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Anxiety Disorders / PTSD

3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomised, double-blind, dose-response, phase 2 clinical trial.

May 1, 2018 / Anxiety Disorders / PTSD, MDMA, Papers, Psychology, Publications / By / , , , , ,

Abstract

BACKGROUND:
Post-traumatic stress disorder (PTSD) is prevalent in military personnel and first responders, many of whom do not respond to currently available treatments. This study aimed to assess the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for treating chronic PTSD in this population.
METHODS:
We did a randomised, double-blind, dose-response, phase 2 trial at an outpatient psychiatric clinic in the USA. We included service personnel who were 18 years or older, with chronic PTSD duration of 6 months or more, and who had a Clinician-Administered PTSD Scale (CAPS-IV) total score of 50 or greater. Using a web-based randomisation system, we randomly assigned participants (1:1:2) to three different dose groups of MDMA plus psychotherapy: 30 mg (active control), 75 mg, or 125 mg. We masked investigators, independent outcome raters, and participants until after the primary endpoint. MDMA was administered orally in two 8-h sessions with concomitant manualised psychotherapy. The primary outcome was mean change in CAPS-IV total score from baseline to 1 month after the second experimental session. Participants in the 30 mg and 75 mg groups subsequently underwent three 100-125 mg MDMA-assisted psychotherapy sessions in an open-label crossover, and all participants were assessed 12 months after the last MDMA session. Safety was monitored through adverse events, spontaneously reported expected reactions, vital signs, and suicidal ideation and behaviour. This study is registered with ClinicalTrials.gov, number NCT01211405.
FINDINGS:
Between Nov 10, 2010, and Jan 29, 2015, 26 veterans and first responders met eligibility criteria and were randomly assigned to receive 30 mg (n=7), 75 mg (n=7), or 125 mg (n=12) of MDMA plus psychotherapy. At the primary endpoint, the 75 mg and 125 mg groups had significantly greater decreases in PTSD symptom severity (mean change CAPS-IV total scores of -58·3 [SD 9·8] and -44·3 [28·7]; p=0·001) than the 30 mg group (-11·4 [12·7]). Compared with the 30 mg group, Cohen’s d effect sizes were large: 2·8 (95% CI 1·19-4·39) for the 75 mg group and 1·1 (0·04-2·08) for the 125 mg group. In the open-label crossover with full-dose MDMA (100-125 mg), PTSD symptom severity significantly decreased in the group that had previously received 30 mg (p=0·01), whereas no further significant decreases were observed in the group that previously achieved a large response after 75 mg doses in the blinded segment (p=0·81). PTSD symptoms were significantly reduced at the 12-month follow-up compared with baseline after all groups had full-dose MDMA (mean CAPS-IV total score of 38·8 [SD 28·1] vs 87·1 [16·1]; p<0·0001). 85 adverse events were reported by 20 participants. Of these adverse events, four (5%) were serious: three were deemed unrelated and one possibly related to study drug treatment.
INTERPRETATION:
Active doses (75 mg and 125 mg) of MDMA with adjunctive psychotherapy in a controlled setting were effective and well tolerated in reducing PTSD symptoms in veterans and first responders.
FUNDING:
Multidisciplinary Association for Psychedelic Studies.
Mithoefer, M. C., Mithoefer, A. T., Feduccia, A. A., Jerome, L., Wagner, M., Wymer, J., … & Doblin, R. (2018). 3, 4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomised, double-blind, dose-response, phase 2 clinical trial. The Lancet Psychiatry, 5(6), 486-497, 10.1016/S2215-0366(18)30135-4
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Effects of N, N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression

April 24, 2018 / Anxiety Disorders / PTSD, Ayahuasca, Depressive Disorders, DMT, Papers, Psychology, Publications / By / , , ,

Abstract

Depression and anxiety disorders are debilitating diseases resulting in substantial economic costs to society. Traditional antidepressants often take weeks to months to positively affect mood and are ineffective for about 30% of the population. Alternatives, such as ketamine, a dissociative anesthetic capable of producing hallucinations, and the psychoactive tisane ayahuasca, have shown great promise due to their fast-acting nature and effectiveness in treatment-resistant populations. Here, we investigate the effects of N, N-dimethyltryptamine (DMT), the principle hallucinogenic component of ayahuasca, in rodent behavioral assays relevant to anxiety and depression using adult, male, Sprague-Dawley rats. We find that while DMT elicits initial anxiogenic responses in several of these paradigms, its long-lasting effects tend to reduce anxiety by facilitating the extinction of cued fear memory. Furthermore, DMT reduces immobility in the forced swim test, which is a characteristic behavioral response induced by many antidepressants. Our results demonstrate that DMT produces antidepressant and anxiolytic behavioral effects in rodents, warranting further investigation of ayahuasca and classical psychedelics as treatments for depression and post-traumatic stress disorder.
Cameron, L. P., Benson, C. J., Dunlap, L. E., & Olson, D. E. (2018). Effects of N, N-dimethyltryptamine on rat behaviors relevant to anxiety and depression. ACS chemical neuroscience. 10.1021/acschemneuro.8b00134
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Hypothesis: The Psychedelic Ayahuasca Heals Traumatic Memories via a Sigma 1 Receptor-Mediated Epigenetic-Mnemonic Process

