Electroconvulsive therapy (ECT) and subanesthetic intravenous ketamine are both currently used for treatment-resistant major depression, but the comparative effectiveness of the two treatments remains uncertain. We conducted an open-label, randomized, noninferiority trial involving patients referred to ECT clinics for treatment-resistant major depression. Patients with treatment-resistant major depression without psychosis were recruited and assigned in a 1:1 ratio to receive ketamine or ECT. During an initial 3-week treatment phase, patients received either ECT three times per week or ketamine (0.5 mg per kilogram of body weight over 40 minutes) twice per week. The primary outcome was a response to treatment (i.e., a decrease of ≥50% from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report; scores range from 0 to 27, with higher scores indicating greater depression). The noninferiority margin was -10 percentage points. Secondary outcomes included scores on memory tests and patient-reported quality of life. After the initial treatment phase, the patients who had a response were followed over a 6-month period. A total of 403 patients underwent randomization at five clinical sites; 200 patients were assigned to the ketamine group and 203 to the ECT group. After 38 patients had withdrawn before initiation of the assigned treatment, ketamine was administered to 195 patients and ECT to 170 patients. A total of 55.4% of the patients in the ketamine group and 41.2% of those in the ECT group had a response (difference, 14.2 percentage points; 95% confidence interval, 3.9 to 24.2; P<0.001 for the noninferiority of ketamine to ECT). ECT appeared to be associated with a decrease in memory recall after 3 weeks of treatment (mean [±SE] decrease in the T-score for delayed recall on the Hopkins Verbal Learning Test-Revised, -0.9±1.1 in the ketamine group vs. -9.7±1.2 in the ECT group; scores range from -300 to 200, with higher scores indicating better function) with gradual recovery during follow-up. Improvement in patient-reported quality-of-life was similar in the two trial groups. ECT was associated with musculoskeletal adverse effects, whereas ketamine was associated with dissociation. Ketamine was noninferior to ECT as therapy for treatment-resistant major depression without psychosis. (Funded by the Patient-Centered Outcomes Research Institute; ELEKT-D ClinicalTrials.gov number, NCT03113968.).

Microtubules are polarized polymers that exhibit dynamic instability, with alternating phases of elongation and shortening, particularly at the more dynamic plus-end. Microtubule plus-end tracking proteins (+TIPs) localize to and track with growing microtubule plus-ends in the cell. +TIPs regulate microtubule dynamics and mediate interactions with other cellular components. The molecular mechanisms responsible for the +TIP tracking activity are not well understood, however. We reconstituted the +TIP tracking of mammalian proteins EB1 and CLIP-170 in vitro at single-molecule resolution using time-lapse total internal reflection fluorescence microscopy. We found that EB1 is capable of dynamically tracking growing microtubule plus-ends. Our single-molecule studies demonstrate that EB1 exchanges rapidly at microtubule plus-ends with a dwell time of <1 s, indicating that single EB1 molecules go through multiple rounds of binding and dissociation during microtubule polymerization. CLIP-170 exhibits lattice diffusion and fails to selectively track microtubule ends in the absence of EB1; the addition of EB1 is both necessary and sufficient to mediate plus-end tracking by CLIP-170. Single-molecule analysis of the CLIP-170–EB1 complex also indicates a short dwell time at growing plus-ends, an observation inconsistent with the copolymerization of this complex with tubulin for plus-end-specific localization. GTP hydrolysis is required for +TIP tracking, because end-specificity is lost when tubulin is polymerized in the presence of guanosine 5′-[α,β-methylene]triphosphate (GMPCPP). Together, our data provide insight into the mechanisms driving plus-end tracking by mammalian +TIPs and suggest that EB1 specifically recognizes the distinct lattice structure at the growing microtubule end.

