Blinderman, C. D. (2016). Psycho-existential distress in cancer patients: A return to “entheogens”. Journal of Psychopharmacology, 30(12), 1205-1206. 10.1177/0269881116675761
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Lieberman, J. A., & Shalev, D. (2016). Back to the future: Research renewed on the clinical utility of psychedelic drugs. Journal of Psychopharmacology, 30(12), 1198-1200. 10.1177/0269881116675755
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Kleber, H. D. (2016). The successful return of psychedelics to psychiatry. Journal of Psychopharmacology, 30(12), 1211-1211. 10.1177/0269881116675779
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In major depressive disorder, women exhibit higher lifetime prevalence and different antidepressant response rates than men, which illustrates the importance of examining individual differences in the pathophysiology of depression and therapeutic response. In recent years, the consideration of sex in related preclinical research has thus gained interest — particularly in light of novel evidence for rapid-acting antidepressants. Notably, the literature recently revealed a higher sensitivity of females to the antidepressant effects of the N-methyl-d-aspartate receptor antagonist ketamine, in both baseline and preclinical conditions. Combined with its fast-acting and relatively sustained properties, this evidence highlights ketamine as a particularly interesting therapeutic alternative for this sensitive population, and supports the value in considering sex as a critical factor for improved individualized therapeutic strategies.
Saland, S. K., Duclot, F., & Kabbaj, M. (2017). Integrative analysis of sex differences in the rapid antidepressant effects of ketamine in preclinical models for individualized clinical outcomes. Current Opinion in Behavioral Sciences, 14, 19-26. 10.1016/j.cobeha.2016.11.002
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d-Lysergic Acid Diethylamide (LSD) is known for its hallucinogenic properties and psychotic-like symptoms, especially at high doses. It is indeed used as a pharmacological model of psychosis in preclinical research. The goal of this review was to understand the mechanism of action of psychotic-like effects of LSD. We searched Pubmed, Web of Science, Scopus, Google Scholar and articles’ reference lists for preclinical studies regarding the mechanism of action involved in the psychotic-like effects induced by LSD. LSD’s mechanism of action is pleiotropic, primarily mediated by the serotonergic system in the Dorsal Raphe, binding the 5-HT2Areceptor as a partial agonist and 5-HT1A as an agonist. LSD also modulates the Ventral Tegmental Area, at higher doses, by stimulating dopamine D2, Trace Amine Associate receptor 1 (TAAR1) and 5-HT2A. More studies clarifying the mechanism of action of the psychotic-like symptoms or psychosis induced by LSD in humans are needed. LSD’s effects are mediated by a pleiotropic mechanism involving serotonergic, dopaminergic, and glutamatergic neurotransmission. Thus, the LSD-induced psychosis is a useful model to test the therapeutic efficacy of potential novel antipsychotic drugs, particularly drugs with dual serotonergic and dopaminergic (DA) mechanism or acting on TAAR1 receptors.
De Gregorio, D., Comai, S., Posa, L., & Gobbi, G. (2016). d-Lysergic Acid Diethylamide (LSD) as a Model of Psychosis: Mechanism of Action and Pharmacology. International Journal of Molecular Sciences, 17(11), 1953. 10.3390/ijms17111953
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Major depression is a serious psychiatric disorder and remains a leading cause of disability worldwide. Conventional antidepressants take at least several weeks to achieve a therapeutic response and this lag period has hindered their ability to attain beneficial effects in depressed individuals at high risk of suicide. The non-competitive N-methyl-D-aspartate glutamate receptor antagonist ketamine has been shown to have rapid antidepressant effects in both rodents and humans. The emergence of ketamine as a fast-acting antidepressant provides promising new insights into the development of a rapid treatment response in patients with clinical depression. However, its safety and toxicity remain a concern. In this review, we focus on the limitations of ketamine, including neurotoxicity, cognitive dysfunction, adverse events associated with mental status, psychotomimetic effects, cardiovascular events, and uropathic effects. Studies have shown that its safety and tolerability profiles are generally good at low doses and with short-term treatment in depressed patients. The adverse events associated with ketamine usually occur with very high doses that are administered for prolonged periods of time and can be relieved by cessation. The antidepressant actions of its two enantiomers, S-ketamine (esketamine) and R-ketamine, are also discussed. R-ketamine has greater antidepressant actions than S-ketamine, without ketamine-related side-effects. Future treatment strategies should consider using R-ketamine for the treatment of depressed patients to decrease the risk of adverse events associated with long-term ketamine use.
Zhu, W., Ding, Z., Zhang, Y., Shi, J., Hashimoto, K., & Lu, L. (2016). Risks associated with misuse of ketamine as a rapid-acting antidepressant. Neuroscience Bulletin, 32(6), 557-564. 10.1007/s12264-016-0081-2
Ketamine’s antidepressant effects have variously been attributed to its wide-acting N-methyl-D-aspartate (NMDA) antagonism, its high-affinity for the NMDA receptor (Sanacora et al., 2008), and its trapping mechanism of blockade (Autry et al., 2011; Duman et al., 2016; Zarate et al., 2013). Several novel agents are being developed and tested that attempt to maintain ketamine’s antidepressant efficacy while minimizing its side effects, particularly its psychotomimetic properties and abuse potential.