April 5, 2018 / Anxiety Disorders / PTSD, Ayahuasca, DMT, Neuroscience, Papers, Psychology, Publications / By /

Abstract

Ayahuasca ingestion modulates brain activity, neurotransmission, gene expression and epigenetic regulation. N,N-Dimethyltryptamine (DMT, one of the alkaloids in Ayahuasca) activates sigma 1 receptor (SIGMAR1) and others. SIGMAR1 is a multi-faceted stress-responsive receptor which promotes cell survival, neuroprotection, neuroplasticity, and neuroimmunomodulation. Simultaneously, monoamine oxidase inhibitors (MAOIs) also present in Ayahuasca prevent the degradation of DMT. One peculiarity of SIGMAR1 activation and MAOI activity is the reversal of mnemonic deficits in pre-clinical models. Since traumatic memories in post-traumatic stress disorder (PTSD) are often characterised by “repression” and PTSD patients ingesting Ayahuasca report the retrieval of such memories, it cannot be excluded that DMT-mediated SIGMAR1 activation and the concomitant MAOIs effects during Ayahuasca ingestion might mediate such “anti-amnesic” process. Here I hypothesise that Ayahuasca, via hyperactivation of trauma and emotional memory-related centres, and via its concomitant SIGMAR1- and MAOIs- induced anti-amnesic effects, facilitates the retrieval of traumatic memories, in turn making them labile (destabilised). As Ayahuasca alkaloids enhance synaptic plasticity, increase neurogenesis and boost dopaminergic neurotransmission, and those processes are involved in memory reconsolidation and fear extinction, the fear response triggered by the memory can be reprogramed and/or extinguished. Subsequently, the memory is stored with this updated significance. To date, it is unclear if new memories replace, co-exist with or bypass old ones. Although the mechanisms involved in memory are still debated, they seem to require the involvement of cellular and molecular events, such as reorganisation of homo and heteroreceptor complexes at the synapse, synaptic plasticity, and epigenetic re-modulation of gene expression. Since SIGMAR1 mobilises synaptic receptor, boosts synaptic plasticity and modulates epigenetic processes, such effects might be involved in the reported healing of traumatic memories in PTSD patients. If this theory proves to be true, Ayahuasca could come to represent the only standing pharmacological treatment which targets traumatic memories in PTSD. Lastly, since SIGMAR1 activation triggers both epigenetic and immunomodulatory programmes, the mechanism here presented could help understanding and treating other conditions in which the cellular memory is dysregulated, such as cancer, diabetes, autoimmune and neurodegenerative pathologies and substance addiction.
Inserra, A. (2018). Hypothesis: The Psychedelic Ayahuasca Heals Traumatic Memories via a Sigma 1 Receptor-Mediated Epigenetic-Mnemonic Process. Frontiers in pharmacology, 9, 330. 10.3389/fphar.2018.00330
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Individual Experiences in Four Cancer Patients Following Psilocybin-Assisted Psychotherapy.

April 3, 2018 / Anxiety Disorders / PTSD, Depressive Disorders, Mushrooms / Psilocybin, Papers, Psychology, Publications / By / , , , , , ,

Abstract

A growing body of evidence shows that existential and spiritual well-being in cancer patients is associated with better medical outcomes, improved quality of life, and serves as a buffer against depression, hopelessness, and desire for hastened death. Historical and recent research suggests a role for psilocybin-assisted psychotherapy in treating cancer-related anxiety and depression. A double-blind controlled trial was performed, where 29 patients with cancer-related anxiety and depression were randomly assigned to treatment with single-dose psilocybin (0.3 mg/kg) or niacin in conjunction with psychotherapy. Previously published results of this trial demonstrated that, in conjunction with psychotherapy, moderate-dose psilocybin produced rapid, robust, and enduring anxiolytic, and anti-depressant effects. Here, we illustrate unique clinical courses described by four participants using quantitative measures of acute and persisting effects of psilocybin, anxiety, depression, quality of life, and spiritual well-being, as well as qualitative interviews, written narratives, and clinician notes. Although the content of each psilocybin-assisted experience was unique to each participant, several thematic similarities and differences across the various sessions stood out. These four participants’ personal narratives extended beyond the cancer diagnosis itself, frequently revolving around themes of self-compassion and love, acceptance of death, and memories of past trauma, though the specific details or narrative content differ substantially. The results presented here demonstrate the personalized nature of the subjective experiences elicited through treatment with psilocybin, particularly with respect to the spiritual and/or psychological needs of each patient.
Malone, T. C., Mennenga, S. E., Guss, J., Podrebarac, S. K., Owens, L. T., Bossis, A. P., … & Ross, S. (2018). Individual Experiences in Four Cancer Patients Following Psilocybin-Assisted Psychotherapy. Frontiers in pharmacology, 9, 256, 10.3389/fphar.2018.00256
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Out of the box: A psychedelic model to study the creative mind

