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Psychedelic-assisted therapy for functional neurological disorders: A theoretical framework and review of prior reports

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Abstract

Functional neurological disorders (FNDs), which are sometimes also referred to as psychogenic neurological disorders or conversion disorder, are common disabling neuropsychiatric disorders with limited treatment options. FNDs can present with sensory and/or motor symptoms, and, though they may mimic other neurological conditions, they are thought to occur via mechanisms other than those related to identifiable structural neuropathology and, in many cases, appear to be triggered and sustained by recognizable psychological factors. There is intriguing preliminary evidence to support the use of psychedelic-assisted therapy in a growing number of psychiatric illnesses, including FNDs. We review the theoretical arguments for and against exploring psychedelic-assisted therapy as a treatment for FNDs. We also provide an in-depth discussion of prior published cases detailing the use of psychedelics for psychosomatic conditions, analyzing therapeutic outcomes from a contemporary neuroscientific vantage as informed by several recent neuroimaging studies on psychedelics and FNDs.

Stewart, B., Dean, J. G., Koek, A., Chua, J., Wabl, R., Martin, K., Davoodian, N., Becker, C., Himedan, M., Kim, A., Albin, R., Chou, K. L., & Kotagal, V. (2020). Psychedelic-assisted therapy for functional neurological disorders: A theoretical framework and review of prior reports. Pharmacology research & perspectives, 8(6), e00688. https://doi.org/10.1002/prp2.688

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Post-Marketing Safety Concerns with Esketamine: A Disproportionality Analysis of Spontaneous Reports Submitted to the FDA Adverse Event Reporting System

/ Ketamine, Papers, Psychiatry & Medicine, Publications / / , , , ,

Abstract

Introduction: Esketamine nasal spray received approval for treatment-resistant depression in March 2019.

Objective: Using the FDA Adverse Event Reporting System (FAERS) database (March 2019-March 2020), we analysed esketamine-related adverse events (AEs) to detect and characterize relevant safety signals.

Methods: We used the consolidated case/non-case approach to estimate the reporting odds ratio (ROR) and information component (IC) with relevant confidence intervals (95% CI) for esketamine-related AEs with ≥4 counts. Comparisons between serious and non-serious AEs were performed using non-parametric tests.

Results: The FAERS database contained 962 cases of esketamine-related AEs, with signals detected for several AEs, such as dissociation (ROR = 1,612.64, 95% CI = 1,354.63, 1,919.79; IC = 8.19, 95% CI = 7.96, 8.35), sedation (ROR = 238.46, 95% CI = 202.98, 280.15; IC = 7, 95% CI = 6.75, 7.18), feeling drunk (ROR = 96.17, 95% CI = 61.42, 150.57; IC = 4.84, 95% CI = 4.09, 5.36), suicidal ideation (ROR = 24.03, 95% CI = 18.72, 30.84; IC = 4.31, 95% CI = 3.9, 4.61), and completed suicide (ROR = 5.75, 95% CI = 3.18, 10.41; IC = 2.25, 95% CI = 1.23, 2.94). Signals for suicidal and self-injurious ideation, but not suicide attempt and completed suicide, remained when comparing esketamine to venlafaxine. Females and patients receiving antidepressant polypharmacy, co-medication with mood stabilizers, antipsychotics, benzodiazepines, or somatic medications were more likely to suffer from serious versus non-serious AEs (χ2 = 125.29, p < 0.001, χ2 = 9.08, p = 0.003, χ2 = 8.14, p = 0.004, χ2 = 19.48, p < 0.001, χ2 = 25.62, p < 0.001, and χ2 = 16.79, p < 0.001, respectively).

Conclusions: Esketamine may carry a clear potential for serious AEs, which deserves urgent clarification by means of further prospective studies.

