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Potential involvement of serotonergic signaling in ketamine's antidepressant actions: A critical review

June 2, 2016 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / By / , , , , ,

Abstract

A single i.v. infusion of ketamine, classified as an N-methyl-d-aspartate (NMDA) receptor antagonist, may alleviate depressive symptoms within hours of administration in treatment resistant depressed patients, and the antidepressant effect may last for several weeks. These unique therapeutic properties have prompted researchers to explore the mechanisms mediating the antidepressant effects of ketamine, but despite many efforts, no consensus on its antidepressant mechanism of action has been reached. Recent preclinical reports have associated the neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) with the antidepressant-like action of ketamine. Here, we review the current evidence for a serotonergic role in ketamine’s antidepressant effects.

The pharmacological profile of ketamine may include equipotent activity on several non-NMDA targets, and the current hypotheses for the mechanisms responsible for ketamine’s antidepressant activity do not appear to preclude the possibility that non-glutamate neurotransmitters are involved in the antidepressant effects. At multiple levels, the serotonergic and glutamatergic systems interact, and such crosstalk could support the notion that changes in serotonergic neurotransmission may impact ketamine’s antidepressant potential. In line with these prospects, ketamine may increase 5-HT levels in the prefrontal cortex of rats, plausibly via hippocampal NMDA receptor inhibition and activation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. In addition, a number of preclinical studies suggest that the antidepressant-like effects of ketamine may depend on endogenous activation of 5-HT receptors. Recent imaging and behavioral data predominantly support a role for 5-HT1A or 5-HT1B receptors, but the full range of 5-HT receptors has currently not been systematically investigated in this context. Furthermore, the nature of any 5-HT dependent mechanism in ketamine’s antidepressant effect is currently not understood, and therefore, more studies are warranted to confirm this hypothesis and explore the specific pathways that might implicate 5-HT.

du Jardin, K. G., Müller, H. K., Elfving, B., Dale, E., Wegener, G., & Sanchez, C. (2016). Potential involvement of serotonergic signaling in ketamine’s antidepressant actions: A critical review. Progress in Neuro-Psychopharmacology and Biological Psychiatry. http://dx.doi.org/10.1016/j.pnpbp.2016.05.007
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The potential use of ayahuasca in psychiatry

June 1, 2016 / Ayahuasca, Papers, Psychology, Publications / By / , , ,

Abstract

Ayahuasca is a decoctum made of admixture plants containing dimethyltryptamine and harmine. For millennia it has been used as a central element of spiritual, religious, initiation, and other – foremost healing – rituals, originally by the indigenous groups of the Amazon basin and later by the mestizo populations of the region. During the last two decades the brew has raised increased scientific and lay interest about its healing potentials within the framework of Western therapeutic settings. The typical ayahuasca effects consist of strong somatic reactions, vivid visions, relived personal memories, cathartic emotions, and insightful, introspective experiences when the emerging mental contents take different context and get deeper perspectives. The ayahuasca-experience can be exhausting necessitating the presence of an experienced leader for helping participants to pass difficult phases and for maximizing therapeutic benefits. No health damaging adverse effect has been confirmed thus far as result of its well-structured, institutionalized use. The scientific investigation of ayahuasca is hindered by legal issues, methodical problems, and sociocultural preconceptions. The present review outlines the therapeutic potentials of ayahuasca use in psychiatry with its psychobiological and spiritual background.

Frecska, E., Bokor, P., Andrassy, G., & Kovacs, A. (2016). The potential use of ayahuasca in psychiatry. Neuropsychopharmacologia Hungarica: a Magyar Pszichofarmakologiai Egyesulet lapja= official journal of the Hungarian Association of Psychopharmacology, 18(2), 79.
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Efficacy and safety of oral ketamine versus diclofenac to alleviate mild to moderate depression in chronic pain patients: A double-blind, randomized, controlled trial

June 1, 2016 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , , , , , ,

Abstract

Background: Ketamine is a glutamate N-methyl-d-aspartate receptor antagonist capable of exerting antidepressive effects in single or repeated intravenous infusions. The objective of this study was to investigate the safety and the efficacy of oral ketamine vs. diclofenac monotherapy in reducing symptoms of mild to moderate depression among patients with chronic pain.

