Ketamine’s pharmacological profile makes it an interesting and useful drug to challenge treatment-resistant-depression (TRD). Emerging adverse events associated with single-slow-sub-anaesthetic doses for the treatment of depression are common, although generally transient and self-limited. Nevertheless, data on the safety of this practice are scarce. Thus, it seems timely before ketamine is used for clinical treatment of depression to recommend careful monitoring and reporting of all potential adverse events related to ketamine administration. Here, we describe a case of apnea during slow sub-anaesthetic infusion of intravenous ketamine for the treatment of resistant depression. As far as we are concerned, this is an uncommon, previously unreported, and potentially severe adverse event that clinicians should be aware of, and specific management measures should be implemented.
Gómez-Revuelta, M., Fernández-Rodríguez, M., Boada-Antón, L., & Vázquez-Bourgon, J. (2020). Apnea during slow sub-anaesthetic infusion of intravenous ketamine for treatment-resistant depression. Therapeutic advances in psychopharmacology, 10, 2045125320981498. https://doi.org/10.1177/2045125320981498
Objective: To conduct a systematic review of modern-era (post-millennium) clinical studies assessing the therapeutic effects of serotonergic psychedelics drugs for mental health conditions. Although the main focus was on efficacy and safety, study characteristics, duration of antidepressants effects across studies, and the role of the subjective drug experiences were also reviewed and presented.
Method: A systematic literature search (1 Jan 2000 to 1 May 2020) was conducted in PubMed and PsychINFO for studies of patients undergoing treatment with a serotonergic psychedelic.
Results: Data from 16 papers, representing 10 independent psychedelic-assisted therapy trials (psilocybin = 7, ayahuasca = 2, LSD = 1), were extracted, presented in figures and tables, and narratively synthesized and discussed. Across these studies, a total of 188 patients suffering either cancer- or illness-related anxiety and depression disorders (C/I-RADD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD) or substance use disorder (SUD) were included. The reviewed studies established feasibility and evidence of safety, alongside promising early data of efficacy in the treatment of depression, anxiety, OCD, and tobacco and alcohol use disorders. For a majority of patients, the therapeutic effects appeared to be long-lasting (weeks-months) after only 1 to 3 treatment session(s). All studies were conducted in line with guidelines for the safe conduct of psychedelic therapy, and no severe adverse events were reported.
Conclusion: The resurrection of clinical psychedelic research provides early evidence for treatment efficacy and safety for a range of psychiatric conditions, and constitutes an exciting new treatment avenue in a health area with major unmet needs.
Andersen, K., Carhart-Harris, R., Nutt, D. J., & Erritzoe, D. (2021). Therapeutic effects of classic serotonergic psychedelics: A systematic review of modern-era clinical studies. Acta psychiatrica Scandinavica, 143(2), 101–118. https://doi.org/10.1111/acps.13249
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 Link to full text
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
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
Salvinorin A is the main bioactive compound in Salvia divinorum, an endemic plant with ancestral use by the inhabitants of the Mazateca mountain range (Sierra Mazateca) in Oaxaca, México. The main use of la pastora, as locally known, is in spiritual rites due to its extraordinary hallucinogenic effects. Being the first known nonalkaloidal opioid-mediated psychotropic molecule, salvinorin A set new research areas in neuroscience. The absence of a protonated amine group, common to all previously known opioids, results in a fast metabolism with the concomitant fast elimination and swift loss of activity. The worldwide spread and psychotropic effects of salvinorin A account for its misuse and classification as a drug of abuse. Consequently, salvinorin A and Salvia divinorum are now banned in many countries. Several synthetic efforts have been focused on the improvement of physicochemical and biological properties of salvinorin A: from total synthesis to hundreds of analogues. In this Review, we discuss the impact of salvinorin A in chemistry and neuroscience covering the historical relevance, isolation from natural sources, synthetic efforts, and pharmacological and safety profiles. Altogether, the chemistry behind and the taboo that encloses salvinorin A makes it one of the most exquisite naturally occurring drugs.
