Acute Mood-Elevating Properties of Microdosed Lysergic Acid Diethylamide in Healthy Volunteers: A Home-Administered Randomized Controlled Trial.

BACKGROUND: Microdosing psychedelic drugs is a widespread social phenomenon with diverse benefits claimed for mood and cognition. Randomized controlled trials have failed to support these claims, but the laboratory-based dosing in trials conducted to date may have limited ecological validity. METHODS: Healthy male volunteers were randomized into lysergic acid diethylamide (LSD) (n = 40) and placebo (n = 40) groups and received 14 doses of either 10 µg LSD or an inactive placebo every 3 days for 6 weeks. First doses were given in a supervised laboratory setting, with other doses self-administered in a naturalistic setting. Results of safety data, blinding, daily questionnaires, expectancy, and pre-/postintervention psychometrics and cognitive tasks are presented here. RESULTS: The most notable reported adverse event was treatment-related anxiety, which prompted the withdrawal of 4 participants from the LSD group. Daily questionnaires showed credible evidence (>99% posterior probability) of improved ratings of creativity, connectedness, energy, happiness, irritability, and wellness on dose days compared with nondose days, and these effects remained when controlling for preintervention expectancy. No questionnaire or cognitive task showed a credible change between baseline and 6-week assessment time points. CONCLUSIONS: Microdosing LSD appears to be relatively safe in healthy adult men, notwithstanding a risk of anxiety. While microdosing elicited transient increases in scales associated with mood-elevating effects, it was not sufficient to promote enduring changes to overall mood or cognition in healthy adults. Future microdosing trials in clinical populations will require the use of active placebos to control for placebo effects and dose titration to adjust for interindividual variability in drug response.

A randomised, double-blind, active placebo-controlled, parallel groups, dose-response study of scopolamine hydrobromide (4-6 µg/kg) in patients with major depressive disorder.

BACKGROUND: Depressive disorders are a leading cause of disability, but current behavioural and pharmacological therapies have a slow onset of response, typically taking several weeks before achieving efficacy. Prior studies using triplicate intravenous scopolamine infusions have been shown to reduce depressive symptomologies within days compared to saline placebo infusions. However, several parameters of scopolamine's potential antidepressant effect remain unknown, such as its dose-response profile and its washout period. There is also the question as to whether the previously reported antidepressant responses were confounded by unblinding effects due to the lack of an active placebo control. Glycopyrronium bromide was selected as placebo for this trial given it has similar antimuscarinic properties to scopolamine hydrobromide but an inability to cross the blood-brain barrier, thereby hypothetically mimicking only the peripheral effects of scopolamine. METHODS/DESIGN: A parallel group trial of single intravenous scopolamine infusions at three doses (4, 5, and 6 µg/kg) along with one glycopyrronium bromide 4 µg/kg group will be administered to 40 participants with major depressive disorder in a 1:1:1:2 ratio, respectively. The primary outcome measure will be the Montgomery-Åsberg Depression Rating Scale (MADRS) administered at baseline, 4 hours, 1 day, 3 days, 1 week, 2 weeks, 4 weeks, and 6 weeks post-infusion to determine antidepressant efficacy. As a secondary measure, the Quick Inventory of Depressive Symptomatology will be administered alongside the MADRS to further track potential antidepressant responses. Other secondary measures include electroencephalography, blood samples, and Bowdle visual acuity scales recorded at baseline, 5, 10, 15, 20, 30, 60, 120, and 240 min post-infusion to determine the pharmacokinetic-pharmacodynamic profile of scopolamine in depressed participants. DISCUSSION: This trial contributes to the literature surrounding the efficacy of scopolamine as an antidepressant. Determining the dose-response profile and washout period of scopolamine's antidepressant effect will also provide important information for designing and conducting crossover trials. The use of an active placebo is important to reduce potentially confounding expectancy effects. TRIAL REGISTRATION: The trial was registered in the Australian New Zealand Clinical Trials Registry (registration number ACTRN12619000569101). Registered on 11 April 2019.