Lysergic Acid Diethylamide–Assisted Therapy in Patients With Anxiety With and Without a Life-Threatening Illness: A Randomized, Double-Blind, Placebo-Controlled Phase II Study
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BACKGROUND: This study aimed to investigate the efficacy and safety of lysergic acid diethylamide (LSD)-assisted therapy in patients who experienced anxiety with or without association with a life-threatening illness. METHODS: The study is an investigator-initiated 2-center trial that used a double-blind, placebo-controlled, 2-period, random-order, crossover design with 2 sessions with either oral LSD (200 μg) or placebo per period. The primary end point was anxiety symptoms 16 weeks after the last treatment session, assessed by the Spielberger State-Trait Anxiety Inventory-Global score in 42 patients. Further outcome measures included ratings for depression symptoms (Beck Depression Inventory and Hamilton Depression Rating Scale, 21-item version) and ratings for acute subjective drug effects. The outcomes for the first period (between-subjects analysis) are primarily shown due to carryover effects. RESULTS: LSD treatment resulted in significant reductions of State-Trait Anxiety Inventory-Global scores up to 16 weeks after treatment (least-square mean [standard error] change from baseline difference = -16.2 [5.8], 95% CI, -27.8 to -4.5, d = -1.18, p = .007). Similar effects were observed for ratings of comorbid depression on the Hamilton Depression Rating Scale, 21-item version (-7.0 [1.9], 95% CI, -10.8 to -3.2, d = -1.1, p = .0004) and the Beck Depression Inventory (-6.1 [2.6], 95% CI, -11.4 to -0.9, d = -0.72, p = .02). Positive acute subjective drug effects and mystical-type experiences correlated with the long-term reductions in anxiety symptoms. Transient, mild, acute untoward effects of LSD treatment were reported by 8 patients (19%). One treatment-related serious adverse event (acute transient anxiety) occurred (2%). CONCLUSIONS: LSD produced long-lasting and notable reductions in anxiety and comorbid depression symptoms up to 16 weeks.
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The remaining 7 SAEs occurred in 2 studies and were deemed unrelated to LSD: 2 pregnancies followed by spontaneous abortion; a planned nasal surgery; a radial fracture at a personal event unrelated to the study procedures; a suspected transient ischemic attack; and 2 events (death and esophageal cancer metastasis) during a 1-year follow-up period attributed to preexisting life-threatening illness.
“The remaining 7 SAEs occurred in 2 studies20,27 and were deemed unrelated to LSD: 2 pregnancies followed by spontaneous abortion; a planned nasal surgery; a radial fracture at a personal event unrelated to the study procedures; a suspected transient ischemic attack (2 weeks following LSD dose in a participant with Marfan syndrome and at least 4 prior suspected transient ischemic attack episodes);”
From Adverse Events in Studies of Classic Psychedelics: A Systematic Review and Meta-Analysis (2024) · cites this paper as [20]
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Experimental — accuracy not yet measuredAmong 128 outpatient participants given LSD, 1 participant (0.8%) experienced an acute and subacute SAE involving acute transient anxiety and delusions refractory to lorazepam, requiring olanzapine and overnight observation.
“Among 128 outpatient participants given LSD, 1 participant (0.8%) who received LSD, 200 ug, in a study for anxiety20 experienced an acute and subacute SAE involving “acute transient anxiety and delusions” refractory to lorazepam, requiring olanzapine and overnight observation.”
From Adverse Events in Studies of Classic Psychedelics: A Systematic Review and Meta-Analysis (2024) · cites this paper as [20]
The LSD-Assisted Therapy in Patients with Anxiety section reports one treatment-related SAE involving acute transient anxiety and delusions during an LSD session. It says lorazepam alone did not fully block the symptoms, so olanzapine was given and the patient was kept overnight. The paper reports this SAE as 2%, not 0.8%, and does not establish a denominator of 128 or describe the event as subacute. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPrior psychedelic-assisted therapy trials have used inactive placebos, active placebos whose effects considerably differ from the acute effects of serotonergic psychedelics, or doses of psilocybin presumably too low to maintain blinding.
“Studies have used inactive placebos (e.g., [17, 35]), active placebos whose effects considerably differ from the acute effects of serotonergic psychedelics (e.g., [15, 36, 37]), or doses of psilocybin presumably too low to maintain blinding (e.g., [38, 39])”
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- LSD-Assisted Therapy in Patients with Anxiety Biological Psychiatry February 1, 2023; 93:215-223 www.sobp.org/journal
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“Interestingly, current evidence suggests that PAT might also be effective in treating major depressive disorder [16] and anxiety disorders [17], syndromes that are often comorbid with AUD [18, 19].”
BackgroundMethodSerotonergic psychedelics for depression: A comprehensive overview
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- Authors
- Holze, F., Gasser, P., Müller, F., Dolder, P. C., & Liechti, M. E.
- Affiliations
- University of Basel (CH)
- Corresponding author
- Liechti, Matthias E.
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2023-02
- Volume
- 93
- Issue
- 3
- Pages
- 215-223
- ISSN
- 0006-3223 (ISSN-L)
- OpenAlex
- W4294631080
- Cited by
- 318
- References
- 24
- Citations by year
- 2026: 71 · 2025: 92 · 2024: 91 · 2023: 60 · 2022: 3
- FWCI
- 56.17
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Biological Psychiatry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Universitätsspital Basel
- Topics
- Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Social Sciences › Psychology › Social Psychology › Music Therapy and Health
- Keywords
- lysergic acid diethylamide, anxiety, life-threatening illness, comorbid depression, subjective drug effects, psychedelic therapy, treatment safety
- MeSH terms
- Anxiety, Anxiety Disorders, Double-Blind Method, Humans, Lysergic Acid Diethylamide, Treatment Outcome, Cross-Over Studies
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