This study will examine the effect of a low dose of the 5HT2A agonist LSD (26 µg), compared to placebo, on acute and protracted mood states in individuals with depression. The investigators will assess the relationship between mood-related symptoms and EEG as a neurophysiological marker.

Depression is one of the leading mental health disorders in the U.S, with an estimated 21 million adults having at least one major depressive episode in the past year. Existing antidepressant medications have limited efficacy, undesirable side effects and can take weeks to months to provide relief of symptoms. Compounds that modulate serotonin 2A receptor signaling have potential to elicit rapid antidepressant effects, and one promising example of these compounds is lysergic acid diethylamide (LSD). There are widespread reports that very low doses of LSD improve mood and energy without producing hallucinogenic effects. Yet, these effects have not been rigorously tested under blinded, placebo-controlled conditions. There is an urgent need for controlled studies to assess the potential efficacy and the mechanisms that mediate any therapeutic effects.

In a preliminary double-blind, placebo-controlled study, the investigators found that depressed individuals reported acute mood enhancing effects after a single low dose of LSD, as well as improvements in anhedonia and sleep disturbance related symptoms, for as long as two days after the dose (preliminary data). The mechanisms underlying these effects are not known. While the acute mood enhancing effects may be due to direct actions of the drug at serotonin 2A receptors, animal models suggest that the sustained antidepressant-like effects of LSD are mediated by enhanced neural plasticity. In healthy humans, low doses of LSD produce sustained neurophysiological changes detected via EEG and on sleep measures, some of which may be related to antidepressant effects. In animal models, LSD produces long-lasting antidepressant-like responses as well as increased synaptic and dendritic growth in cortical regions days after drug exposure. Notably, these changes in structural plasticity are dependent on brain derived neurotrophic factor (BDNF), a protein that peaks after 24 hours in animal models.

In the current study the investigators will examine acute and delayed improvements in mood following a single low dose of LSD, in individuals with major depressive disorder (MDD). The investigators will examine the mechanisms underlying these antidepressant effects by assessing drug-induced neurophysiological changes using depression-sensitive behavioral tasks, EEG, and changes in sleep quality and architecture.

Inclusion Criteria:

• English Fluency
• high school education or higher
• BMI between 19-30 kg/m2

Exclusion Criteria:

• individuals with a medical condition contraindicating study participation as determined by the study physician (e.g., liver disease, abnormal EKG, liver or cardiovascular disease)
• high blood pressure (>140/90)
• current suicidal ideation or suicide attempt in past 12 months
• past year severe substance use disorder
• personal or first-degree relative with history of psychosis
• currently taking any psychiatric medication (for conventional antidepressants must be off for ≥ 2 weeks)
• active panic disorder
• severe obsessive-compulsive disorder
• severe post-traumatic stress disorder
• women who are pregnant or planning to become pregnant