Hernández-Alvarado, R. B., Madariaga-Mazón, A., Ortega, A., & Martinez-Mayorga, K. (2020). DARK Classics in Chemical Neuroscience: Salvinorin A. ACS chemical neuroscience, 10.1021/acschemneuro.0c00608. Advance online publication. https://doi.org/10.1021/acschemneuro.0c00608
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
Introduction: Ketamine exhibits antidepressant properties in treatment-resistant depression (TRD) with some concern over its cardiovascular safety and tolerability issues. This paper reports on the cardiovascular safety in short-term intravenous ketamine treatment in TRD inpatients with major depressive disorder (MDD) and bipolar disorder (BP).
Materials and methods: The observational study population comprises 35 MDD and 14 BP subjects treated with intravenous ketamine.
Results: Blood pressure (RR) and heart rate (HR) values returned to baseline within 1.5-hours post infusion with no sequelae for all study subjects. Six time points were analyzed for each infusion: 0′, 15′, 30′, 45′, 60′ and 90′ for RR and HR. After the infusion significant peaks in systolic (p = 0.004) and diastolic (p = 0.038) RR were seen. In concomitant medication with selective serotonin reuptake inhibitors (SSRIs), higher RR peaks (p = 0.020; p = 0.048) were seen as compared to other subjects. The decrease in HR was greater (p = 0.02) in the absence of concomitant medication with mood stabilizers as compared to subjects receiving mood stabilizing medication accompanied by the observation of a greater decrease in diastolic RR among those taking mood stabilizers (p = 0.009).
Limitations: The study may be underpowered due to the small sample size. The observations apply to an inhomogeneous TRD population in a single-site, pilot study, with no blinding and are limited to the acute administration.
Conclusion: The study demonstrates good safety and tolerability profile of intravenous ketamine as add-on intervention to current psychotropic medication in TRD, regardless of the MDD or BP type of mood disorders. The abatement of elevated RR and BP scores was observed in time with no sequelae nor harm. Still, cardiovascular risks appear to be more pronounced in subjects with comorbid arterial hypertension and diabetes mellitus.
Szarmach, J., Cubała, W. J., Włodarczyk, A., & Gałuszko-Węgielnik, M. (2020). Metabolic Risk Factors and Cardiovascular Safety in Ketamine Use for Treatment Resistant Depression. Neuropsychiatric disease and treatment, 16, 2539–2551. https://doi.org/10.2147/NDT.S273287
Background: Psilocybin therapy has shown promise as a rapid-acting treatment for depression, anxiety, and demoralization in patients with serious medical illness (e.g., cancer) when paired with individual psychotherapy. This study assessed the safety and feasibility of psilocybin-assisted group therapy for demoralization in older long-term AIDS survivor (OLTAS) men, a population with a high degree of demoralization and traumatic loss.
Methods: Self-identified gay men OLTAS with moderate-to-severe demoralization (Demoralization Scale-II ≥8) were recruited from the community of a major US city for a single-site open-label study of psilocybin-assisted group therapy comprising 8-10 group therapy visits and one psilocybin administration visit (0·3-0·36 mg/kg po). Primary outcomes were rate and severity of adverse events, and participant recruitment and retention. The primary clinical outcome was change in mean demoralization from baseline to end-of-treatment and to 3-month follow-up assessed with a two-way repeated measures ANOVA. Trial registration: Clinicaltrials.gov (NCT02950467).
Findings: From 17 July 2017 to 16 January 2019, 18 participants (mean age 59·2 years (SD 4·4)) were enrolled, administered group therapy and psilocybin, and included in intent-to-treat analyses. We detected zero serious adverse reactions and two unexpected adverse reactions to psilocybin; seven participants experienced self-limited, severe expected adverse reactions. We detected a clinically meaningful change in demoralization from baseline to 3-month follow-up (mean difference -5·78 [SD 6·01], ηp2 = 0·47, 90% CI 0·21-0·60).
