OPEN Foundation

Psychosis

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

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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[Psychedelics in the treatment of substance use disorders and psychosis]

Abstract

After psychedelics were banned in 1968, the flourishing research on the use of psychedelics in patients with a mental disorder stopped abruptly. Recently, we see a renaissance of this research.<br/> AIM: To present an overview of what is known about the treatment of addiction and psychosis with psychedelics.<br/> METHOD: Literature study based on Medline en PubMed publications till December 2019.<br/> RESULTS: Studies on the effectiveness of psychedelics in the treatment of addiction and psychosis is still very limited in size and methodological quality. Nevertheless, most studies show positive effects of both classical and atypical psychedelics in a variety of addictions on motivation, craving, reduced consumption, and abstinence often following a single dose and with long-lasting benefits (3-24 months). Use of ketamine in patients with a psychosis stabilized on an antipsychotic might reduce negative symptoms.<br/> CONCLUSION: Before psychedelics can be used in standard clinical practice for the treatment of patients with an addiction or a psychosis, larger and methodologically better studies are needed. The use of psychedelics also creates an opportunity to better understand the shared underlying pathology of many different mental disorders.
van den Brink, W., Breeksema, J. J., Vermetten, E., & Schoevers, R. A. (2020). Psychedelics in the treatment of substance use disorders and psychosis. Tijdschrift Voor Psychiatrie62(8), 650-658., https://pubmed.ncbi.nlm.nih.gov/32816293/
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Psychedelic Treatment for Trauma-Related Psychological and Cognitive Impairment Among US Special Operations Forces Veterans

U.S. Special Operations Forces Veterans are at increased risk for a variety of mental health problems and cognitive impairment associated with military service. Current treatments are lacking in effectiveness and adherence. Therefore, this study examined psychedelic treatment with ibogaine and 5-methoxy-N,N-dimethyltryptamine for trauma-related psychological and cognitive impairment among U.S. Special Operations Forces Veterans.

We conducted a survey of Veterans who completed a specific psychedelic clinical program in Mexico between 2017 and 2019. Questions probed retrospective reports of mental health and cognitive functioning during the 30 days before and 30 days after treatment. A total of 65 people completed treatment during this time frame and were eligible for contact. Of these, 51 (78%) completed the survey and were included in data analyses (mean age = 40; male = 96%; married = 55%; Caucasian/White = 92%; Operation Enduring Freedom/Operation Iraqi Freedom Service = 96%).

Results indicated significant and very large reductions in retrospective report of suicidal ideation (p < .001; d = −1.9), cognitive impairment (p < .001; d = −2.8), and symptoms of posttraumatic stress disorder (p < .001; d = −3.6), depression (p < .001; d = −3.7), and anxiety (p < .001; d = −3.1). Results also showed a significant and large increase in retrospective report of psychological flexibility (p < .001; d = 2.9) from before-to-after the psychedelic treatment. Increases in the retrospective report of psychological flexibility were strongly associated with retrospective report of reductions in cognitive impairment, and symptoms of posttraumatic stress disorder, depression, and anxiety (rs range −0.61 to −0.75; p < .001). Additionally, most participants rated the psychedelic experiences as one of the top five personally meaningful (84%), spiritually significant (88%), and psychologically insightful (86%) experiences of their lives.
Limitations: Several limitations should be considered including the retrospective, self-report, survey design of the study, and the lack of randomization and blinding, thus making these finding preliminary.

U.S. Special Operations Forces Veterans may have unique treatment needs because of the sequela of problems associated with repeated trauma exposure and the nature of the exposure. Psychedelic-assisted therapy with these under-researched psychedelics may hold unique promise for this population. However, controlled studies are needed to determine whether this treatment is efficacious in relieving mental health and cognitive impairment among U.S. Special Operations Forces Veterans.

Davis, A. K., Averill, L. A., Sepeda, N. D., Barsuglia, J. P., & Amoroso, T. (2020). Psychedelic Treatment for Trauma-Related Psychological and Cognitive Impairment Among US Special Operations Forces Veterans. Chronic Stress4, 2470547020939564; 10.1177/2470547020939564
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A review of emerging therapeutic potential of psychedelic drugs in the treatment of psychiatric illnesses

Abstract

Though there was initial interest in the use of psychedelic drugs for psychiatric treatment, bad outcomes and subsequent passage of the Substance Act of 1970, which placed psychedelic drugs in the Schedule I category, significantly limited potential progress. More recently, however, there has been renewal in interest and promise of psychedelic research. The purpose of this review is to highlight contemporary human studies on the use of select psychedelic drugs, such as psilocybin, LSD, MDMA and ayahuasca, in the treatment of various psychiatric illnesses, including but not limited to treatment-resistant depression, post-traumatic stress disorder, end-of-life anxiety, and substance use disorders. The safety and efficacy as reported from human and animal studies will also be discussed. Accumulated research to date has suggested the potential for psychedelics to emerge as breakthrough therapies for psychiatric conditions refractory to conventional treatments. However, given the unique history and high potential for misuse with popular distribution, special care and considerations must be undertaken to safeguard their use as viable medical treatments rather than drugs of abuse.