Recent years have seen renewed interest and research about the use of hallucinogens as possible agents in the treatment of psychiatric disorders. However, we are unaware of studies assessing the current attitudes of American psychiatrists regarding hallucinogens. Therefore, we e-mailed surveys to 1000 members of the American Psychiatric Association—250 resident-fellows and 750 attending psychiatrists. The response rate was 32.4%. Respondents tended to perceive hallucinogens as potentially hazardous and appropriately illegal for recreational purposes. However, a large minority expressed optimism about the potential use of hallucinogens for psychiatric treatment. Male and trainee respondents, as compared with female and attending respondents, reported less concern about the risks of hallucinogens and greater optimism about their therapeutic potential. Younger psychiatrists also seemed more optimistic. Optimism among trainees and younger psychiatrists may possibly reflect greater exposure to recent positive publications about hallucinogens and less awareness of more negative past reports.

Despite resurgent interest in psychedelic-assisted therapy, our insights into psychiatrists’ knowledge and opinions about medicinal psychedelic applications are surprisingly narrow. Therefore, we anonymously surveyed psychiatrists attending psychedelic didactic presentations at two national meetings about these issues using a 26-item questionnaire. Response rate was 40.20% (106/264). Respondents were 41.73 ± 13.31 years old (range: 24–80) and 64.42% were male. They largely believed psychedelics show treatment promise and strongly supported federal funding for medicinal psychedelic research. The most common concerns were the lack of trained psychedelic-assisted therapy providers, the logistics of psychedelic-assisted therapy delivery, the administration of psychedelics for patients with contraindications, and diversion. The most desired psychedelic-related educational topics were potential benefits of psychedelic-assisted therapy, how to conduct psychedelic-assisted therapy, psychedelic pharmacology, and psychedelic side effects. Factors associated with increased belief in psychedelics’ treatment potential included working primarily in research, scoring higher on a psychedelic knowledge test, and reporting less concern about psychedelics’ addictive potential. Working primarily in research and consult-liaison psychiatry fellowship training were positively associated with support for medicinal psychedelic legalization, while increased concerns about addictive potential and attending psychiatrist status were negatively associated. Support for legalization of non-medicinal psychedelic use was negatively associated with age and positively associated with support for legalization of medicinal psychedelic use.

Background: In the wake of positive clinical trial outcomes of psychedelic-assisted psychotherapy for the treatment of various psychiatric disorders, there has been an influx of financial investment into psychedelic drug development from the pharmaceutical and biotech sectors. Psychedelics are now a multibillion dollar industry, with hundreds of companies that are seeking to commercialize therapeutic applications of psychedelics formed over the course of just a few years. Materials and Methods: This paper aims to provide a broad overview of the psychedelic industry by detailing the history and current state of psychedelic drug commercialization, exploring challenges to commercial viability, highlighting ethical considerations, and incorporating lessons from the analogous ketamine and cannabis industries, which largely preceded the psychedelic industry. Results: We found that although the roots of the psychedelic industry go back decades, financial investment did not take off in earnest until the late 2010s and early 2020s. The main focus of companies in the psychedelic sector can be broadly grouped into: (1) drug discovery and development; (2) novel formulations and routes of administration; (3) manufacturing and synthesis; (4) treatment centers and wellness clinics; (5) consumer packaged goods and adult use; and (6) adjunct technologies. Challenges to commercial viability include regulatory barriers to drug development, treatment costs and logistics of administration, and intellectual property and patent issues. In terms of ethics, the industry must consider the potential adverse effects of psychedelics, cost-cutting inclinations, ensuring therapeutic benefits reach vulnerable and marginalized communities, and indigenous reciprocity. We also underscore the potential benefits commercialization may bring. Lastly, the ketamine and cannabis industries can provide blueprints for regulatory approval, clinical implementation, insurance reimbursement, and federal policy more broadly. Conclusion: Altogether, this article provides a wide-spanning overview of the emerging commercialization of psychedelics, acknowledging both the monumental progress and critical challenges that remain for the industry.