Methods: This study is a 6-week, randomized, double-blind, controlled, parallel-group trial with two intervention arms (ketamine, fixed daily dosage of 150 mg vs. diclofenac, fixed daily dosage of 150 mg). Twenty participants in each arm completed the trial program all of whom had two post-baseline measurements at week 3 and week 6. Reduction in depression symptoms was assessed using the Hamilton Depression Rating Scale (HDRS) and the hospital anxiety and depression subscale for depression (HADSDepression) scores at baseline and week 3 and week 6 post-intervention.

Results: Significantly lower HDRS scores were observed in the ketamine treatment group as early as 6 weeks post-intervention (P=0.008). By comparison, mean (±standard deviation) HADS depression subscale scores were significantly lower for individuals receiving ketamine compared to diclofenac for both post-baseline measures at week 3 (6.95±1.47 vs. 8.40±1.6, P=0.005) and week 6 (6.20±1.15 vs. 7.35±1.18, p=0.003).

Limitations: The limitations of the present study were its small sample size and the short-term follow-up period.

Conclusions: Oral ketamine appears to be a safe and effective option in improving depressive symptoms of patients with chronic pain with mild-to-moderate depression.

Jafarinia, M., Afarideh, M., Tafakhori, A., Arbabi, M., Ghajar, A., Noorbala, A. A., … & Akhondzadeh, S. (2016). Efficacy and Safety of Oral Ketamine versus Diclofenac to Alleviate Mild to Moderate Depression in Chronic Pain Patients: A Double-Blind, Randomized, Controlled Trial. Journal of Affective Disorders. http://dx.doi.org/10.1016/j.jad.2016.05.076

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Using the Theory of Planned Behavior to predict implementation of harm reduction strategies among MDMA/ecstasy users

June 1, 2016 / MDMA, Papers, Psychology, Publications, Substance Use Disorder / By / ,

Abstract

This prospective study was designed to test whether the variables proposed by the Theory of Planned Behavior (TPB) were associated with baseline intention to implement and subsequent use of 2 MDMA/ecstasy-specific harm reduction interventions: preloading/postloading and pill testing/pill checking. Using targeted Facebook advertisements, an international sample of 391 recreational ecstasy users were recruited to complete questionnaires assessing their ecstasy consumption history, and their attitudes, subjective norms, perceived behavioral control, habit strength (past strategy use), and intention to use these two strategies. Attitudes, subjective norms, and perceived behavioral control were significantly associated with baseline intention to preload/postload and pill test/pill check. Out of the 391 baseline participants, 100 completed the two-month follow-up assessment. Baseline habit strength and frequency of ecstasy consumption during the three months prior to baseline were the only significant predictors of how often participants used the preloading/postloading strategy during the follow-up. Baseline intention to pill test/pill check was the only significant predictor of how often participants used this strategy during the follow-up. These findings provide partial support for TPB variables as both correlates of baseline intention to implement and predictors of subsequent use of these two strategies. Future investigations could assess whether factors related to ecstasy consumption (e.g., subjective level of intoxication, craving, negative consequences following consumption), and environmental factors (e.g., accessibility and availability of harm reduction resources) improve the prediction of how often ecstasy users employ these and other harm reduction strategies.