March 23, 2018 / Anxiety Disorders / PTSD, Depressive Disorders, Mushrooms / Psilocybin, Neuroscience, Papers, Psychiatry & Medicine, Publications / By /

Abstract

Our creativity is challenged daily when facing new situations asking for novel solutions. Creativity, a multicomponent construct includes flexible divergent and rigid convergent thinking. Psychedelic drugs like psilocybin can enhance creativity and affect state of mind (mood, empathy, openness). Of note, flexible thinking is disturbed in psychopathological conditions like anxiety disorders and depression and preliminary findings have shown psychedelics to be efficacious in the treatment of those conditions. The question how psychedelics induce this state of enhanced flexible thinking remains to be answered and investigating the neurobiology underlying this phenomenon will not only help in understanding why psychedelics are of use in the therapeutic setting but also in other settings where flexible thinking is challenged. A model including neuronal networks, neurotransmitters and personal factors playing a role in this process will be proposed which can be put to the test by means of placebo-controlled pharmaco-imaging studies in healthy volunteers.

Kuypers, K. P. C. (2018). Out of the box: A psychedelic model to study the creative mind. Medical hypotheses, 115, 13-16.,  10.1016/j.mehy.2018.03.010

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Psilocin and ketamine microdosing: effects of subchronic intermittent microdoses in the elevated plus-maze in male Wistar rats

March 13, 2018 / Anxiety Disorders / PTSD, Ketamine, Mushrooms / Psilocybin, Papers, Psychology, Publications / By / , , ,

Abstract

Short-term moderate doses of serotonergic and dissociative hallucinogens can be useful in the treatment of anxiety. Recently, a trend has developed for long-term intermittent ‘microdosing’ (usually one-tenth of a ‘full’ active dose), with reports of long-lasting relief from anxiety and related disorders; however, there is no scientific evidence for the efficacy of therapeutic microdosing nor to show its lasting effects. The objective of this study was to test for lasting effects on anxiety in rats after microdosing with ketamine or psilocin. Over 6 days, Wistar rats (N=40) were administered ketamine (0.5 or 3 mg/kg), psilocin (0.05 or 0.075 mg/kg), or saline on three occasions. A 5-min elevated plus-maze test was conducted 48 h after the final drug treatment (n=8). Dependent variables were entries (frequency), spent time (%), and distance traveled (cm) in each zone, as well as total frequency of rears, stretch-attend postures, and head dips. Statistical analyses of drug effects used separate independent one-way analysis of variance and pair-wise comparisons using independent t-tests. Statistical effects were modest or borderline and were most consistent with a mildly anxiogenic profile, which was significant at lower doses; however, this conclusion remains tentative. The lower doses of ketamine and psilocin produced comparable effects (to one another) across each variable, as did the higher doses. This pattern of effects may suggest a common (e.g. neurotransmitter/receptor) mechanism. We conclude that microdosing with hallucinogens for therapeutic purposes might be counter-productive; however, more research is needed to confirm our findings and to establish their translational relevance to clinical ‘psychedelic’ therapy.
Horsley, R. R., Páleníček, T., Kolin, J., & Valeš, K. (2018). Psilocin and ketamine microdosing: effects of subchronic intermittent microdoses in the elevated plus-maze in male Wistar rats. Behavioural pharmacology. 10.1097/FBP.0000000000000394
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MDMA-assisted psychotherapy for PTSD: Are memory reconsolidation and fear extinction underlying mechanisms?