Interpretation: We demonstrated the feasibility, relative safety, and potential efficacy of psilocybin-assisted group therapy for demoralization in OLTAS. Groups may be an effective and efficient means of delivering psychotherapy pre- and post-psilocybin to patients with complex medical and psychiatric needs.
Anderson, B. T., Danforth, A., Daroff, P. R., Stauffer, C., Ekman, E., Agin-Liebes, G., Trope, A., Boden, M. T., Dilley, P. J., Mitchell, J., & Woolley, J. (2020). Psilocybin-assisted group therapy for demoralized older long-term AIDS survivor men: An open-label safety and feasibility pilot study. EClinicalMedicine, 27, 100538. https://doi.org/10.1016/j.eclinm.2020.100538
Over the last decade, psychedelics have made a comeback in the world of research and academia. As they enter into a new phase of clinical trials, they bear the promise of improving people’s well-being by reducing their depression and anxiety, helping them overcome addiction, or even helping them cope with death and bereavement. This has caused a wave of new publicity, acceptance, and enthusiasm around psychedelic science.
Given that this area of research has been taboo for many decades, there is reason to be optimistic. There is an amount of new data coming in from numerous new clinical trials across various patient groups. As we anticipate the results of these investigations, it is equally important to remain critical, however, in order to ensure that this newly found enthusiasm does not reinstate the myth of the magic bullet that will ultimately cure all our mental ailments.
As research is being conducted in ever more places, some key challenges for the field are also becoming apparent. This piece wants to address those scientific issues as psychedelic science moves forward. Science in Crisis
The scientific study of psychedelics is not immune from broader crises that are currently ongoing in the scientific realm, like the replication crisis, the lack of Open Science practices and the increasingly privatized funding of research.
The replication crisis comes from research that has shown that many results across different scientific studies cannot be reproduced. This has sometimes led to questionable research practices, such as modifying the results, fabricating data, or selective reporting of false positive findings, by individual actors. Prior hypotheses most often do not yield positive results, and researchers are often faced with unexpected findings.
Publishing these chance findings becomes problematic if the researchers do not clearly demarcate them as such, and conceal the failure of the initial hypothesis and post-hoc explanation of their findings. According to a meta-analysis conducted by Daniela Fanelli (2009), up to 72% of all scientists admit to witnessing questionable research practices concerning the behavior of their colleagues. Misconduct was reported most frequently in the areas of medical and pharmacological research, hence the area of psychedelic research is likely to be implicated. This is something to be acutely aware of. Positivity bias
Many researchers in the field are understandably psychedelic enthusiasts. This bears a significant risk of selective reporting and motivated reasoning. The promise of psychedelics shown in clinical trials has already led to a nearly one-sided emphasis on the positive effects in the scientific literature, while ignoring the potentially adverse consequences such as mystic ego inflation, neuroticism, or the potential to induce false memories.
Combined with the earlier mentioned broader current problems in science, these over-positive tendencies are incentivized on a community-wide level due to a strong bias towards publishing positive findings, while the negative results are left unpublished in a file drawer.
This problem may be especially pertinent given the relatively high costs and investments involved in conducting psychedelic research, thereby creating a strong incentive for publishing positive results. And what may further limit the researcher’s degree of freedom, is that most studies on psychedelics are sponsored by private foundations with a vested interest.
Open Science practices
Many of these issues can be addressed by adhering to the guidelines of the Open Science Framework. This includes the preregistration of all hypotheses, the study design, data collection methods, and analysis pipelines to increase transparency throughout every step of the scientific process.