Davis, A. K., & Rosenberg, H. (2016). Using the Theory of Planned Behavior to predict implementation of harm reduction strategies among MDMA/ecstasy users. Psychology of Addictive Behaviors, 30(4), 500.  http://dx.doi.org/10.1037/adb0000167
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LSD Acutely Impairs Fear Recognition and Enhances Emotional Empathy and Sociality

June 1, 2016 / LSD, Papers, Psychology, Publications / By / , , , ,

Abstract

Lysergic acid diethylamide (LSD) is used recreationally and has been evaluated as an adjunct to psychotherapy to treat anxiety in patients with life-threatening illness. LSD is well-known to induce perceptual alterations, but unknown is whether LSD alters emotional processing in ways that can support psychotherapy. We investigated the acute effects of LSD on emotional processing using the Face Emotion Recognition Task (FERT) and Multifaceted Empathy Test (MET). The effects of LSD on social behavior were tested using the Social Value Orientation (SVO) test. Two similar placebo-controlled, double-blind, random-order, cross-over studies were conducted using 100 μg LSD in 24 subjects and 200 μg LSD in 16 subjects. All of the subjects were healthy and mostly hallucinogen-naive 25- to 65-year-old volunteers (20 men, 20 women). LSD produced feelings of happiness, trust, closeness to others, enhanced explicit and implicit emotional empathy on the MET, and impaired the recognition of sad and fearful faces on the FERT. LSD enhanced the participants’ desire to be with other people and increased their prosocial behavior on the SVO test. These effects of LSD on emotion processing and sociality may be useful for LSD-assisted psychotherapy.

Dolder, P. C., Schmid, Y., Müller, F., Borgwardt, S., & Liechti, M. E. (2016). Lsd acutely impairs fear recognition and enhances emotional empathy and sociality. Neuropsychopharmacology. http://dx.doi.org/10.1038/npp.2016.82
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Ibogaine and addiction in the animal model, a systematic review and meta-analysis

May 31, 2016 / Iboga / Ibogaine, Neuroscience, Papers, Psychology, Publications, Substance Use Disorder / By / , , , , ,

Abstract

Ibogaine is a naturally occurring substance which has been increasingly used in the lay-scene to reduce craving and relapse in patients with substance use disorders (SUDs). Although human clinical trials on the safety and efficacy of ibogaine are lacking, animal studies do support the efficacy of ibogaine. In this systematic review and meta-analysis (MA), we summarise these animal findings, addressing three questions: (1) does ibogaine reduce addictive behaviour in animal models of SUDs?; (2) what are the toxic effects of ibogaine on motor functioning, cerebellum and heart rhythm?; (3) what are neuropharmacological working mechanisms of ibogaine treatment in animal models of SUDs? MA of 27 studies showed that ibogaine reduced drug self-administration, particularly during the first 24 h after administration. Ibogaine had no effect on drug-induced conditioned place preference. Ibogaine administration resulted in motor impairment in the first 24 h after supplementation, and cerebral cell loss even weeks after administration. Data on ibogaines effect on cardiac rhythm, as well as on its neuropharmacological working mechanisms are limited. Our results warrant further studies into the clinical efficacy of ibogaine in SUD patients in reducing craving and substance use, but close monitoring of the patients is recommended because of the possible toxic effects. In addition, more work is needed to unravel the neuropharmacological working mechanisms of ibogaine and to investigate its effects on heart rhythm.

Belgers, M., Leenaars, M., Homberg, J. R., Ritskes-Hoitinga, M., Schellekens, A. F. A., & Hooijmans, C. R. (2016). Ibogaine and addiction in the animal model, a systematic review and meta-analysis. Translational psychiatry, 6(5), e826. http://dx.doi.org/10.1038/tp.2016.71
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±3,4-Methylenedioxymethamphetamine: Treating PTSD in The Modern World

May 26, 2016 / Anxiety Disorders / PTSD, MDMA, Papers, Psychology, Publications / By /

Abstract

Post-traumatic stress disorder (PTSD) is a serious condition that afflicts millions of individuals in the United States. Its complexity has resulted in physicians struggling to effectively implement and maintain treatment. Emerging studies suggest that ±3,4-Methylenedioxymethamphetamine (MDMA), or “ecstasy”, may prove beneficial in treating PTSD in combination with conventional psychotherapy. By acting on the 5-HT transporter in the brain, MDMA has been found to have positive effects on brain activity; encouraging neuroplasticity through the accumulation of brain-derived neurotrophic factor (BDNF). Integrating psychoactive drugs into polytrauma therapy will broaden our understanding of the components involved in maintaining wellness in the human psyche.