Gastaldon, C., Raschi, E., Kane, J. M., Barbui, C., & Schoretsanitis, G. (2021). Post-marketing safety concerns with esketamine: a disproportionality analysis of spontaneous reports submitted to the FDA adverse event reporting system. Psychotherapy and psychosomatics, 90(1), 41-48; 10.1159/000510703
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Rethinking enhancement substance use: A critical discourse studies approach

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Abstract

Background: We draw on both interdisciplinary enhancement substance use research and critical drug studies scholarship to reconceptualise enhancement substance use. Our critical discourse approach illuminates how a variety of substances are positioned as tools for self-improvement. In reconceptualising enhancement substance use, we ask what different substances can be positioned as providing enhancement? How are they positioned as tools for achieving enhancement or self-improvement goals? What discursive repertoires are employed to achieve these aims?

Methods: Forty interviews were conducted with people who use substances, such as ayahuasca, psilocybin, cocaine, alcohol, nootropics and non-prescription pharmaceuticals, including Adderall and modafinil. To explore the meanings of and motivations for substance consumption, we apply the sociocognitive approach (SCA) pioneered by Teun van Dijk (2014; 2015) and examine language through the triangulation of cognition, discourse and society. We analyse how different substances are positioned as tools for achieving enhancement or self-improvement goals.

Results: We identify three distinct discursive repertoires that frame substance use as enhancement: the discourse of transformation, the discourse of healing and the discourse of productivity. When accounting for enhancement substance use, our participants employ a number of discursive strategies, including ideological polarisation or ‘othering’, analogies, examples, maxims, metaphors and figurative speech. We also find evidence of interdiscursivity with most participants drawing on more than one discourse when speaking about how substances are positioned as providing enhancement.

Conclusion: We conclude that the concept of enhancement has wider applicability than current understandings allow. We argue that if we reframe all substance use as providing enhancement or achieving a self-improvement goal, we have the potential to destigmatise substance use and eliminate the over-simplistic binaries that surround it.

Askew, R., & Williams, L. (2021). Rethinking enhancement substance use: A critical discourse studies approach. The International journal on drug policy, 95, 102994. https://doi.org/10.1016/j.drugpo.2020.102994

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

/ Ketamine, LSD, MDMA, Mushrooms / Psilocybin, Papers / Leave a Comment / / , , , , , ,

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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Combining Ketamine, Brain Stimulation (rTMS) and Mindfulness Therapy (TIMBER) for Opioid Addiction

/ Anxiety Disorders / PTSD, Ketamine, Papers, Substance Use Disorder / Leave a Comment / / ,

Abstract

Opioid addiction in the United States currently presents a national crisis despite availability of different treatments. Prior findings suggest that both repetitive transcranial magnetic stimulation (rTMS) and subanesthetic dose of ketamine are efficacious in patients with opioid use disorders (OUD) when administered in isolation. However, their therapeutic value may be undermined by varying clinical responses that tend to dissipate with treatment cessation. There has been no study to date that has used a combination of both for OUD, and there are still many unanswered questions with respect to both. TIMBER (Trauma Interventions using Mindfulness Based Extinction and Reconsolidation of memories) therapy attempts to alter the expression of emotionally charged memories such as traumatic memories, and has been successfully tried in chronic post-traumatic stress disorder (PTSD) and in combination with memory-altering pharmacotherapy like ketamine infusion. By a combination of extinction and reconsolidation of memory approaches, TIMBER works to not over-flood and/or retraumatize as is seen in other treatment approaches. TIMBER involves a balanced combination of both the memory extinction and memory reconsolidation approaches (rather than extinction-only approaches) which explains its superior efficacy in PTSD and benefit in substance use disorders.

Pradhan, B., & Rossi, G. (2020). Combining Ketamine, Brain Stimulation (rTMS) and Mindfulness Therapy (TIMBER) for Opioid Addiction. Cureus, 12(11), e11798. https://doi.org/10.7759/cureus.11798

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

/ Depressive Disorders, Ketamine, Papers / Leave a Comment / / , , , ,

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

/ Depressive Disorders, Ketamine, Neuroscience, Papers / Leave a Comment / / , , , , , ,

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 Psychedelic Personality: Personality Structure and Associations in a Sample of Psychedelics Users

