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Psychiatry

Hallucinations Under Psychedelics and in the Schizophrenia Spectrum: An Interdisciplinary and Multiscale Comparison

November 18, 2021 / Anthropology, Neuroscience, Papers, Phenomenology, Psychiatry, Psychopharmacology, Psychosis / Leave a Comment / By / , , , , , , , , , , , , ,

Abstract

The recent renaissance of psychedelic science has reignited interest in the similarity of drug-induced experiences to those more commonly observed in psychiatric contexts such as the schizophrenia-spectrum. This report from a multidisciplinary working group of the International Consortium on Hallucinations Research (ICHR) addresses this issue, putting special emphasis on hallucinatory experiences. We review evidence collected at different scales of understanding, from pharmacology to brain-imaging, phenomenology and anthropology, highlighting similarities and differences between hallucinations under psychedelics and in the schizophrenia-spectrum disorders. Finally, we attempt to integrate these findings using computational approaches and conclude with recommendations for future research.

Leptourgos, P., Fortier-Davy, M., Carhart-Harris, R., Corlett, P. R., Dupuis, D., Halberstadt, A. L., Kometer, M., Kozakova, E., LarØi, F., Noorani, T. N., Preller, K. H., Waters, F., Zaytseva, Y., & Jardri, R. (2020). Hallucinations Under Psychedelics and in the Schizophrenia Spectrum: An Interdisciplinary and Multiscale Comparison. Schizophrenia bulletin, 46(6), 1396–1408. https://doi.org/10.1093/schbul/sbaa117

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Hallucinogens in Mental Health: Preclinical and Clinical Studies on LSD, Psilocybin, MDMA, and Ketamine

January 7, 2022 / Ketamine, LSD, MDMA, Mushrooms / Psilocybin, Papers, Psychiatry, Psychopharmacology, Psychotherapy / Leave a Comment / By / , , , , , ,

Abstract

A revamped interest in the study of hallucinogens has recently emerged, especially with regard to their potential application in the treatment of psychiatric disorders. In the last decade, a plethora of preclinical and clinical studies have confirmed the efficacy of ketamine in the treatment of depression. More recently, emerging evidence has pointed out the potential therapeutic properties of psilocybin and LSD, as well as their ability to modulate functional brain connectivity. Moreover, MDMA, a compound belonging to the family of entactogens, has been demonstrated to be useful to treat post-traumatic stress disorders. In this review, the pharmacology of hallucinogenic compounds is summarized by underscoring the differences between psychedelic and nonpsychedelic hallucinogens as well as entactogens, and their behavioral effects in both animals and humans are described. Together, these data substantiate the potentials of these compounds in treating mental diseases.

De Gregorio, D., Aguilar-Valles, A., Preller, K. H., Heifets, B. D., Hibicke, M., Mitchell, J., & Gobbi, G. (2021). Hallucinogens in Mental Health: Preclinical and Clinical Studies on LSD, Psilocybin, MDMA, and Ketamine. The Journal of neuroscience : the official journal of the Society for Neuroscience, 41(5), 891–900. https://doi.org/10.1523/JNEUROSCI.1659-20.2020

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Is ketamine an appropriate alternative to ECT for patients with treatment resistant depression? A systematic review

January 21, 2022 / Depression, Ketamine, Papers, Psychiatry / Leave a Comment / By / , , , ,

Abstract

Objective: Ketamine has repeatedly shown to have rapid and robust antidepressant effects in patients with treatment resistant depression (TRD). An important question is whether ketamine is as effective and safe as the current gold standard electroconvulsive therapy (ECT).

Methods: The literature was searched for trials comparing ketamine treatment with ECT for depression in the Pubmed/MEDLINE database and Cochrane Trials Library.

Results: A total of 137 manuscripts were identified, 6 articles were included in this review. Overall quality of the included studies was diverse with relevant risk of bias for some of the studies. Results suggest that ketamine treatment might give faster but perhaps less durable antidepressant effects. Side effects differed from ECT, in particular less cognitive impairment was apparent in ketamine treatment.

Limitations: The included studies have limited sample sizes, use different treatment protocols and in most trials, longer term follow up is lacking. Furthermore, allocation bias appears likely in the non-randomized trials.

Conclusions: Current available literature does not yet provide convincing evidence to consider ketamine as an equally effective treatment alternative to ECT in patients with TRD. There are indications for a more favourable short term cognitive side effect profile after ketamine treatment. Methodologically well-designed studies with larger sample sizes and longer follow up duration are warranted.

