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Lysergic Acid Diethylamide (LSD) for the Treatment of Anxiety Disorders: Preclinical and Clinical Evidence

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Abstract

Anxiety disorders (ADs) represent the sixth leading cause of disability worldwide, resulting in a significant global economic burden. Over 50% of individuals with ADs do not respond to standard therapies, making the identification of more effective anxiolytic drugs an ongoing research priority. In this work, we review the preclinical literature concerning the effects of lysergic acid diethylamide (LSD) on anxiety-like behaviors in preclinical models, and the clinical literature on anxiolytic effects of LSD in healthy volunteers and patients with ADs. Preclinical and clinical findings show that even if LSD may exacerbate anxiety acutely (both in “microdoses” and “full doses”), it induces long-lasting anxiolytic effects. Only two randomized controlled trials combining LSD and psychotherapy have been performed in patients with ADs with and without life-threatening conditions, showing a good safety profile and persisting decreases in anxiety outcomes. The effect of LSD on anxiety may be mediated by serotonin receptors (5-HT1A/1B, 5-HT2A/2C, and 5-HT7) and/or transporter in brain networks and circuits (default mode network, cortico–striato–thalamo–cortical circuit, and prefrontal cortex-amygdala circuit), involved in the modulation of anxiety. It remains unclear whether LSD can be an efficacious treatment alone or only when combined with psychotherapy, and if “microdosing” may elicit the same sustained anxiolytic effects as the “full doses”. Further randomized controlled trials with larger sample size cohorts of patients with ADs are required to clearly define the effective regimens, safety profile, efficacy, and feasibility of LSD for the treatment of ADs.

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Authors and Affiliations

  1. Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Avenue des Pins Ouest, Montreal, QC, H3A 1A1, Canada

    Antonio Inserra & Gabriella Gobbi

  2. UCL Queen Square Institute of Neurology, University College London, London, UK

    Alexandre Piot

  3. Division of Neuroscience, Vita-Salute San Raffaele University, Milan, Italy

    Danilo De Gregorio

  4. McGill University Health Center, Montreal, QC, Canada

    Gabriella Gobbi

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  1. Antonio Inserra
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  2. Alexandre Piot
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  4. Gabriella Gobbi
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Correspondence to Gabriella Gobbi.

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Funding

This work was supported by grants from the CIHR (Canadian Institutes of Health Research), FRQS (Fonds de Recherche Santé du Québec), and RQSHA (Réseau Québécois sur le Suicide, les Troubles de l’Humeur et Troubles Associés). G.G. holds the Canada Research Chair in Therapeutics for Mental Health. A.I. received the CIHR post-doctoral fellowship.

Conflict of interest

D.D.G. is a consultant at Diamond Therapeutics Inc., Toronto, ON, Canada. D.D.G. and G.G. are inventors of a pending patent on the method-of-use of LSD.

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Conceptualization: IA, GG; writing—original draft preparation: IA, AP, DDG, GG; writing—review and editing: IA, AP, DDG, GG; supervision: GG.

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Inserra, A., Piot, A., De Gregorio, D. et al. Lysergic Acid Diethylamide (LSD) for the Treatment of Anxiety Disorders: Preclinical and Clinical Evidence. CNS Drugs 37, 733–754 (2023). https://doi.org/10.1007/s40263-023-01008-5

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