/ Papers, Psychology / Leave a Comment / /

Abstract

Research on the relationship between personality and psychedelics use has found evidence of a two-way influence where the personality structure predicts individual responses to psychedelics, and psychedelics use results in lasting changes to the individual’s personality structure. This study used brief personality measures in the form of the Ten-Item Personality Inventory (TIPI) and a simplified version of the Risk Taking Index (RTI) in order to measure personality traits in a sample of psychedelics users (N = 319). The participants in the study scored consistently higher than norms on each of the Big Five traits except Extraversion, and on every dimension of risk taking in the RTI. In multivariate logistic regression analyses, personality structure was associated with characteristics of the psychedelic experience that included the feelings of fear, love, and peace as well as states of perceived contact with non-ordinary beings and transcendent forces.

Johnstad P. G. (2021). The Psychedelic Personality: Personality Structure and Associations in a Sample of Psychedelics Users. Journal of psychoactive drugs, 53(2), 97–103. https://doi.org/10.1080/02791072.2020.1842569

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Evaluation of the Cytotoxicity of Ayahuasca Beverages

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Abstract

Ayahuasca is a beverage consumed at shamanic ceremonies and currently has gained popularity on recreational scenarios. It contains beta-carboline alkaloids and N,N-dimethyltryptamine, which possesses hallucinogenic effects. Only a few studies have elicited the psychoactive effects and the dose of such compounds on neurological dopaminergic cells or animals. In this work, we aimed to study the cytotoxic effects of these compounds present in ayahuasca beverages and on five different teas (Banisteriopsis caapi, Psychotria viridis, Peganum harmala, Mimosa tenuiflora and Dc Ab (commercial name)) preparations on dopaminergic immortalized cell lines. Moreover, a characterization of the derivative alkaloids was also performed. All the extracts were characterized by chromatographic systems and the effect of those compounds in cell viability and total protein levels were analyzed in N27 dopaminergic neurons cell line. This is the first article where cytotoxicity of ayahuasca tea is studied on neurological dopaminergic cells. Overall, results showed that both cell viability and protein contents decreased when cells were exposed to the individual compounds, as well as to the teas and to the two mixtures based on the traditional ayahuasca beverages.

Simão, A. Y., Gonçalves, J., Gradillas, A., García, A., Restolho, J., Fernández, N., Rodilla, J. M., Barroso, M., Duarte, A. P., Cristóvão, A. C., & Gallardo, E. (2020). Evaluation of the Cytotoxicity of Ayahuasca Beverages. Molecules (Basel, Switzerland), 25(23), 5594. https://doi.org/10.3390/molecules25235594

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Psychedelics as an emerging novel intervention in the treatment of substance use disorder: a review

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Abstract

Classical psychedelics are a group of drugs characterized by their activation of the serotonin-2A (5-hydroxytryptamine-2A; 5-HT2A) receptor and the unique hallucinogenic and mystical-type experiences that result. After a substantial period of restrictions limiting investigations into the therapeutic potential of psychedelics, a relatively recent recommencement of interest has sparked the burgeoning possibility for these drugs to play a part in the treatment of a wide array of psychopathologies. One of the most promising is in the study of addiction. Evidence has emerged that psychedelic agents may provide a novel avenue for the clinical treatment of patients dealing with substance use disorders (SUD). These serotonergic hallucinogens have displayed remarkable and enduring positive outcomes in this area, even when administered as one or two doses. The neural targets for these psychedelics are varied and underlie a complex mechanism of action-modulating multiple neural networks. It is believed that these agents allow for the reorganization of disordered neural pathways in the default mode network and attenuate maladaptive signaling in mesolimbic reward circuitry. The aim of this review is to examine the current standing of evidence regarding psychedelic psychopharmacology and to provide an overview of the use and effectiveness of these drugs in the treatment of SUD, alcohol use disorder, and for smoking cessation.

DiVito, A. J., & Leger, R. F. (2020). Psychedelics as an emerging novel intervention in the treatment of substance use disorder: a review. Molecular biology reports, 47(12), 9791–9799. https://doi.org/10.1007/s11033-020-06009-x

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Reciprocity and the Nagoya Protocol in Psychedelic Therapy - June 30

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