Veraart, J., Smith-Apeldoorn, S. Y., Spaans, H. P., Kamphuis, J., & Schoevers, R. A. (2021). Is ketamine an appropriate alternative to ECT for patients with treatment resistant depression? A systematic review. Journal of affective disorders, 281, 82–89. https://doi.org/10.1016/j.jad.2020.11.123

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Corticosterone as a Potential Confounding Factor in Delineating Mechanisms Underlying Ketamine’s Rapid Antidepressant Actions

January 27, 2022 / Depression, Ketamine, Neuroscience, Papers, Psychiatry, Psychopharmacology / Leave a Comment / By / , , , , , ,

Abstract

Recent research into the rapid antidepressant effect of subanesthetic doses of ketamine have identified a series of relevant protein cascades activated within hours of administration. Prior to, or concurrent with, these activation cascades, ketamine treatment generates dissociative and psychotomimetic side effects along with an increase in circulating glucocorticoids. In rats, we observed an over 3-fold increase in corticosterone levels in both serum and brain tissue, within an hour of administration of low dose ketamine (10 mg/kg), but not with (2R, 6R)-hydroxynorketamine (HNK) (10 mg/kg), a ketamine metabolite shown to produce antidepressant-like action in rodents without inducing immediate side-effects. Hippocampal tissue from ketamine, but not HNK, injected animals displayed a significant increase in the expression of sgk1, a downstream effector of glucocorticoid receptor signaling. To examine the role conscious sensation of ketamine’s side effects plays in the release of corticosterone, we assessed serum corticosterone levels after ketamine administration while under isoflurane anesthesia. Under anesthesia, ketamine failed to increase circulating corticosterone levels relative to saline controls. Concurrent with its antidepressant effects, ketamine generates a release of glucocorticoids potentially linked to disturbing cognitive side effects and the activation of distinct molecular pathways which should be considered when attempting to delineate the molecular mechanisms of its antidepressant function.

Wegman-Points, L., Pope, B., Zobel-Mask, A., Winter, L., Wauson, E., Duric, V., & Yuan, L. L. (2020). Corticosterone as a Potential Confounding Factor in Delineating Mechanisms Underlying Ketamine’s Rapid Antidepressant Actions. Frontiers in pharmacology, 11, 590221. https://doi.org/10.3389/fphar.2020.590221

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The time course of psychotic symptom side effects of ketamine in the treatment of depressive disorders: a systematic review and meta-analysis

January 3, 2022 / Depression, Ketamine, Papers, Psychiatry, Safety / Leave a Comment / By / , , , ,

Abstract

Objective: Ketamine is a potential rapid-acting treatment for depression. Studies have suggested that the side effects are minimal and temporary, but the psychotic symptom side effects have yet to be fully examined. This study investigated whether ketamine infusion in the treatment of mood disorders is associated with increases in positive symptoms and whether these symptom effects endure over time.

Methods: A systematic review and meta-analysis of studies of ketamine in the treatment of depression. Embase and Medline databases were searched for studies including (a) participants with major affective disorders, (b) 0.4 or 0.5 mg intravenously administered ketamine, (c) measurement of positive symptoms using BPRS+, and (d) a within-subject repeated-measures design with participants serving as their own baseline.

Results: Seventeen studies met the inclusion criteria, comprising 458 participants. The meta-analyses examined symptom change occurring within the first 4 h, after 1 day, and after 3 days. Results showed significant BPRS+ increases within the first 30-60 min in 72% of studies, followed by a return to baseline levels.

Conclusion: Peak symptom change occurred within the first hour post infusion. There are limited data to determine if ketamine is safe in the longer term, but there were no indications that psychotic symptoms re-occurred after the first hour and in the days following administration.