March 7, 2018 / Anxiety Disorders / PTSD, MDMA, Neuroscience, Papers, Psychology, Publications / By / ,

Abstract

MDMA-assisted psychotherapy for treatment of PTSD has recently progressed to Phase 3 clinical trials and received Breakthrough Therapy designation by the FDA. MDMA used as an adjunct during psychotherapy sessions has demonstrated effectiveness and acceptable safety in reducing PTSD symptoms in Phase 2 trials, with durable remission of PTSD diagnosis in 68% of participants. The underlying psychological and neurological mechanisms for the robust effects in mitigating PTSD are being investigated in animal models and in studies of healthy volunteers. This review explores the potential role of memory reconsolidation and fear extinction during MDMA-assisted psychotherapy. MDMA enhances release of monoamines (serotonin, norepinephrine, dopamine), hormones (oxytocin, cortisol), and other downstream signaling molecules (BDNF) to dynamically modulate emotional memory circuits. By reducing activation in brain regions implicated in the expression of fear- and anxiety-related behaviors, namely the amygdala and insula, and increasing connectivity between the amygdala and hippocampus, MDMA may allow for reprocessing of traumatic memories and emotional engagement with therapeutic processes. Based on the pharmacology of MDMA and the available translational literature of memory reconsolidation, fear learning, and PTSD, this review suggests a neurobiological rationale to explain, at least in part, the large effect sizes demonstrated for MDMA in treating PTSD.

Feduccia, A. A., & Mithoefer, M. C. (2018). MDMA-assisted psychotherapy for PTSD: Are memory reconsolidation and fear extinction underlying mechanisms?. Progress in neuro-psychopharmacology and biological psychiatry. 10.1016/j.pnpbp.2018.03.003
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The re-emergence of hallucinogenic research

February 20, 2018 / Anxiety Disorders / PTSD, MDMA, Papers, Psychology, Publications / By / ,

Abstract

Due to the intractability, at times, in the treatment of PTSD, clinicians and researchers continue to explore different options for treatment. This article discusses the renewed interest in hallucinogens for such treatment.
Begola, M. J., & Dowben, J. S. (2018). The re‐emergence of hallucinogenic research. Perspectives in psychiatric care. 10.1111/ppc.12263
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The re-emergence of hallucinogenic research

February 20, 2018 / Anxiety Disorders / PTSD, LSD, Mushrooms / Psilocybin, Papers, Psychology, Publications / By / ,

Abstract

Due to the intractability, at times, in the treatment of PTSD, clinicians and researchers continue to explore different options for treatment. This article discusses the renewed interest in hallucinogens for such treatment.
Begola, M. J., & Dowben, J. S. (2018). The re‐emergence of hallucinogenic research. Perspectives in psychiatric care. 10.1111/ppc.12263
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Psychedelics and related drugs: therapeutic possibilities, mechanisms and regulation

February 14, 2018 / Anxiety Disorders / PTSD, Depressive Disorders, Ketamine, LSD, MDMA, Mushrooms / Psilocybin, Papers, Psychology, Publications, Substance Use Disorder / By / , ,

Abstract

The word “psychedelic” derives from the Greek terms for mind—psyche—and “delos” which means “clear, manifest,” so in essence, psychedelic drugs can be seen as the prototype “window on the mind” concept. The term was originally coined in the 1950s to describe lysergic acid diethylamide (LSD), mescaline, and other hallucinogens, drugs that profoundly alter human experience. These have subsequently been shown to act primarily as agonists at the 5-HT2Areceptor in the brain. Research into the therapeutic potential and mechanisms of action of psychedelic and related drugs peaked in the late 1960s but then stagnated for 50 years after the 1971 UN Psychotropics Convention made psychedelic research with humans almost impossible to carry out (Kyzar et al. 2017).

Recently, however, this area is experiencing a renaissance as drugs often associated with recreational use—such as LSD, ketamine, and cannabis/cannabinoids—have been shown to have therapeutic potential in a range of disorders such as treatment-resistant depression, suicidal ideation, and some pediatric epilepsies. Further, recent pilot studies suggest that MDMA as well as the classic psychedelics, LSD, and psilocybin may contribute to the pharmacopeia for post-traumatic stress disorder (PTSD) and other difficult-to-treat psychiatric disorders. Research has also been stimulated by functional neuroimaging studies of single doses of psychedelics showing that they produce widespread changes in brain connectivity as well as profound alterations to perception and cognition. At the same time, as one would expect from a relatively fledgling area, many questions remain about mechanisms of action, safety, and efficacy. These include what type of psychological therapies best combine with which type of psychedelic drug, whether some types of drug have benefits even without psychological treatment, what the optimal doses are, from single dose through to intermittent or repeated dosing. The current renaissance in empirical psychedelic research stimulated this Special Issue of Psychopharmacology. The articles are grouped into three sections: Clinical efficacy and clinical issues; Effects and Mechanisms of action; Regulation and history.

Curran, H. V., Nutt, D., & de Wit, H. (2018). Psychedelics and related drugs: therapeutic possibilities, mechanisms and regulation. 10.1007/s00213-017-4822-3
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