L., Haijen, E., Idialu-Ikato, K., Kaelen, M., Watts, R., & Carhart-Harris, R. (2019). Emotional breakthrough and psychedelics: validation of the emotional breakthrough inventory. Journal of Psychopharmacology, 33(9), 1076-1087., https://doi.org/10.1177/0269881119855974
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‘Never drop without your significant other, cause that way lies ruin’: The boundary work of couples who use MDMA together.

June 3, 2019 / MDMA, Other subjects, Papers, Personal development, Phenomenology, Psychology, Psychopharmacology, Publications / By / , ,

Abstract

MDMA has a variety of pro-social effects, such as increased friendliness and heightened empathy, yet there is a distinct lack of research examining how these effects might intertwine with a romantic relationship. This article seeks to compensate for this absence and explore heterosexual couples’ use of MDMA through the lens of the boundaries they construct around these experiences. Three couple interviews, two diary interviews and eight written diaries about couples’ MDMA practices were analysed. Douglas’ (2001) and Stenner’s (2013) work around order, disorder and what lies at the threshold between the two are employed here. This conceptual approach allows us to see what happens at the border of MDMA experiences as crucial to their constitution. Two main themes are identified in the data. First, MDMA use was boundaried from daily life both temporally and corporeally: the drug was tied to particular times in people’s lives as well as the performance of rituals which engaged the material world and reenchanted everyday spaces and selves. Secondly, other people are excluded from MDMA experiences to varying degrees in order to preserve the emotionally intense space for the couple alone. This paper claims that MDMA use forms part of a spectrum of relationship ‘work’ practices; a unique kind of ‘date night’ that revitalises couples’ connection. Hence, MDMA should be recognised as transforming couple as well as individual practices. Finally, it is suggested that harm reduction initiatives could distinguish more ‘messy’ forms of emotional harm and engage with users’ language of ‘specialness’ to limit negative impacts of MDMA use.
Anderson, K., Reavey, P., & Boden, Z. (2019). ‘Never drop without your significant other, cause that way lies ruin’: The boundary work of couples who use MDMA together. International Journal of Drug Policy, 71, 10-18., https://doi.org/10.1016/j.drugpo.2019.05.004
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'Never drop without your significant other, cause that way lies ruin': The boundary work of couples who use MDMA together.

June 3, 2019 / MDMA, Other subjects, Papers, Personal development, Phenomenology, Psychology, Psychopharmacology, Publications / By / , ,

Abstract

MDMA has a variety of pro-social effects, such as increased friendliness and heightened empathy, yet there is a distinct lack of research examining how these effects might intertwine with a romantic relationship. This article seeks to compensate for this absence and explore heterosexual couples’ use of MDMA through the lens of the boundaries they construct around these experiences. Three couple interviews, two diary interviews and eight written diaries about couples’ MDMA practices were analysed. Douglas’ (2001) and Stenner’s (2013) work around order, disorder and what lies at the threshold between the two are employed here. This conceptual approach allows us to see what happens at the border of MDMA experiences as crucial to their constitution. Two main themes are identified in the data. First, MDMA use was boundaried from daily life both temporally and corporeally: the drug was tied to particular times in people’s lives as well as the performance of rituals which engaged the material world and reenchanted everyday spaces and selves. Secondly, other people are excluded from MDMA experiences to varying degrees in order to preserve the emotionally intense space for the couple alone. This paper claims that MDMA use forms part of a spectrum of relationship ‘work’ practices; a unique kind of ‘date night’ that revitalises couples’ connection. Hence, MDMA should be recognised as transforming couple as well as individual practices. Finally, it is suggested that harm reduction initiatives could distinguish more ‘messy’ forms of emotional harm and engage with users’ language of ‘specialness’ to limit negative impacts of MDMA use.
Anderson, K., Reavey, P., & Boden, Z. (2019). ‘Never drop without your significant other, cause that way lies ruin’: The boundary work of couples who use MDMA together. International Journal of Drug Policy, 71, 10-18., https://doi.org/10.1016/j.drugpo.2019.05.004
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Psychedelic drugs-a new era in 
psychiatry?


June 1, 2019 / Anxiety disorders / PTSD, Depression, LSD, MDMA, Mushrooms / Psilocybin, Other disciplines, Papers, Psychology, Psychopharmacology, Psychotherapy, Publications, Substance Use Disorder / By /

Abstract

This article covers the renaissance of classical psychedelic drugs such as psilocybin and LSD plus 3,4-methylene dioxymethamphetamine (MDMA-ecstasy) in psychiatric research. These drugs were used quite extensively before they became prohibited. This ban had little impact on recreational use, but effectively stopped research and clinical treatments, which up to that point had looked very promising in several areas of psychiatry. In the past decade a number of groups have been working to re-evaluate the utility of these substances in medicine. So far highly promising preliminary data have been produced with psilocybin in anxiety, depression, smoking, alcoholism, and with MDMA for post-traumatic stress disorder (PTSD) and alcoholism. These findings have led to the European Medicines Agency approving psilocybin for a phase 3 study in treatment-resistant depression and the Food and Drug Administration for PTSD with MDMA. Both trials should read out in 2020, and if the results are positive we are likely to see these medicines approved for clinical practice soon afterwards.