Chi, T., & Gold, J. A. (2020). A review of emerging therapeutic potential of psychedelic drugs in the treatment of psychiatric illnesses. Journal of the Neurological Sciences, 116715., 10.1016/j.jns.2020.116715
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Interaction of Sex and Age on the Dissociative Effects of Ketamine Action in Young Healthy Participants.

Abstract

Ketamine is a drug that reduces depressive and elicits schizophrenia-like symptoms in humans. However, it is largely unexplored whether women and men differ with respect to ketamine-action and whether age contributes to drug-effects. In this study we assessed dissociative symptoms via the Clinician Administered Dissociative States Scale (CADSS) in a total of 69 healthy subjects aged between 18 and 30 years (early adulthood) after ketamine or placebo infusion. Dissociative symptoms were generally increased only in the ketamine group post-infusion. Specifically, within the ketamine group, men reported significantly more depersonalization and amnestic symptoms than women. Furthermore, with rising age only men were less affected overall with respect to dissociative symptoms. This suggests a sex-specific protective effect of higher age which may be due to delayed brain maturation in men compared to women. We conclude that it is crucial to include sex and age in studies of drug effects in general and of ketamine-action in specific to tailor more efficient psychiatric treatments. Clinical Trial Registration: EU Clinical Trials Register (EudraCT), trial number: 2010-023414-31.
Derntl, B., Hornung, J., Sen, Z. D., Colic, L., Li, M., & Walter, M. (2019). Interaction of sex and age on the dissociative effects of ketamine action in young healthy participants. Frontiers in neuroscience13, https://doi.org/10.3389/fnins.2019.00616
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100 years of mescaline

Abstract

In the hundred years since Ernst Späth’s synthesis of mescaline, it has been used in clinical research for many purposes, including the study of hallucinations, creativity, and schizophrenia. After Aldous Huxley described his experience with it in The Doors of Perception, it became a public sensation. During the 1960s it was largely replaced as a research compound by LSD. Today its scientific use is subject to strict controls, but the synthetic phenethylamines developed from it are widely used.

Jay, M. (2019). 100 years of mescaline. Monatshefte für Chemie-Chemical Monthly150(5), 957-959., https://doi.org/10.1007/s00706-019-02425-3
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Classic psychedelics: the special role of the visual system

Abstract

Here, we briefly overview the various aspects of classic serotonergic hallucinogens reported by a number of studies. One of the key hypotheses of our paper is that the visual effects of psychedelics might play a key role in resetting fears. Namely, we especially focus on visual processes because they are among the most prominent features of hallucinogen-induced hallucinations. We hypothesize that our brain has an ancient visual-based (preverbal) intrinsic cognitive process that, during the transient inhibition of top-down convergent and abstract thinking (mediated by the prefrontal cortex) by psychedelics, can neutralize emotional fears of unconscious and conscious life experiences from the past. In these processes, the decreased functional integrity of the self-referencing processes of the default mode network, the modified multisensory integration (linked to bodily self-consciousness and self-awareness), and the modified amygdala activity may also play key roles. Moreover, the emotional reset (elimination of stress-related emotions) by psychedelics may induce psychological changes and overwrite the stress-related neuroepigenetic information of past unconscious and conscious emotional fears.

Császár-Nagy, N., Kapócs, G., & Bókkon, I. (2019). Classic psychedelics: the special role of the visual system. Reviews in the neurosciences.,  10.1515/revneuro-2018-0092
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How effective and safe is medical cannabis as a treatment of mental disorders? A systematic review.

