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Psychiatry

Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial

June 15, 2018 / Ayahuasca, Depression, Papers, Psychiatry, Psychology, Psychotherapy, Publications / By / , , , , , ,

Abstract

BACKGROUND:
Recent open-label trials show that psychedelics, such as ayahuasca, hold promise as fast-onset antidepressants in treatment-resistant depression.
METHODS:
To test the antidepressant effects of ayahuasca, we conducted a parallel-arm, double-blind randomized placebo-controlled trial in 29 patients with treatment-resistant depression. Patients received a single dose of either ayahuasca or placebo. We assessed changes in depression severity with the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating scale at baseline, and at 1 (D1), 2 (D2), and 7 (D7) days after dosing.
RESULTS:
We observed significant antidepressant effects of ayahuasca when compared with placebo at all-time points. MADRS scores were significantly lower in the ayahuasca group compared with placebo at D1 and D2 (p = 0.04), and at D7 (p < 0.0001). Between-group effect sizes increased from D1 to D7 (D1: Cohen’s d = 0.84; D2: Cohen’s d = 0.84; D7: Cohen’s d = 1.49). Response rates were high for both groups at D1 and D2, and significantly higher in the ayahuasca group at D7 (64% v. 27%; p = 0.04). Remission rate showed a trend toward significance at D7 (36% v. 7%, p = 0.054).
CONCLUSIONS:
To our knowledge, this is the first controlled trial to test a psychedelic substance in treatment-resistant depression. Overall, this study brings new evidence supporting the safety and therapeutic value of ayahuasca, dosed within an appropriate setting, to help treat depression.

Palhano-Fontes, F., Barreto, D., Onias, H., Andrade, K. C., Novaes, M. M., Pessoa, J. A., … & Tófoli, L. F. (2018). Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial. Psychological medicine, 1-9. 10.1017/S0033291718001356
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Psychedelics Promote Structural and Functional Neural Plasticity

June 12, 2018 / Depression, LSD, Mushrooms / Psilocybin, Neuroscience, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By / , , , , , ,

Abstract

Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse number and function, as measured by fluorescence microscopy and electrophysiology. The structural changes induced by psychedelics appear to result from stimulation of the TrkB, mTOR, and 5-HT2A signaling pathways and could possibly explain the clinical effectiveness of these compounds. Our results underscore the therapeutic potential of psychedelics and, importantly, identify several lead scaffolds for medicinal chemistry efforts focused on developing plasticity-promoting compounds as safe, effective, and fast-acting treatments for depression and related disorders.
Ly, C., Greb, A. C., Cameron, L. P., Wong, J. M., Barragan, E. V., Wilson, P. C., … & Duim, W. C. (2018). Psychedelics Promote Structural and Functional Neural Plasticity. Cell reports, 23(11), 3170-3182. 10.1016/j.celrep.2018.05.022
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The abuse potential of medical psilocybin according to the 8 factors of the Controlled Substances Act

June 5, 2018 / Mushrooms / Psilocybin, Papers, Psychiatry, Psychology, Psychotherapy, Publications, Safety / By / , , ,

Abstract

This review assesses the abuse potential of medically-administered psilocybin, following the structure of the 8 factors of the US Controlled Substances Act (CSA). Research suggests the potential safety and efficacy of psilocybin in treating cancer-related psychiatric distress and substance use disorders, setting the occasion for this review. A more extensive assessment of abuse potential according to an 8-factor analysis would eventually be required to guide appropriate schedule placement.

Psilocybin, like other 5-HT2A agonist classic psychedelics, has limited reinforcing effects, supporting marginal, transient non-human self-administration. Nonetheless, mushrooms with variable psilocybin content are used illicitly, with a few lifetime use occasions being normative among users. Potential harms include dangerous behavior in unprepared, unsupervised users, and exacerbation of mental illness in those with or predisposed to psychotic disorders. However, scope of use and associated harms are low compared to prototypical abused drugs, and the medical model addresses these concerns with dose control, patient screening, preparation and follow-up, and session supervision in a medical facility.

