Of the eight studies that met the eligibility criteria, five indicated that CBT has statistically significant efficacy in reducing positive psychotic symptoms of TRS. There was also evidence that in implementing CBT, a follow-up period of at least six months helps to sustain improvements.

Oral esketamine in patients with treatment-resistant depression: a double-blind, randomized, placebo-controlled trial w/ open-label extension (Apeldoorn et al, 2024) was released on March 25th, 2024.

About one-third of patients with depression do not achieve adequate response to current treatment options. Although intravenous and intranasal administrations of (es)ketamine have shown antidepressant properties, their accessibility and scalability are limited. We investigated the efficacy, safety, and tolerability of generic oral esketamine in patients with treatment-resistant depression (TRD) in a randomized placebo-controlled trial with open-label extension. This study consisted of 1) a six-week fixed low-dose treatment phase during which 111 participants received oral esketamine 30 mg or placebo three times a day; 2) a four-week wash-out phase; and 3) an optional six-week open-label individually titrated treatment phase during which participants received 0.5 to 3.0 mg/kg oral esketamine two times a week. The primary outcome measure was change in depressive symptom severity, assessed with the Hamilton Depression Rating Scale (HDRS17), from baseline to 6 weeks. Fixed low-dose oral esketamine when compared to placebo had no benefit on the HDRS17 total score (p = 0.626). Except for dizziness and sleep hallucinations scores, which were higher in the esketamine arm, we found no significant difference in safety and tolerability aspects. During the open-label individually titrated treatment phase, the mean HDRS17 score decreased from 21.0 (SD 5.09) to 15.1 (SD 7.27) (mean difference -6.0, 95% CI -7.71 to -4.29, p < 0.001). Our results suggest that fixed low-dose esketamine is not effective in TRD. In contrast, individually titrated higher doses of oral esketamine might have antidepressant properties.

This paper illustrates the importance of proper dosing if by mouth to achieve similar effects and safety profiles of other routes of administration of ketamine and its variant, esketamine. Similar outcomes were found in the last four years with racemic ketamine (Nunez, 2020 , Swainson, 2020, Swainson, 2022, Dutton, 2023, Hassan, 2023).

Psychedelic drugs are currently being investigated for their potential to facilitate a variety of long-lasting psychological changes. One area that has yet to be systematically investigated in psychedelic research, however, regards changes in aesthetic experience (i.e., one’s attitudes, perceptions, and expression of art). This is surprising given the wealth of anecdotes directly noting increased appreciation of aesthetic experiences after psychedelic use and that psychedelics have facilitated their own distinctive aesthetic (i.e., “psychedelic art”). To address this gap in the literature, participants in the current study ( N = 54) completed a validated and multifaceted measure of aesthetic experience 1-week before, 1-week after, and 1-month after attending an ayahuasca retreat. We found that compared with baseline, participants exhibited increased levels of aesthetic experience at both the 1-week and 1-month follow-ups. Contrary to our hypotheses, measures of acute drug effects (e.g., mystical-type experiences, awe, and ego dissolution) did not predict changes in aesthetic experience. Although the study was limited by an open-label design, the results support anecdotal reports noting changes in aesthetic experience after psychedelic use. Further research is needed to address limitations related to the study design as well as to identify predictors and mechanisms of changes in aesthetic experience following psychedelic use.

Lisa Luan, MSc. discusses study findings of a novel DMT administration technique that extends the traditionally transient psychedelic effects into a sustained altered state. This makes the substance a powerful candidate in the field of psychedelic research and therapy, allowing neuroscientists to advance their study of human consciousness.

Naturally occurring and psychedelic drug–occasioned experiences interpreted as personal encounters with God are well described but have not been systematically compared. In this study, five groups of individuals participated in an online survey with detailed questions characterizing the subjective phenomena, interpretation, and persisting changes attributed to their single most memorable God encounter experience (n = 809 Non-Drug, 1184 psilocybin, 1251 lysergic acid diethylamide (LSD), 435 ayahuasca, and 606 N,N-dimethyltryptamine (DMT)). Analyses of differences in experiences were adjusted statistically for demographic differences between groups. The Non-Drug Group was most likely to choose "God" as the best descriptor of that which was encountered while the psychedelic groups were most likely to choose "Ultimate Reality." Although there were some other differences between non-drug and the combined psychedelic group, as well as between the four psychedelic groups, the similarities among these groups were most striking. Most participants reported vivid memories of the encounter experience, which frequently involved communication with something having the attributes of being conscious, benevolent, intelligent, sacred, eternal, and all-knowing. The encounter experience fulfilled a priori criteria for being a complete mystical experience in approximately half of the participants. More than two-thirds of those who identified as atheist before the experience no longer identified as atheist afterwards. These experiences were rated as among the most personally meaningful and spiritually significant lifetime experiences, with moderate to strong persisting positive changes in life satisfaction, purpose, and meaning attributed to these experiences. Among the four groups of psychedelic users, the psilocybin and LSD groups were most similar and the ayahuasca group tended to have the highest rates of endorsing positive features and enduring consequences of the experience. Future exploration of predisposing factors and phenomenological and neural correlates of such experiences may provide new insights into religious and spiritual beliefs that have been integral to shaping human culture since time immemorial.

Phase 2a trial shows 60% decrease in depression symptoms with LSD microdoses.

The data suggest that access to a psychedelic helpline surrounding psychedelic experiences may avert harmful outcomes and offset the burden on emergency and medical services.

“…the new bill that’s now being unveiled would provide regulated access to psychedelics in a facilitated setting, without removing criminal penalties for possession outside of that context. It does not lay out any specific qualifying medical conditions that a person must have in order to access the services.”

Treatment of psychiatric disorders with psychedelic substances represents one of the most promising current treatment approaches in psychiatry. Since its inception in the 1950s, therapy with psychedelics has been conceptualised as psychedelic-assisted psychotherapy—ie, a form of psychotherapy that uses the profound biological effects of this class of substances as a catalyst for changing thinking, emotions, and behaviour. In this view, the psychotherapy component of the treatment is considered as being of the utmost importance for both the safety and efficacy of the therapy. This conceptualisation has been challenged by the idea that the latest clinical studies suggest that the potential therapeutic effects of psychedelics must be attributed solely to the substance itself, with no role for psychotherapy. Here, accompaniment by therapists is understood as mere psychological support, to maintain the safety of the substance administration. In this Personal View, we contrast these two views and argue that the characterisation of treatment with psychedelics as a biological intervention (with psychological support as a purely safety-related component) represents an outdated and reductionistic dualism that has dominated psychiatric treatment and research for far too long. This discussion has important implications for the study and the regulation of these compounds.

The main areas of serotonin research provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations. Some evidence was consistent with the possibility that long-term antidepressant use reduces serotonin concentration.

The history of psychedelics spans the spiritual, the recreational, and the legal—and now the medical, thanks to safer and more convenient molecules and protocols