Abstract

We conducted a review of systematic reviews (SRs) and randomized-controlled trials (RCTs) to analyze efficacy and safety of cannabis-based medication in patients with mental disorders. Five data bases were systematically searched (2006-August 2018); 4 SRs (of 11 RCTs) and 14 RCTs (1629 participants) were included. Diagnoses were: dementia, cannabis and opioid dependence, psychoses/schizophrenia, general social anxiety, posttraumatic stress disorder, anorexia nervosa, attention-deficit hyperactivity disorder, and Tourette`s disorder. Outcome variables were too heterogeneous to conduct a  meta-analysis. A narrative synthesis method was applied. The study quality was assessed using the risk-of-bias tool and SIGN-checklists. THC- and CBD-based medicines, given as adjunct to pharmaco- and psychotherapy, were associated with improvements of several symptoms of mental disorders, but not with remission. Side effects occurred, but severe adverse effects were mentioned in single cases only. In order to provide reliable treatment recommendations, more and larger RCTs with follow-up assessments, consistent outcome measures and active comparisons are needed.
Hoch, E., Niemann, D., von Keller, R., Schneider, M., Friemel, C. M., Preuss, U. W., … & Pogarell, O. (2019). How effective and safe is medical cannabis as a treatment of mental disorders? A systematic review. European archives of psychiatry and clinical neuroscience269(1), 87-105., https://doi.org/10.1007/s00406-019-00984-4
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The neuropharmacology of sleep paralysis hallucinations: serotonin 2A activation and a novel therapeutic drug

Abstract

Sleep paralysis is a state of involuntary immobility occurring at sleep onset or offset, often accompanied by uncanny “ghost-like” hallucinations and extreme fear reactions. I provide here a neuropharmacological account for these hallucinatory experiences by evoking the role of the serotonin 2A receptor (5-HT2AR). Research has shown that 5-HT2AR activation can induce visual hallucinations, “mystical” subjective states, and out-of-body experiences (OBEs), and modulate fear circuits. Hallucinatory experiences triggered by serotonin-serotonergic (“pseudo”) hallucinations, induced by hallucinogenic drugs-tend to be “dream-like” with the experiencer having insight (“meta-awareness”) that he is hallucinating, unlike dopaminergic (“psychotic” and “life-like”) hallucinations where such insight is lost. Indeed, hallucinatory experiences during sleep paralysis have the classic features of serotonergic hallucinations, and are strikingly similar to perceptual and subjective states induced by hallucinogenic drugs (e.g., lysergic acid diethylamide [LSD] and psilocybin), i.e., they entail visual hallucinations, mystical experiences, OBEs, and extreme fear reactions. I propose a possible mechanism whereby serotonin could be functionally implicated in generating sleep paralysis hallucinations and fear reactions through 5-HT2AR activity. Moreover, I speculate on the role of 5-HT2C receptors vis-à-vis anxiety and panic during sleep paralysis, and the orbitofrontal cortex-rich with 5-HT2A receptors-in influencing visual pathways during sleep paralysis, and, in effect, hallucinations. Finally, I propose, for the first time, a drug to target sleep paralysis hallucinations and fear reactions, namely the selective 5-HT2AR inverse agonist, pimavanserin. This account implicates gene HTR2A on chromosome 13q as the underlying cause of sleep paralysis hallucinations and could be explored using positron emission tomography.

Jalal, B. (2018). The neuropharmacology of sleep paralysis hallucinations: serotonin 2A activation and a novel therapeutic drug. Psychopharmacology235(11), 3083-3091.,  10.1007/s00213-018-5042-1

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Rapid antidepressant effect of S-ketamine in schizophrenia.

Abstract

Rapid anti-suicidal and antidepressant effects of ketamine have repeatedly been confirmed in unipolar and bipolar depression. Although meaningful antidepressant efficacy of ketamine has also been shown in depressed patients with a history of psychotic symptoms, its administration in psychotic disorders has largely been neglected due to its potential to exacerbate dissociative or psychotic symptoms. Presenting a case of a young female inpatient suffering from schizophrenia with a severe post-psychotic depression, we demonstrate a robust anti-suicidal and antidepressant effect of S-ketamine infusions administered thrice weekly for 3 weeks in total. Importantly, no relevant psychotic or dissociative symptoms occurred during the whole augmentation treatment period leading to a sustained remission of depressive symptoms and suicidality. Our safe and effective experience with intravenous S-ketamine might encourage researchers and clinicians to widen its administration range beyond the diagnosis of depression to enrich the current knowledge of ketamine effects in psychotic disorders.
Bartova, L., Papageorgiou, K., Milenkovic, I., Dold, M., Weidenauer, A., Willeit, M., … & Kasper, S. (2018). Rapid antidepressant effect of S-ketamine in schizophrenia. European Neuropsychopharmacology28(8), 980-982., 10.1016/j.euroneuro.2018.05.007
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