Baxter, A. (2016). ±3, 4-Methylenedioxymethamphetamine: Treating PTSD in The Modern World.
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Effects of Ayahuasca and its Alkaloids on Drug Dependence: A Systematic Literature Review of Quantitative Studies in Animals and Humans

May 26, 2016 / Ayahuasca, Neuroscience, Papers, Psychology, Publications, Substance Use Disorder / By / , , , , ,

Abstract

Recently, the anti-addictive potential of ayahuasca, a dimethyltryptamine(DMT)- and β-carboline-rich hallucinogenic beverage traditionally used by indigenous groups of the Northwest Amazon and currently by syncretic churches worldwide, has received increased attention. To better evaluate this topic, we performed a systematic literature review using the PubMed database to find quantitative studies (using statistical analysis) that assessed the effects of ayahuasca or its components in drug-related symptoms or disorders. We found five animal studies (using harmaline, harmine, or ayahuasca) and five observational studies of regular ayahuasca consumers. All animal studies showed improvement of biochemical or behavioral parameters related to drug-induced disorders. Of the five human studies, four reported significant reductions of dependence symptoms or substance use, while one did not report significant results. The mechanisms responsible for the anti-addictive properties of ayahuasca and its alkaloids are not clarified, apparently involving both peripheral MAO-A inhibition by the β-carbolines and central agonism of DMT at 5-HT2A receptors expressed in brain regions related to the regulation of mood and emotions. Although results are promising, controlled studies are needed to replicate these preliminary findings.

Nunes, A. A., dos Santos, R. G., Osório, F. L., Sanches, R. F., Crippa, J. A. S., & Hallak, J. E. (2016). Effects of Ayahuasca and its Alkaloids on Drug Dependence: A Systematic Literature Review of Quantitative Studies in Animals and Humans. Journal of psychoactive drugs, 1-11. http://dx.doi.org/10.1080/02791072.2016.1188225

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Human Pharmacology of Mephedrone in Comparison to MDMA

May 20, 2016 / Neuroscience, Papers, Publications / By / , , , , , ,

Abstract

Mephedrone (4-methylmethcathinone) is a novel psychoactive substance popular among drug users because it displays similar effects to MDMA (3,4-metylenedioxymethamphetamine, ecstasy). Mephedrone consumption has been associated with undesirable effects and fatal intoxications. At present, there is no research available on its pharmacological effects in humans under controlled and experimental administration. This study aims to evaluate the clinical pharmacology of mephedrone, and its relative abuse liability, compared to MDMA. Twelve male volunteers participated in a randomized, double-blind, crossover, and placebo-controlled trial. The single oral dose conditions were: mephedrone 200 mg, MDMA 100 mg, and placebo. Outcome variables included physiological, subjective, and psychomotor effects, and pharmacokinetic parameters. The protocol was registered in ClinicalTrials.gov (NCT02232789). Mephedrone produced a significant increase in systolic and diastolic blood pressure, heart rate, and pupillary diameter. It elicited stimulant-like effects, euphoria, and well-being, and induced mild changes in perceptions with similar ratings to those observed after MDMA administration although effects peaked earlier and were shorter in duration. Maximal plasma concentrations values for mephedrone and MDMA peaked at 1.25 and 2.00 h, respectively. The elimination half-life for mephedrone was 2.15 and 7.89 h for MDMA. In a similar manner to MDMA, mephedrone exhibits high abuse liability. Its earlier onset and shorter duration of effects, probably related to its short elimination half-life, could explain a more compulsive pattern of use as described by users.

Papaseit, E., Pérez-Mañá, C., Mateus, J. A., Pujadas, M., Fonseca, F., Torrens, M., … & Farré, M. (2016). Human Pharmacology of Mephedrone in Comparison to MDMA. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology. http://dx.doi.org/10.1038/npp.2016.75
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