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Psychiatry

Ketamine accelerates fear extinction via mTORC1 signaling

December 30, 2016 / Anxiety disorders / PTSD, Ketamine, Neuroscience, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By / , , , ,

Abstract

Impaired fear extinction contributes to the persistence of post-traumatic stress disorder (PTSD), and can be utilized for the study of novel therapeutic agents. Glutamate plays an important role in the formation of traumatic memories, and in the pathophysiology and treatment of PTSD, highlighting several possible drug targets. Recent clinical studies demonstrate that infusion of ketamine, a glutamate NMDA receptor antagonist, rapidly and significantly reduces symptom severity in PTSD patients. In the present study, we examine the mechanisms underlying the actions of ketamine in a rodent model of fear conditioning, extinction, and renewal. Rats received ketamine or saline 24 h after fear conditioning and were then subjected to extinction-training on each of the following three days. Ketamine administration enhanced extinction on the second day of training (i.e., reduced freezing behavior to cue) and produced a long-lasting reduction in freezing on exposure to cue plus context 8 days later. Additionally, ketamine and extinction exposure increased levels of mTORC1 in the medial prefrontal cortex (mPFC), a region involved in the acquisition and retrieval of extinction, and infusion of the selective mTORC1 inhibitor rapamycin into the mPFC blocked the effects of ketamine on extinction. Ketamine plus extinction also increased cFos in the mPFC and administration of a glutamate-AMPA receptor antagonist blocked the effects of ketamine. These results support the hypothesis that ketamine produces long-lasting mTORC1/protein synthesis and activity dependent effects on neuronal circuits that enhance the expression of extinction and could represent a novel approach for the treatment of PTSD.

Girgenti, M. J., Ghosal, S., LoPresto, D., Taylor, J. R., & Duman, R. S. (2017). Ketamine accelerates fear extinction via mTORC1 signaling. Neurobiology of Disease, 100, 1-8. 10.1016/j.nbd.2016.12.026
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Can 3,4,-methylenedioxymethamphetamine therapy be used to treat alcohol use disorder?

December 30, 2016 / MDMA, Papers, Psychiatry, Psychology, Psychotherapy, Publications, Substance Use Disorder / By /

Abstract

Treating people with alcohol use disorder has been an important target area for psychedelic research – both in the first studies of the 1950s and during the Psychedelic Renaissance of the last 10 years. To date, most studies have looked at the classical psychedelic drugs as adjuncts to psychotherapy; with attention paid to the psychospiritual aspect of the experience as a central therapeutic process in effecting abstinence from drinking. Psychotherapy assisted with 3,4,-methylenedioxymethamphetamine (MDMA) has never been explored for treating alcohol use disorder. However, MDMA has some unique pharmacological characteristics – particularly its capacity for reducing the fear response and facilitating engagement in therapy around past psychological trauma – that could make it a useful candidate for tackling the core features of alcohol use disorder. This paper briefly describes the burden of alcohol use disorders and the history of psychedelic-assisted psychotherapy in the field of addictions. It gives the theoretical and experimental justification for MDMA-assisted psychotherapy for treating people with alcohol use disorder and introduces a forthcoming study from Bristol and London, UK, exploring the role for MDMA in treating a person with this challenging condition.

Sessa, B. (2016). Can 3, 4,-methylenedioxymethamphetamine therapy be used to treat alcohol use disorder?. Journal of Psychedelic Studies, (0), 1-9. 10.1556/2054.01.2016.003
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The antiaddictive effects of ibogaine: A systematic literature review of human studies

December 20, 2016 / Iboga / Ibogaine, Papers, Psychiatry, Psychology, Psychotherapy, Publications, Substance Use Disorder / By / , ,

Abstract

Background and aims: Ibogaine is a naturally occurring hallucinogenic alkaloid with a therapeutic potential for reducing drug craving and withdrawal. To the best of our knowledge, no systematic review was previously performed assessing these effects. Thus, we conducted a systematic literature review of human studies assessing the antiaddictive effects of ibogaine.