Many journals even offer the opportunity of depositing a research question and study design with a registration service or journal before conducting a scientific investigation. Future studies in the domain of psychedelic research would do well by making use of these practices in order to increase the credibility of their findings, and devote extra energy towards replicating some of the existing results via independent research groups. Placebo-problem
The altered states resulting from psychedelics differ so profoundly from other substances, that there is an ongoing search for a good placebo. In a study of mystical experiences, methylphenidate hydrochloride (Ritalin) was used as a placebo (Griffiths, Richards, Mccann, & Jesse, 2006), in studies of psilocybin to treat anxiety in advanced stage cancer patients, niacin (vitamin B3, which produces flushing) was used as a placebo. And in a study of ayahuasca as treatment for depression researchers used zinc sulfate as a placebo, which may induce nausea and vomiting, playing into one of the commonly expected side effects of the hallucinogenic brew. (de Fontes, 2017).
Even within the classical pharmacological research framework for antidepressants, participants could often guess their test condition – which is known as ‘breaking blind’. This boosts the risk of reporting positively on their perceived mental state due to social desirability.
Psychedelic research is particularly prone to these dangers given the profound changes of subjective experiences, which cannot be easily mimicked with active placebos. This inherent risk will always beg the critical question if the subjective effects of psychedelics are determined by social desirability, prior expectations, or suggestibility of the participants.
Current research has partially addressed the placebo-problem by using different dose ranges. For instance, a microdose, minidose, and full-dose within the same cohort. However, the contrasting method of cognitive science and neuroimaging techniques itself, may be a source of ambiguity when interpreting modern day findings. Comparing Altered States
On a fundamental level there is still a critical gap between an empiric understanding around altered states of consciousness, their underlying mechanisms and their application within clinical practice. We don’t know yet how the effects of psychedelics compare to other methods that have been used to induce altered states of consciousness, such as meditation, sensory deprivation, or breathing exercises. And we’re not good at measuring them.
The renowned theory of decreased Default Mode Network connectivity in response to psychedelics, may also have been driven by the effects of the placebo condition. Extreme boredom and mind wandering are associated with heightened activity of the Default Mode Network, which may create an exaggerated impression that psychedelics decrease the activity whereas in fact the placebo condition is increasing it.
Only relying on these types of contrasts may create a one-sided impression that Default Mode Network activity and ego-dissolution are primary mechanisms of action in psychedelics, while disregarding subjective accounts of indigenous ayahuasca practices wherein the ego remains intact.
Future research should address these nuances and develop more elaborate or diverse blinding methods, while an even more effective line of research could focus on comparing psychedelics to altered states across the full diversity of conscious experience.
This way, researchers may draw more elaborate conclusions by comparing the commonalities and differences between the neurophenomenology of different induction methods. Systematic Bias
Like any other field, psychedelic research is not exempt from systematic biases that stem from cultural or socioeconomic differences amongst their respective participants. In the field of psychology, this problem is also known as the W.E.I.R.D bias: the majority of all participants are recruited from Western, Educated, Industrialized, Rich, and Democratic societies.
Given that tribal cultures compared to people from WEIRD populations exhibit significant differences in the most paradigmatic examples of psychology (such as the Müller-Lyer illusion), the subjective experience of psychedelics may be equally contingent on cultural differences.
In the area of clinical research, it is likewise important to represent a diverse sample of society that includes members of marginalized cultures or economic status, or risk inheriting biases that are systemic to society.
And while the contextual effects of set and setting are widely acknowledged within the psychedelic research community, future studies should aim to validate their underlying mechanisms in a cross-cultural manner. The way forward
Much of the research on psychedelics has focused on extreme cases to make psychedelics more politically acceptable for research, like getting psilocybin approved for a study of terminally ill patients, and treating patients who are suffering from treatment-resistant depression. This has created large-scale clinical samples of patients where the etiology of their mental disorders is not represented in a fine-grained manner.
While it is important to test the efficacy of psychedelics on a large scale, it is equally important to maintain a fine-grained perspective as we investigate these substances in a stratified manner. These incremental advancements may require patience and a healthy dose of criticism.
In the long run, it may not only advance the research of psychedelics but elevate the quality of research beyond the caveats and systematic biases of their scientific domain.
4 October - Online psychedelic Q&A with Rick Doblin (founder and president of MAPS)