Conclusions

(1) psilocybin has an abuse potential appropriate for CSA scheduling if approved as medicine; (2) psilocybin can provide therapeutic benefits that may support the development of an approvable New Drug Application (NDA) but further studies are required which this review describes; (3) adverse effects of medical psilocybin are manageable when administered according to risk management approaches; and (4) although further study is required, this review suggests that placement in Schedule IV may be appropriate if a psilocybin-containing medicine is approved.

Johnson, M. W., Griffiths, R. R., Hendricks, P. S., & Henningfield, J. E. (2018). The abuse potential of medical psilocybin according to the 8 factors of the Controlled Substances Act. Neuropharmacology. 10.1016/j.neuropharm.2018.05.012
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Pharmacological fMRI: Effects of subanesthetic ketamine on resting-state functional connectivity in the default mode network, salience network, dorsal attention network and executive control network.

June 1, 2018 / Ketamine, Neuroscience, Other subjects, Papers, Psychiatry, Psychology, Psychopharmacology, Psychosis, Publications / By / , , , , ,

Abstract

BACKGROUND:
Subanesthetic dosages of the NMDAR antagonist, S-Ketamine, can cause changes in behavior in healthy subjects, which are similar to the state acute psychosis and are relevant in translational schizophrenia research. Functional magnetic resonance imaging (fMRI) can be used for non-hypothesis-driven analysis of brain connectivity. The correlation between clinical behavioral scores and neuroimaging can help to characterize ketamine effects on healthy brains in resting state.
METHOD:
seventeen healthy, male subjects (mean: 27.42 years, SD: 4.42) were administered an infusion with S-Ketamine (initial bolus 1 mg/kg and continuous infusion of 0.015625 mg/kg/min with dosage reduction -10%/10 min) or saline in a randomized, double-blind, cross-over study. During infusion, resting state connectivity was measured and analyzed with a seed-to-voxel fMRI analysis approach. The seed regions were located in the posterior cingulate cortex, intraparietal sulcus, dorsolateral prefrontal cortex and fronto-insular cortex. Receiver operating characteristics (ROC) were calculated to assess the accuracy of the ketamine-induced functional connectivity changes. Bivariate Pearson correlation was used for correlation testing of functional connectivity changes with changes of clinical scores (PANSS, 5D-ASC).
RESULTS:
In the executive network (ECN), ketamine significantly increases the functional connectivity with parts of the anterior cingulum and superior frontal gyrus, but no significant correlations with clinical symptoms were found. Decreased connectivity between the salience network (SN) and the calcarine fissure was found, which is significantly correlated with negative symptoms (PANSS) (R2 > 0.4).
CONCLUSION:
Decreased ketamine-induced functional connectivity in the salience network may qualify as accurate and highly predictive biomarkers for ketamine induced negative symptoms.
Mueller, F., Musso, F., London, M., de Boer, P., Zacharias, N., & Winterer, G. (2018). Pharmacological fMRI: Effects of subanesthetic ketamine on resting-state functional connectivity in the default mode network, salience network, dorsal attention network and executive control network. NeuroImage: Clinical., 10.1016/j.nicl.2018.05.037
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A Survey of American Psychiatrists’ Attitudes Toward Classic Hallucinogens

June 1, 2018 / LSD, MDMA, Mushrooms / Psilocybin, Papers, Psychiatry, Psychology, Psychotherapy, Publications, Safety, Sociology / By / , ,

Abstract

Recent years have seen renewed interest and research about the use of hallucinogens as possible agents in the treatment of psychiatric disorders. However, we are unaware of studies assessing the current attitudes of American psychiatrists regarding hallucinogens. Therefore, we e-mailed surveys to 1000 members of the American Psychiatric Association-250 resident-fellows and 750 attending psychiatrists. The response rate was 32.4%. Respondents tended to perceive hallucinogens as potentially hazardous and appropriately illegal for recreational purposes. However, a large minority expressed optimism about the potential use of hallucinogens for psychiatric treatment. Male and trainee respondents, as compared with female and attending respondents, reported less concern about the risks of hallucinogens and greater optimism about their therapeutic potential. Younger psychiatrists also seemed more optimistic. Optimism among trainees and younger psychiatrists may possibly reflect greater exposure to recent positive publications about hallucinogens and less awareness of more negative past reports.
Barnett, B. S., Siu, W. O., & Pope Jr, H. G. (2018). A Survey of American Psychiatrists’ Attitudes Toward Classic Hallucinogens. The Journal of nervous and mental disease, 206(6), 476-480. 10.1097/NMD.0000000000000828
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A Survey of American Psychiatrists' Attitudes Toward Classic Hallucinogens