Methods: Papers published up to July 2, 2016 were included from PubMed, LILACS, and SciELO databases following a comprehensive search strategy and a pre-determined set of criteria for article selection.

Results: Two hundred and fifty-nine studies were identified, of which eight met the established criteria. Seven studies were open-label case series with ibogaine and one study was a randomized, placebo-controlled clinical trial with noribogaine. Case series suggest that a single dose or a few treatments with ibogaine may significantly reduce drug withdrawal, craving, and self-administration in dependent individuals lasting from 24 h to weeks or months. No significant effects of noribogaine on opiate/opioid withdrawal were observed in the clinical trial.

Conclusions: Considering the necessity of new drugs that may produce fast-acting and sustained effects in opiate/opioid and cocaine dependence, the potential beneficial effects of ibogaine/noribogaine should be further investigated in controlled trials.

dos Santos, R. G., Bouso, J. C., & Hallak, J. E. (2016). The antiaddictive effects of ibogaine: A systematic literature review of human studies. Journal of Psychedelic Studies, (0), 1-9. 10.1556/2054.01.2016.001

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A One-Dose Psychedelic Fix for Addiction?

December 8, 2016 / Iboga / Ibogaine, Papers, Psychiatry, Psychology, Psychotherapy, Publications, Substance Use Disorder / By /

Abstract

A drug that mimics ibogaine, a hallucinogen used underground for decades as an antiaddiction agent, is now being tested in clinical trials

The psychedelic drug ibogaine is known for two things: its reputation in some circles as a panacea for addiction and the visceral hallucinations it induces. Positive anecdotes abound from people who have sought out the illegal drug at underground clinics.

Jacobson, R. (2017). A One-Dose Psychedelic Fix for Addiction?. Scientific American Mind, 28(1), 10-11. 10.1038/scientificamericanmind0117-10

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Psilocybin: promising results in double-blind trials require confirmation by real-world evidence

December 6, 2016 / Anxiety disorders / PTSD, Depression, Mushrooms / Psilocybin, Papers, Psychiatry, Psychology, Psychotherapy, Publications / By / ,

Breckenridge, A., & Grobbee, D. E. (2016). Psilocybin: promising results in double-blind trials require confirmation by real-world evidence. Journal of psychopharmacology (Oxford, England), 30(12), 1218. 10.1177/0269881116675784
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Psilocybin for depression and anxiety associated with life-threatening illnesses

December 6, 2016 / Anxiety disorders / PTSD, Depression, Mushrooms / Psilocybin, Papers, Psychiatry, Psychology, Psychotherapy, Publications / By / , ,

Abstract

Life-threatening and terminal illnesses are accompanied by substantial stressors that encumber both patients and their families. Faced with a life-threatening diagnosis such as late-stage cancer, these factors can compound the existential crisis of impending mortality and produce or exacerbate major depressive and anxiety symptoms (Silverstone, 1990; Vergo et al., 2016). Addressing depression and anxiety in the unique context of life-threatening illnesses has been a significant problem for palliative psychiatric care. In this regard, two recent studies suggest that the one-time use of the naturally derived psychoactive compound psilocybin could have the potential to alleviate these symptoms for up to six months.

McCorvy, J. D., Olsen, R. H., & Roth, B. L. (2016). Psilocybin for depression and anxiety associated with life-threatening illnesses. Journal of psychopharmacology (Oxford, England), 30(12), 1209. 10.1177/0269881116675771
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Antisuicidal Response Following Ketamine Infusion Is Associated With Decreased Nighttime Wakefulness in Major Depressive Disorder and Bipolar Disorder

December 6, 2016 / Depression, Ketamine, Papers, Psychiatry, Psychology, Publications / By / , , , , , ,

Abstract

OBJECTIVE: Insomnia and disrupted sleep are associated with increased risk of suicide. The N-methyl-D-aspartate antagonist ketamine has been associated with reduced suicidal thoughts, but the mechanism of action is unknown. This study sought to evaluate differences in nocturnal wakefulness in depressed individuals who did and did not have an antisuicidal response to ketamine.