Tashakkori, M., Ford, A., Dragovic, M., Gabriel, L., & Waters, F. (2021). The time course of psychotic symptom side effects of ketamine in the treatment of depressive disorders: a systematic review and meta-analysis. Australasian psychiatry : bulletin of Royal Australian and New Zealand College of Psychiatrists, 29(1), 80–87. https://doi.org/10.1177/1039856220961642

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Time is of the essence: Coupling sleep-wake and circadian neurobiology to the antidepressant effects of ketamine

January 3, 2022 / Depression, Ketamine, Papers, Psychiatry, Psychopharmacology / Leave a Comment / By / , , , ,

Abstract

Several studies have demonstrated the effectiveness of ketamine in rapidly alleviating depression and suicidal ideation. Intense research efforts have been undertaken to expose the precise mechanism underlying the antidepressant action of ketamine; however, the translation of findings into new clinical treatments has been slow. This translational gap is partially explained by a lack of understanding of the function of time and circadian timing in the complex neurobiology around ketamine. Indeed, the acute pharmacological effects of a single ketamine treatment last for only a few hours, whereas the antidepressant effects peak at around 24 hours and are sustained for the following few days. Numerous studies have investigated the acute and long-lasting neurobiological changes induced by ketamine; however, the most dramatic and fundamental change that the brain undergoes each day is rarely taken into consideration. Here, we explore the link between sleep and circadian regulation and rapid-acting antidepressant effects and summarize how diverse phenomena associated with ketamine’s antidepressant actions – such as cortical excitation, synaptogenesis, and involved molecular determinants – are intimately connected with the neurobiology of wake, sleep, and circadian rhythms. We review several recently proposed hypotheses about rapid antidepressant actions, which focus on sleep or circadian regulation, and discuss their implications for ongoing research. Considering these aspects may be the last piece of the puzzle necessary to gain a more comprehensive understanding of the effects of rapid-acting antidepressants on the brain.

Kohtala, S., Alitalo, O., Rosenholm, M., Rozov, S., & Rantamäki, T. (2021). Time is of the essence: Coupling sleep-wake and circadian neurobiology to the antidepressant effects of ketamine. Pharmacology & therapeutics, 221, 107741. https://doi.org/10.1016/j.pharmthera.2020.107741

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Ketamine in Bipolar Disorder: A Review

January 6, 2022 / Depression, Ketamine, Other subjects, Papers, Psychiatry / Leave a Comment / By / , ,

Abstract

Bipolar disorder (BD) is a psychiatric illness associated with high morbidity, mortality and suicide rate. It has neuroprogressive course and a high rate of treatment resistance. Hence, there is an unquestionable need for new BD treatment strategies. Ketamine appears to have rapid antidepressive and antisuicidal effects. Since most of the available studies concern unipolar depression, here we present a novel insight arguing that ketamine might be a promising treatment for bipolar disorder.

Wilkowska, A., Szałach, Ł., & Cubała, W. J. (2020). Ketamine in Bipolar Disorder: A Review. Neuropsychiatric disease and treatment, 16, 2707–2717. https://doi.org/10.2147/NDT.S282208

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The potential use of N-methyl-3,4-methylenedioxyamphetamine (MDMA) assisted psychotherapy in the treatment of eating disorders comorbid with PTSD

January 6, 2022 / Anxiety disorders / PTSD, Eating Disorders, MDMA, Papers, Psychiatry, Psychotherapy / Leave a Comment / By / , ,

Abstract

Despite advances in the field, eating disorders (EDs) remain very challenging disorders to treat, especially when comorbid with posttraumatic stress disorder (PTSD). N-methyl-3,4-methylenedioxyamphetamine (MDMA)-assisted psychotherapy for treatment refractory PTSD shows great promise, with two-thirds of participants achieving full remission at 1 year or more at follow-up. PTSD is a common comorbidity associated with EDs, and patients with EDs and PTSD (ED-PTSD) are reported to have higher severities of illness, greater comorbidities, higher treatment dropouts, and poorer outcomes. We hypothesize that MDMA-assisted psychotherapy will be efficacious in the ED-PTSD population for both ED and PTSD symptoms. The rationales for and proposed mechanisms of MDMA-assisted psychotherapy for ED-PTSD are considered from neurobiological, psychological and social perspectives. MDMA is associated with unique psychopharmacological effects, including: 1) reduced fear, 2) enhanced wellbeing, 3) increased sociability/extroversion, 4) reduced self-criticism, 5) increased compassion for self/others, 6) increased interpersonal trust, and 7) alert state of consciousness. These anxiolytic and prosocial effects may counteract avoidance and hyperarousal in the context of psychotherapy for those with ED-PTSD. Other clinical features of EDs that may be amenable to MDMA-assisted psychotherapy include body image distortion, cognitive rigidity, and socio-emotional processing difficulties. To illustrate its potential, personal accounts of individuals with ED-PTSD symptoms reporting benefit from MDMA adjunctive to psychotherapy are described. In addition, the possible risks and challenges in conducting this work are addressed, and future implications of this proposal are discussed.