June 1, 2018 / LSD, MDMA, Mushrooms / Psilocybin, Papers, Psychiatry, Psychology, Psychotherapy, Publications, Safety, Sociology / By / , ,

Abstract

Recent years have seen renewed interest and research about the use of hallucinogens as possible agents in the treatment of psychiatric disorders. However, we are unaware of studies assessing the current attitudes of American psychiatrists regarding hallucinogens. Therefore, we e-mailed surveys to 1000 members of the American Psychiatric Association-250 resident-fellows and 750 attending psychiatrists. The response rate was 32.4%. Respondents tended to perceive hallucinogens as potentially hazardous and appropriately illegal for recreational purposes. However, a large minority expressed optimism about the potential use of hallucinogens for psychiatric treatment. Male and trainee respondents, as compared with female and attending respondents, reported less concern about the risks of hallucinogens and greater optimism about their therapeutic potential. Younger psychiatrists also seemed more optimistic. Optimism among trainees and younger psychiatrists may possibly reflect greater exposure to recent positive publications about hallucinogens and less awareness of more negative past reports.
Barnett, B. S., Siu, W. O., & Pope Jr, H. G. (2018). A Survey of American Psychiatrists’ Attitudes Toward Classic Hallucinogens. The Journal of nervous and mental disease, 206(6), 476-480. 10.1097/NMD.0000000000000828
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Psychedelic therapy as a complementary treatment approach for alcohol use disorders

May 30, 2018 / LSD, Mushrooms / Psilocybin, Papers, Psychiatry, Psychology, Psychotherapy, Publications, Substance Use Disorder / By / ,

Abstract

Background

Traditional treatment interventions for alcohol use disorders (AUD) have produced mixed outcomes and the global increase in AUDs demands novel and innovative approaches to addiction treatment. Psychedelic substances have been reintroduced into the Western medical community as a potential intervention to complement the treatment of AUDs.

Objectives

This paper will discuss the implications of using psychedelic substances as a complementary approach within the treatment of AUDs.

Methods

A thorough review of pertinent research focused on the use of psychedelics in relation to the affective, cognitive, social, legal, and spiritual issues commonly associated with AUDs.

Results

Research suggests the clinical efficacy and safety of psychedelic therapy as a complementary treatment for AUDs.

Conclusion

Future directions and implications to AUD treatment are provided.

Eischens, P., & Atherton, W. L. (2018). Psychedelic therapy as a complementary treatment approach for alcohol use disorders. Journal of Psychedelic Studies, 1-9. 10.1556/2054.2018.005
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Biocatalytic production of psilocybin and derivatives in tryptophan synthase-enhanced reactions

May 11, 2018 / Mushrooms / Psilocybin, Neuroscience, Papers, Psychiatry, Psychopharmacology, Psychotherapy, Publications / By / , , ,

Abstract

Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) is the main alkaloid of the fungal genus Psilocybe, the so-called “magic mushrooms.” The pharmaceutical interest in this psychotropic natural product as a future medication to treat depression and anxiety is strongly re-emerging. Here, we present an enhanced enzymatic route of psilocybin production by adding TrpB, the tryptophan synthase of the mushroom Psilocybe cubensis, to the reaction. We capitalized on its substrate flexibility and show psilocybin formation from 4-hydroxyindole and l-serine, which are less cost-intensive substrates, compared to the previous method. Furthermore, we show enzymatic production of 7-phosphoryloxytryptamine (isonorbaeocystin), a non-natural congener of the Psilocybe alkaloid norbaeocystin (4-phosphoryloxytryptamine), and of serotonin (5-hydroxytryptamine) by means of the same in vitro approach.

Blei, F., Baldeweg, F., Fricke, J., & Hoffmeister, D. (2018). Biocatalytic Production of Psilocybin and Derivatives in Tryptophan Synthase‐Enhanced Reactions. Chemistry–A European Journal, 24(40), 10028-10031., 10.1002/chem.201801047.
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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, Psychiatry, Psychology, Psychopharmacology, 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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