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Psychedelics Promote Structural and Functional Neural Plasticity

June 12, 2018 / Depressive Disorders, LSD, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, 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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Cardiac arrest after ibogaine intoxication

June 12, 2018 / Iboga / Ibogaine, Papers, Psychiatry & Medicine, Publications / By / ,

Abstract

Ibogaine is a psychoactive herbal medication with alleged antiaddiction properties. We report a case of ibogaine intoxication mimicking Long-QT syndrome resulting in ventricular flutter and nearby cardiac arrest. A 61-year-old man experienced massive QT prolongation and ventricular flutter at a rate of 270 beats per minute requiring defibrillation after ingestion of a large dose of Ibogaine. The ingested dose of 65-70 mg/kg represents the highest survived ibogaine dose reported to date. As a result of the long plasma half-life of ibogaine, it took 7 days for the patient’s QT interval to normalize.

Steinberg, C., & Deyell, M. W. (2018). Cardiac arrest after ibogaine intoxication. Journal of arrhythmia, 34(4), 455-457.,  10.1002/joa3.12061

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Dark Classics in Chemical Neuroscience: Mescaline

June 8, 2018 / Biology & Ethnobotany, Humanities & Art, Mescaline / Cacti, Neuroscience, Papers, Psychology, Publications / By / ,

Abstract

Archeological studies in the United States, Mexico, and Peru suggest that mescaline, as a cactus constituent, has been used for more than 6000 years. Although it is a widespread cactus alkaloid, it is present in high concentrations in few species, notably the North American peyote ( Lophophora williamsii) and the South American wachuma ( Trichocereus pachanoi, T. peruvianus, and T. bridgesii). Spanish 16th century chroniclers considered these cacti “diabolic”, leading to their prohibition, but their use persisted to our days and has been spreading for the last 150 years. In the late 1800s, peyote attracted scientific attention; mescaline was isolated, and its role in the psychedelic effects of peyote tops or “mescal buttons” was demonstrated. Its structure was established by synthesis in 1929, and alternative routes were developed, providing larger amounts for pharmacological and biosynthetic research. Although its effects are attributed mainly to its action as a 5-HT2Aserotonin receptor agonist, mescaline binds in a similar concentration range to 5-HT1A and α2A receptors. It is largely excreted unchanged in human urine, and its metabolic products are apparently unrelated to its psychedelic properties. Its low potency is probably responsible for its relative neglect by recreational substance users, as the successful search for structure-activity relationships in the hallucinogen field focused largely on finding more potent analogues. Renewed interest in the possible therapeutic applications of psychedelic drugs may hopefully lead to novel insights regarding the commonalities and differences between the actions of individual classic hallucinogens.
Cassels, B., & Sáez-Briones, P. (2018). Dark Classics in Chemical Neuroscience: Mescaline. ACS chemical neuroscience. 10.1021/acschemneuro.8b00215
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Ibogaine Detoxification Transitions Opioid and Cocaine Abusers Between Dependence and Abstinence: Clinical Observations and Treatment Outcomes

June 5, 2018 / Iboga / Ibogaine, Papers, Psychology, Publications, Substance Use Disorder / By / , , ,

Abstract

Ibogaine may be effective for transitioning opioid and cocaine dependent individuals to sobriety. American and European self-help groups provided public testimonials that ibogaine alleviated drug craving and opioid withdrawal symptoms after only a single dose administration. Preclinical studies in animal models of addiction have provided proof-of-concept evidence in support of these claims. However, the purported therapeutic benefits of ibogaine are based on anecdotal reports from a small series of case reports that used retrospective recruitment procedures. We reviewed clinical results from an open label case series (N = 191) of human volunteers seeking to detoxify from opioids or cocaine with medical monitoring during inpatient treatment. Whole blood was assayed to obtain pharmacokinetic measures to determine the metabolism and clearance of ibogaine. Clinical safety data and adverse events (AEs) were studied in male and female subjects. There were no significant adverse events following administration of ibogaine in a dose range that was shown to be effective for blocking opioid withdrawal symptoms in this study. We used multi-dimensional craving questionnaires during inpatient detoxification to test if ibogaine was effective in diminishing heroin and cocaine cravings. Participants also completed standardized questionnaires about their health and mood before and after ibogaine treatment, and at program discharge. One-month follow-up data were reviewed where available to determine if ibogaine’s effects on drug craving would persist outside of an inpatient setting. We report here that ibogaine therapy administered in a safe dose range diminishes opioid withdrawal symptoms and reduces drug cravings. Pharmacological treatments for opioid dependence include detoxification, narcotic antagonists and long-term opioid maintenance therapy. Our results support product development of single oral dose administration of ibogaine for the treatment of opioid withdrawal during medically supervised detoxification to transition drug dependent individuals to abstinence.
Mash, D. C., Duque, L., Page, B., & Allen-Ferdinand, K. (2018). Ibogaine Detoxification Transitions Opioid and Cocaine Abusers Between Dependence and Abstinence: Clinical Observations and Treatment Outcomes. Frontiers in Pharmacology, 9. 10.3389/fphar.2018.00529
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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, Psychology, Publications / 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, Papers, Psychology, Psychotic Disorders, 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, Psychology, Publications / 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, Psychology, Publications / 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, Psychology, 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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Psilocybin and MDMA reduce costly punishment in the Ultimatum Game

May 29, 2018 / MDMA, Mushrooms / Psilocybin, Papers, Psychology, Publications / By / , , , , , ,

Abstract

Disruptions in social decision-making are becoming evident in many psychiatric conditions. These are studied using paradigms investigating the psychological mechanisms underlying interpersonal interactions, such as the Ultimatum Game (UG). Rejection behaviour in the UG represents altruistic punishment – the costly punishment of norm violators – but the mechanisms underlying it require clarification. To investigate the psychopharmacology of UG behaviour, we carried out two studies with healthy participants, employing serotonergic agonists: psilocybin (open-label, within-participant design, N = 19) and 3,4-methylenedioxymethamphetamine (MDMA; placebo-controlled, double-blind, crossover design, N = 20). We found that both MDMA and psilocybin reduced rejection of unfair offers (odds ratio: 0.57 and 0.42, respectively). The reduction in rejection rate following MDMA was associated with increased prosociality (R2 = 0.26, p = 0.025). In the MDMA study, we investigated third-party decision-making and proposer behaviour. MDMA did not reduce rejection in the third-party condition, but produced an increase in the amount offered to others (Cohen’s d = 0.82). We argue that these compounds altered participants’ conceptualisation of ‘social reward’, placing more emphasis on the direct relationship with interacting partners. With these compounds showing efficacy in drug-assisted psychotherapy, these studies are an important step in the further characterisation of their psychological effects.
Gabay, A. S., Carhart-Harris, R. L., Mazibuko, N., Kempton, M. J., Morrison, P. D., Nutt, D. J., & Mehta, M. A. (2018). Psilocybin and MDMA reduce costly punishment in the Ultimatum Game. Scientific reports, 8(1), 8236. 10.1038/s41598-018-26656-2
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