Brewerton, T. D., Lafrance, A., & Mithoefer, M. C. (2021). The potential use of N-methyl-3,4-methylenedioxyamphetamine (MDMA) assisted psychotherapy in the treatment of eating disorders comorbid with PTSD. Medical hypotheses, 146, 110367. https://doi.org/10.1016/j.mehy.2020.110367

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Anti-inflammatory activity of ayahuasca: therapeutical implications in neurological and psychiatric diseases

January 3, 2022 / 5-MeO-DMT, Ayahuasca, DMT, Neuroscience, Papers, Psychiatry, Psychopharmacology, Safety / Leave a Comment / By / , ,

Abstract

Ayahuasca is a decoction with psychoactive properties, used for millennia for therapeutic and religious purposes by indigenous groups and the population of amazonian countries. As described in this narrative review, it is essentially constituted by β-carbolines and tryptamines, and it has therapeutic effects on behavioral disorders due to the inhibition of the monoamine oxidase enzyme and the activation of 5-hydroxytryptamine receptors, demonstrated through preclinical and clinical studies. It was recently observed that the pharmacological response presented by ayahuasca is linked to its anti-inflammatory action, attributed mainly to dimethyltryptamines (N, N-dimethyltryptamine and 5-methoxy-N, N-dimethyltryptamine), which act as endogenous systemic regulators of inflammation and immune homeostasis, also through sigma-1 receptors. Therefore, since neuroinflammation is among the main pathophysiological mechanisms related to the development of neurological and psychiatric diseases, we suggest, based on the available evidence, that ayahuasca is a promising and very safe therapeutic strategy since extremely high doses are required to reach toxicity. However, even so, additional studies are needed to confirm such evidence, as well as the complete elucidation of the mechanisms involved.

da Silva, M. G., Daros, G. C., & de Bitencourt, R. M. (2021). Anti-inflammatory activity of ayahuasca: therapeutical implications in neurological and psychiatric diseases. Behavioural brain research, 400, 113003. https://doi.org/10.1016/j.bbr.2020.113003

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Post-acute psychological effects of classical serotonergic psychedelics: a systematic review and meta-analysis

January 3, 2022 / Ayahuasca, LSD, Mushrooms / Psilocybin, Papers, Personality, Psychiatry, Psychology, Spirituality / Leave a Comment / By / , , , , , ,

Abstract

Background: Scientific interest in the therapeutic effects of classical psychedelics has increased in the past two decades. The psychological effects of these substances outside the period of acute intoxication have not been fully characterized. This study aimed to: (1) quantify the effects of psilocybin, ayahuasca, and lysergic acid diethylamide (LSD) on psychological outcomes in the post-acute period; (2) test moderators of these effects; and (3) evaluate adverse effects and risk of bias.

Methods: We conducted a systematic review and meta-analysis of experimental studies (single-group pre-post or randomized controlled trials) that involved administration of psilocybin, ayahuasca, or LSD to clinical or non-clinical samples and assessed psychological outcomes ⩾24 h post-administration. Effects were summarized by study design, timepoint, and outcome domain.

Results: A total of 34 studies (24 unique samples, n = 549, mean longest follow-up = 55.34 weeks) were included. Classical psychedelics showed significant within-group pre-post and between-group placebo-controlled effects on a range of outcomes including targeted symptoms within psychiatric samples, negative and positive affect-related measures, social outcomes, and existential/spiritual outcomes, with large between-group effect in these domains (Hedges’ gs = 0.84 to 1.08). Moderator tests suggest some effects may be larger in clinical samples. Evidence of effects on big five personality traits and mindfulness was weak. There was no evidence of post-acute adverse effects.

Conclusions: High risk of bias in several domains, heterogeneity across studies, and indications of publication bias for some models highlight the need for careful, large-scale, placebo-controlled randomized trials.

Goldberg, S. B., Shechet, B., Nicholas, C. R., Ng, C. W., Deole, G., Chen, Z., & Raison, C. L. (2020). Post-acute psychological effects of classical serotonergic psychedelics: a systematic review and meta-analysis. Psychological medicine, 50(16), 2655–2666. https://doi.org/10.1017/S003329172000389X

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