This work may not be copied, distributed, displayed, published, reproduced, transmitted, modified, posted, sold, licensed, or used for commercial purposes. By downloading this file, you are agreeing to the publisher’s Terms & Conditions.

Brief Report

Psilocybin Can Diminish Depression

Teresa Kay Jones, APRN, and Steven Lippmann, MD

Published: September 3, 2020

Psilocybin Can Diminish Depression

Depressive disorders were the third leading cause of disability in the world according to findings from the Global Burden of Disease Study.1 Therapeutic options for depression with psychedelic substances such as psilocybin and lysergic acid diethylamide are undergoing research.2 Treatment-resistant depression investigations with psilocybin have shown it to be effective with no serious adverse effects.2 In terminally ill depressed cancer patients, treatment benefits lasted 6 months.3 Long-term studies of psilocybin efficacy are not available, but there is support for the medication as pharmacotherapy for mental illnesses.2

Psilocybin is an indolealkylamine (4-phosphoryloxy-N,N-dimethyltryptamine), which acts on serotonergic receptor subtypes 5-HT1A, 5-HT2A, and 5-HT2C.4 The actions of psilocybin are correlated to 5-HT2A activation and downstream release of dopamine in the striatum.4 The emotional effects include depersonalization, euphoria, and mystical experiences.2,4 These mystical feelings reportedly prompt a reduction in anxiety and depression.2 Described as psychospiritual events, they may activate inner mechanisms for healing.5 This phenomenon is part of neurotheology and is a biological basis of spiritual experiences.5

Patients with major depressive disorder have persistent amygdala dysregulations.6 Psilocybin decreases the connectivity of the amygdala during stress.6 Imaging reveals increased blood flow and metabolism in the amygdala of depressed patients; following psilocybin administration, there is a decrease in blood flow to the left amygdala and improved mood.7 There are decreased amygdala responses (and less emotional response) after prescribing selective serotonin reuptake inhibitors (SSRIs), while treatment with interventions applying psilocybin increase emotional responses.8 Psilocybin and SSRI administration induce different therapeutic actions in the amygdala.8

Brain functionality is divided into large-scale bioelectric networks.9 In a resting state network, the functional connectivity evidences how such networks interact in patterns with psychological phenomena.9 In the prefrontal cortex, 5-HT2A increased expression or binding is linked to depression, suicidality, and negative affect.6 Psilocybin decreases activity in the medial prefrontal cortex and decreases connectivity within smaller networks such as the default mode network of the prefrontal cortex, while increasing other brain connections.9 This disintegration of connections may be the cause of mystical or transcendent experiences.9 Once interrupted, unhealthy pathways are replaced with healthier ones.9 Resting state networks in patients with neurologic or psychiatric disorders deviate from optimal connectivity patterns, such that reintegration to optimal networking can reportedly restore the brain to a predisease state.9

Psilocybin has been used historically for spiritual purposes. Evidence is mounting that psilocybin can successfully improve mood. The long-standing effects are currently under evaluation.

Published online: September 3, 2020.

Potential conflicts of interest: None.

Funding/support: None.


1.Institute for Health Metrics and Evaluation (IHME). Findings from the Global Burden of Disease Study 2017. Seattle, WA: Institute for Health Metrics and Evaluation; 2018.

2.Johnson MW, Griffiths RR. Potential therapeutic effects of psilocybin. Neurotherapeutics. 2017;14(3):734-740. PubMed CrossRef

3.Strauss N. Psilocybin-assisted therapy for anxiety and depression: implications for euthanasia. Med J Aust. 2017;206(11):468-469. PubMed CrossRef

4.Hasler F, Grimberg U, Benz MA, et al. Acute psychological and physiological effects of psilocybin in healthy humans: a double-blind, placebo-controlled dose-effect study. Psychopharmacology (Berl). 2004;172(2):145-156. PubMed CrossRef

5.Mithoefer MC, Grob CS, Brewerton TD. Novel psychopharmacological therapies for psychiatric disorders: psilocybin and MDMA. Lancet Psychiatry. 2016;3(5):481-488. PubMed CrossRef Veen BT, Schellekens AF, Verheij MM, et al. Psilocybin for treating substance use disorders? Expert Rev Neurother. 2017;17(2):203-212. PubMed CrossRef

7.Carhart-Harris RL, Roseman L, Bolstridge M, et al. Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms. Sci Rep. 2017;7(1):13187. PubMed CrossRef

8.Roseman L, Demetriou L, Wall MB, et al. Increased amygdala responses to emotional faces after psilocybin for treatment-resistant depression. Neuropharmacology. 2018;142:263-269. PubMed CrossRef

9.Nichols DE, Johnson MW, Nichols CD. Psychedelics as medicines: an emerging new paradigm. Clin Pharmacol Ther. 2017;101(2):209-219. PubMed CrossRef

aPrivate practice, Louisville, Kentucky

bDepartment of Psychiatry, University of Louisville School of Medicine, Louisville, Kentucky

*Corresponding author: Teresa Kay Jones, APRN, 4827 Manslick Road, Louisville, KY 40216 (

Prim Care Companion CNS Disord 2020;22(5):19br02580

To cite: Jones TK, Lippmann S. Psilocybin can diminish depression. Prim Care Companion CNS Disord. 2020;22(5):19br02580.

To share:

© Copyright 2020 Physicians Postgraduate Press, Inc.

Related Articles

Volume: 22

Quick Links:


Buy this Article as a PDF