Lepow, L., Luckenbaugh, D. A., Park, L., Henter, I. D., & Zarate, C. A. (2017). Case series: Antidepressant effects of low-affinity and low-trapping NMDA receptor antagonists did not predict response to ketamine in seven subjects. Journal of psychiatric research, 86, 55-57. 10.1016/j.jpsychires.2016.10.023
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Ketamine, an uncompetitive glutamatergic NMDA antagonist, was first synthesised as an anaesthetic agent, though its unwanted induction of post-operative ‘dissociative’ states led to its gradual withdrawal from mainstream use. It has remained a common drug of abuse ever since, in the same class as the more powerful phencyclidine (‘PCP’ or ‘angel-dust’). However, as well as subjectively pleasurable perceptual changes and alterations to consciousness, data began to emerge of a positive effect upon depressed mood states. Of particular interest, such effects, where they occurred, were seen to develop far more rapidly than with ‘traditional’ antidepressants. Scientific trials of effectiveness have included work exploring ketamine as the sole medication, co-prescribing studies, and work looking at augmentation of ECT. Overall these early data are showing some interesting and exciting results, with general support for efficacy in all settings tested. However, significant challenges remain. Firstly, benefits derived tend to be temporary, with rapid relapse after several weeks, and there is a need to find a mechanism to sustain the drug effects. Secondly, most studies utilised intravenous administration, which carries an obvious clinical burden. Finally, the risks of dependency and ketamine-induced psychosis remain as yet uncertain. Nevertheless the societal burden of depression mandates further work on this compound, not least to better understand the mechanism of action of any therapeutic changes.
Tracy, D. K., Caddy, C., & Shergill, S. S. (2016). Ketamine: The Glutamatergic Antidepressant and Its Efficacy. In Melatonin, Neuroprotective Agents and Antidepressant Therapy (pp. 687-706). Springer India. 10.1007/978-81-322-2803-5_41
Different cognitive impairments have been reported as a result of long-term MDMA/ecstasy use. Increased impulsivity and altered decision-making have been shown to be associated with the development and maintenance of addictive disorders pointing towards the necessity to understand a potential impairment of decision-making due to MDMA use. Thus, assessing the long-term effects of MDMA is crucial in order to evaluate its controversially discussed therapeutic use. The aim of this systematic review is to summarize the scientific literature on potential effects of chronic MDMA use on higher order decision-making processes in humans. Therefore, a systematic search for controlled trials relevant to the topic has been performed. Only studies using specific tasks on decision-making were included that involved subjects in the drug-free interval with drug-naïve, and/or polydrug control groups. A total of twelve studies could be identified that met the inclusion criteria, all of which were cross-sectional studies. The findings on decision-making disturbances in MDMA users were heterogeneous. Seven studies reported increased risky decisions, whereas five studies did not find MDMA-specific influences on decision-making. Increased impulsivity was observed both in MDMA groups and in (poly)drug control groups in almost all studies. Thus, the current state of research does not allow for the conclusion that long-term use of MDMA affects decision-making behavior in general. More detailed specifications as well as further investigations of the relevant processes are needed. Significant tendencies towards risky decision-making among long-term MDMA use have been observed, but need to be confirmed by studies using a longitudinal design.
Betzler, F., Viohl, L., & Romanczuk‐Seiferth, N. (2016). Decision‐making in chronic ecstasy users: a systematic review. European Journal of Neuroscience. 10.1111/ejn.13480
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Classic hallucinogens share pharmacology as serotonin 5-HT2A, 5-HT2B, and 5-HT2Creceptor agonists. Unique among most other Schedule 1 drugs, they are generally non-addictive and can be effective tools in the treatment of addiction. Mechanisms underlying these attributes are largely unknown. However, many preclinical studies show that 5-HT2C agonists counteract the addictive effects of drugs from several classes, suggesting this pharmacological property of classic hallucinogens may be significant. Drawing from a comprehensive analysis of preclinical behavior, neuroanatomy, and neurochemistry studies, this review builds rationale for this hypothesis, and also proposes a testable, neurobiological framework. 5-HT2C agonists work, in part, by modulating dopamine neuron activity in the ventral tegmental area—nucleus accumbens (NAc) reward pathway. We argue that activation of 5-HT2Creceptors on NAc shell, GABAergic, medium spiny neurons inhibits potassium Kv1.x channels, thereby enhancing inhibitory activity via intrinsic mechanisms. Together with experiments that show that addictive drugs, such as cocaine, potentiate Kv1.x channels, thereby suppressing NAc shell GABAergic activity, this hypothesis provides a mechanism by which classic hallucinogen-mediated stimulation of 5-HT2C receptors could thwart addiction. It also provides a potential reason for the non-addictive nature of classic hallucinogens.
Canal, C. E., & Murnane, K. S. (2016). The serotonin 5-HT2C receptor and the non-addictive nature of classic hallucinogens. Journal of Psychopharmacology, 0269881116677104.
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