Antidepressant Effects of Psilocybin in the Absence of Psychedelic                     Effects

Rosenblat, Joshua D.; Leon-Carlyle, Marisa; Ali, Shaun; Husain, Muhammad Ishrat; McIntyre, Roger S.

doi:10.1176/appi.ajp.20220835

Cited by 23 publications

(7 citation statements)

References 4 publications

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“…This is also supported by a previous study on the non-psychedelic lysergic acid diethylamide (LSD) analogue 2-bromo-LSD (also known as BOL-148) that showed promising clinical effects in a small openlabel study 37 and case reports in patients with depression. 38,39 More generally, this supports the idea that it may be possible to induce clinically beneficial effects using non-psychedelic 5-HT 2A R agonists, which some researchers are actively pursuing. 40 Importantly, one patient (Patient 5) reported substantially enhanced quality of life despite long-term unchanged headache burden (Table 2).…”

Section: Plasma Psilocin Level and Treatment Effectsupporting

confidence: 63%

CCH attack frequency reduction after psilocybin correlates with hypothalamic functional connectivity

Madsen,

Petersen,

Stenbæk

et al. 2024

Headache

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ObjectiveTo evaluate the feasibility and prophylactic effect of psilocybin as well as its effects on hypothalamic functional connectivity (FC) in patients with chronic cluster headache (CCH).BackgroundCCH is an excruciating and difficult‐to‐treat disorder with incompletely understood pathophysiology, although hypothalamic dysfunction has been implicated. Psilocybin may have beneficial prophylactic effects, but clinical evidence is limited.MethodsIn this small open‐label clinical trial, 10 patients with CCH were included and maintained headache diaries for 10 weeks. Patients received three doses of peroral psilocybin (0.14 mg/kg) on the first day of weeks five, six, and seven. The first 4 weeks served as baseline and the last 4 weeks as follow‐up. Hypothalamic FC was determined using functional magnetic resonance imaging the day before the first psilocybin dose and 1 week after the last dose.ResultsThe treatment was well tolerated. Attack frequency was reduced by mean (standard deviation) 31% (31) from baseline to follow‐up (pFWER = 0.008). One patient experienced 21 weeks of complete remission. Changes in hypothalamic–diencephalic FC correlated negatively with a percent change in attack frequency (pFWER = 0.03, R = −0.81), implicating this neural pathway in treatment response.ConclusionOur results indicate that psilocybin may have prophylactic potential and implicates the hypothalamus in possible treatment response. Further clinical studies are warranted.

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Section: Plasma Psilocin Level and Treatment Effectsupporting

confidence: 63%

CCH attack frequency reduction after psilocybin correlates with hypothalamic functional connectivity

Madsen,

Petersen,

Stenbæk

et al. 2024

Headache

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“…Our results showing a robust antidepressant-like effect of lisuride without inducing HTR in CDM mice also support the notion that a psychedelic experience might not be required for the therapeutic response to 5-HT 2A R agonists [ 46 ]. Consistent with this hypothesis, a recent case report showed that the antidepressant effect of psilocybin is independent of 5-HT 2A R activation and, accordingly, of its psychedelic activity [ 47 ]. However, another report from patients/volunteers showing that the altered state of consciousness produced by psychedelics is critical for their clinical efficacy [ 48 ] indicates that the role of psychedelic properties of 5-HT 2A R agonists in their antidepressant effects remains an open question.…”

Section: Discussionmentioning

confidence: 77%

Antidepressant-like effects of psychedelics in a chronic despair mouse model: is the 5-HT2A receptor the unique player?

Sekssaoui,

Bockaert,

Marin

et al. 2024

Neuropsychopharmacol.

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Major depressive disorder (MDD) is one of the most disabling psychiatric disorders in the world. First-line treatments such as selective serotonin reuptake inhibitors (SSRIs) still have many limitations, including a resistance to treatment in 30% of patients and a delayed clinical benefit that is observed only after several weeks of treatment. Increasing clinical evidence indicates that the acute administration of psychedelic agonists of the serotonin 5-HT2A receptor (5-HT2AR), such as psilocybin, to patients with MDD induce fast antidepressant effects, which persist up to five weeks after the treatment. However, the involvement of the 5-HT2AR in these antidepressant effects remains controversial. Furthermore, whether the hallucinogenic properties of 5-HT2AR agonists are mandatory to their antidepressant activity is still an open question. Here, we addressed these issues by investigating the effect of two psychedelics of different chemical families, DOI and psilocybin, and a non-hallucinogenic 5-HT2AR agonist, lisuride, in a chronic despair mouse model exhibiting a robust depressive-like phenotype. We show that a single injection of each drug to wild type mice induces anxiolytic- and antidepressant-like effects in the novelty-suppressed feeding, sucrose preference and forced swim tests, which last up to 15 days. DOI and lisuride administration did not produce antidepressant-like effects in 5-HT2A−/− mice, whereas psilocybin was still effective. Moreover, neither 5-HT1AR blockade nor dopamine D1 or D2 receptor blockade affected the antidepressant-like effects of psilocybin in 5-HT2A−/− mice. Collectively, these findings indicate that 5-HT2AR agonists can produce antidepressant-like effects independently of hallucinogenic properties through mechanisms involving or not involving the receptor.

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“…Nevertheless, the convergent effects of ketamine and psychedelics upon many downstream signaling mechanisms ( 147 , 149 , 215 ) may suggest that strategies outlined above for augmenting ketamine efficacy and safety might apply to psychedelics. In turn, efforts to create “nonhallucinogenic” psychedelics via biased 5-HT 2A receptor agonism, partial 5-HT 2A receptor agonism, combinations of 5-HT 2A receptor agonists and antagonists, and other strategies ( 216 – 222 ) may suggest strategies for improving upon ketamine.…”

Section: Discussionmentioning

confidence: 99%

Ketamine and the neurobiology of depression: Toward next-generation rapid-acting antidepressant treatments

Krystal,

Kaye,

Jefferson

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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Ketamine has emerged as a transformative and mechanistically novel pharmacotherapy for depression. Its rapid onset of action, efficacy for treatment-resistant symptoms, and protection against relapse distinguish it from prior antidepressants. Its discovery emerged from a reconceptualization of the neurobiology of depression and, in turn, insights from the elaboration of its mechanisms of action inform studies of the pathophysiology of depression and related disorders. It has been 25 y since we first presented our ketamine findings in depression. Thus, it is timely for this review to consider what we have learned from studies of ketamine and to suggest future directions for the optimization of rapid-acting antidepressant treatment.

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Antidepressant Effects of Psilocybin in the Absence of Psychedelic Effects

Cited by 23 publications

References 4 publications

CCH attack frequency reduction after psilocybin correlates with hypothalamic functional connectivity

CCH attack frequency reduction after psilocybin correlates with hypothalamic functional connectivity

Antidepressant-like effects of psychedelics in a chronic despair mouse model: is the 5-HT2A receptor the unique player?

Ketamine and the neurobiology of depression: Toward next-generation rapid-acting antidepressant treatments

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