Nutt, D. (2019). Psychedelic drugs—a new era in psychiatry?. Dialogues in clinical neuroscience, 21(2), 139., https://dx.doi.org/10.31887%2FDCNS.2019.21.2%2Fdnutt
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MDMA-assisted psychotherapy for treatment of PTSD: study design and rationale for phase 3 trials based on pooled analysis of six phase 2 randomized controlled trials.

May 7, 2019 / Anxiety disorders / PTSD, MDMA, Papers, Psychiatry, Psychology, Psychopharmacology, Psychotherapy, Publications / By / , , , , , ,

Abstract

BACKGROUND:
Posttraumatic stress disorder is a prevalent mental health condition with substantial impact on daily functioning that lacks sufficient treatment options. Here we evaluate six phase 2 trials in a pooled analysis to determine the study design for phase 3 trials of MDMA-assisted psychotherapy for PTSD.
METHODS:
Six randomized, double-blind, controlled clinical trials at five study sites were conducted from April 2004 to February 2017. Active doses of MDMA (75-125 mg, n = 72) or placebo/control doses (0-40 mg, n = 31) were administered to individuals with PTSD during manualized psychotherapy sessions in two or three 8-h sessions spaced a month apart. Three non-drug 90-min therapy sessions preceded the first MDMA exposure, and three to four followed each experimental session.
RESULTS:
After two blinded experimental sessions, the active group had significantly greater reductions in CAPS-IV total scores from baseline than the control group [MMRM estimated mean difference (SE) between groups - 22.0 (5.17), P < 0.001]. The between-group Cohen’s d effect size was 0.8, indicating a large treatment effect. After two experimental sessions, more participants in the active group (54.2%) did not meet CAPS-IV PTSD diagnostic criteria than the control group (22.6%). Depression symptom improvement on the BDI-II was greatest for the active group compared to the control group, although only trended towards significant group differences [MMRM, estimated mean difference (SE) between groups - 6.0 (3.03), P = 0.053]. All doses of MDMA were well tolerated, with some expected reactions occurring at greater frequency for the active MDMA group during experimental sessions and the 7 days following.
CONCLUSIONS:
MDMA-assisted psychotherapy was efficacious and well tolerated in a large sample of adults with PTSD. These studies supported expansion into phase 3 trials and led to FDA granting Breakthrough Therapy designation for this promising treatment.
Mithoefer, M. C., Feduccia, A. A., Jerome, L., Mithoefer, A., Wagner, M., Walsh, Z., … & Doblin, R. (2019). MDMA-assisted psychotherapy for treatment of PTSD: study design and rationale for phase 3 trials based on pooled analysis of six phase 2 randomized controlled trials. Psychopharmacology, 1-11., https://doi.org/10.1007/s00213-019-05249-5
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Effects of MDMA on attention to positive social cues and pleasantness of affective touch.

April 30, 2019 / MDMA, Other subjects, Papers, Psychiatry, Psychology, Psychopharmacology, Psychotherapy, Publications / By / , , , , ,

Abstract

The psychostimulant drug ±3,4-methylenedioxymethamphetamine (MDMA) reportedly produces distinctive feelings of empathy and closeness with others. MDMA increases social behavior in animal models and has shown promise in psychiatric disorders, such as autism spectrum disorder (ASD) and post-traumatic stress disorder (PTSD). How it produces these prosocial effects is not known. This behavioral and psychophysiological study examined the effects of MDMA, compared with the prototypical stimulant methamphetamine (MA), on two measures of social behavior in healthy young adults: (i) responses to socially relevant, “affective” touch, and (ii) visual attention to emotional faces. Men and women (N = 36) attended four sessions in which they received MDMA (0.75 or 1.5 mg/kg), MA (20 mg), or a placebo in randomized order under double-blind conditions. Responses to experienced and observed affective touch (i.e., being touched or watching others being touched) were assessed using facial electromyography (EMG), a proxy of affective state. Responses to emotional faces were assessed using electrooculography (EOG) in a measure of attentional bias. Subjective ratings were also included. We hypothesized that MDMA, but not MA, would enhance the ratings of pleasantness and psychophysiological responses to affective touch and increase attentional bias toward positive facial expressions. Consistent with this, we found that MDMA, but not MA, selectively enhanced ratings of pleasantness of experienced affective touch. Neither drug altered the ratings of pleasantness of observed touch. On the EOG measure of attentional bias, MDMA, but not MA, increased attention toward happy faces. These results provide new evidence that MDMA can enhance the experience of positive social interactions; in this case, pleasantness of physical touch and attentional bias toward positive facial expressions. The findings are consistent with evidence that the prosocial effects are unique to MDMA relative to another stimulant. Understanding the behavioral and neurobiological processes underlying the distinctive social effects of MDMA is a key step to developing the drug for psychiatric disorders.
Bershad, A. K., Mayo, L. M., Van Hedger, K., McGlone, F., Walker, S. C., & de Wit, H. (2019). Effects of MDMA on attention to positive social cues and pleasantness of affective touch. Neuropsychopharmacology, 1, https://doi.org/10.1038/s41386-019-0402-z
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