METHODS: Thirty-four participants with baseline suicidal ideation diagnosed with either DSM-IV major depressive disorder (n = 23) or bipolar depression (n = 11) between 2006 and 2013 completed nighttime electroencephalography (EEG) the night before and the night after a single ketamine infusion (0.5 mg/kg over 40 minutes). Suicidal ideation was assessed at baseline and the morning after ketamine infusion via several measures, including the Hamilton Depression Rating Scale suicide item, the suicide item of the Montgomery-Asberg Depression Rating Scale, and the first 5 items of the Scale for Suicide Ideation. A generalized linear mixed model evaluated differences in nocturnal wakefulness, as verified by EEG, between those who had an antisuicidal response to ketamine and those who did not, controlling for baseline nocturnal wakefulness. Results were also compared to the sleep of healthy controls (n = 22).

RESULTS: After analyses adjusted for baseline sleep, participants with an antisuicidal response to ketamine showed significantly reduced nocturnal wakefulness the night after ketamine infusion compared to those without an antisuicidal response (F₁,₂₂ = 5.04, P = .04). Level of nocturnal wakefulness after antisuicidal response to ketamine did not differ significantly from nocturnal wakefulness in the control sample but did differ at a trend level (F₁,₄₀ = 3.15, P = .08).

CONCLUSIONS: Reductions in wakefulness following ketamine may point to a biological mechanism underlying the effect of ketamine on suicidal ideation.

Vande Voort, J. L., Ballard, E. D., Luckenbaugh, D. A., Bernert, R. A., Richards, E. M., Niciu, M. J., … & Zarate, C. A. (2016). Antisuicidal response following ketamine infusion is associated with decreased nighttime wakefulness in major depressive disorder and bipolar disorder. Journal of clinical psychiatry. 10.4088/JCP.15m10440
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Predicting the Abuse Liability of Entactogen-Class, New and Emerging Psychoactive Substances via Preclinical Models of Drug Self-administration

December 2, 2016 / MDMA, Other substances, Papers, Psychiatry, Psychology, Publications, Substance Use Disorder / By / ,

Abstract

Animal models of drug self-administration are currently the gold standard for making predictions regarding the relative likelihood that a recreational drug substance will lead to continued use and addiction. Such models have been found to have high predictive accuracy and discriminative validity for a number of drug classes including ethanol, nicotine, opioids, and psychostimulants such as cocaine and methamphetamine. Members of the entactogen class of psychostimulants (drugs that produce an “open mind state” including feelings of interpersonal closeness, intimacy and empathy) have been less frequently studied in self-administration models. The prototypical entactogen 3,4-methylenedioxymethamphetamine (MDMA; “Ecstasy”) supports self-administration but not with the same consistency nor with the same efficacy as structurally related drugs amphetamine or methamphetamine. Consistent with these observations, MDMA use is more episodic in the majority of those who use it frequently. Nevertheless, substantial numbers of MDMA users will meet the criteria for substance dependence at some point in their use history. This review examines the currently available evidence from rodent self-administration studies of MDMA and two of the new and emerging psychoactive substances (NPS) that produce entactogen type neuropharmacological responses – mephedrone (4-methylmethcathinone; 4MMC; “meow meow”) and methylone (3,4-methylenedioxymethcathinone). Overall, the current evidence predicts that these NPS entactogens have enhanced abuse liability compared with MDMA.

Aarde, S. M., & Taffe, M. A. (2016). Predicting the Abuse Liability of Entactogen-Class, New and Emerging Psychoactive Substances via Preclinical Models of Drug Self-administration. 10.1007/7854_2016_54
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