Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia
Open accessAbstract
Cannabidiol is a component of marijuana that does not activate cannabinoid receptors, but moderately inhibits the degradation of the endocannabinoid anandamide. We previously reported that an elevation of anandamide levels in cerebrospinal fluid inversely correlated to psychotic symptoms. Furthermore, enhanced anandamide signaling let to a lower transition rate from initial prodromal states into frank psychosis as well as postponed transition. In our translational approach, we performed a double-blind, randomized clinical trial of cannabidiol vs amisulpride, a potent antipsychotic, in acute schizophrenia to evaluate the clinical relevance of our initial findings. Either treatment was safe and led to significant clinical improvement, but cannabidiol displayed a markedly superior side-effect profile. Moreover, cannabidiol treatment was accompanied by a significant increase in serum anandamide levels, which was significantly associated with clinical improvement. The results suggest that inhibition of anandamide deactivation may contribute to the antipsychotic effects of cannabidiol potentially representing a completely new mechanism in the treatment of schizophrenia.
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CBD has neuromodulatory and neuroprotective effects through mechanisms including blocking neuroinflammation, potentiating anti-inflammatory pathways, improving mitochondrial function, GABAA agonist potentiation, stimulation of 5HT1A receptors, and enhancing levels of anandamide.
“CBD has both neuromodulatory and neuroprotective effects through a number of mechanisms including blocking neuroinflammation and potentiating anti-inflammatory pathways, improving mitochondrial function, GABAA agonist potentiation, stimulation of 5HT1A receptors, and enhancing levels of anandamide (AEA) [116–119].”
From An Update on Psychopharmacological Treatment of Autism Spectrum Disorder (2022) · cites this paper as [118]
CBD (up to 800 mg/day) and amisulpride both significantly reduced psychotic symptoms in schizophrenia patients over 4 weeks, with no differences between them; CBD induced fewer side effects.
“One study compared the effects of CBD (up to 800 mg/day) to amisulpride in 42 schizophrenia patients treated for 4 weeks (77). Both treatments significantly reduced psychotic symptoms, with no differences between them; however, CBD induced fewer side effects compared to amisulpride.”
From Translational investigation of the therapeutic potential of Cannabidiol (CBD): Toward a new age (2018) · cites this paper as [77]
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Kevin, R. C., Allsop, D. J., Lintzeris, N., Dunlop, A. J., Booth, J., & McGregor, I. S. (2017) · Forensic Toxicology · doi:10.1007/s11419-016-0330-0 · Cited by 24 · see citing works
The endocannabinoid system in social anxiety disorder: from pathophysiology to novel therapeutics
Ahmed, M., Boileau, I., Le Foll, B., Carvalho, A. F., & Kloiber, S. (2022) · Brazilian Journal of Psychiatry · doi:10.1590/1516-4446-2021-1926 · Cited by 11 · see citing works
Ricci, V., Ciavarella, M. C., Marrangone, C., Messas, G., Maina, G., & Martinotti, G. (2025) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2025.1543673 · Cited by 6 · see citing works
- Authors
- Leweke, F. M., Piomelli, D., Pahlisch, F., Muhl, D., Gerth, C. W., Hoyer, C., Klosterkötter, J., Hellmich, M., & Koethe, D.
- Affiliations
- Heidelberg University (DE)
- University of California, Irvine (US)
- University of Cologne (DE)
- Corresponding author
- Leweke, F M
- Piomelli, D
- Venue
- Translational Psychiatry
- Published
- 2012-03-20
- Volume
- 2
- Issue
- 3
- Pages
- e94-e94
- ISSN
- 2158-3188 (ISSN-L)
- PMC
- PMC3316151
- OpenAlex
- W2169269177
- Cited by
- 1,059
- References
- 36
- Citations by year
- 2026: 35 · 2025: 64 · 2024: 89 · 2023: 90 · 2022: 100 · 2021: 104 · 2020: 115 · 2019: 100 · 2018: 83 · 2017: 71 · 2016: 63 · 2015: 49 · 2014: 44 · 2013: 36 · 2012: 13
- FWCI
- 33.40
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- www.springer.com/tdm (unspecified)
- Locations
- Translational Psychiatry (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- Stanley Medical Research Institute
- National Institute on Drug Abuse
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
- Keywords
- cannabidiol, anandamide, endocannabinoid system, schizophrenia, psychotic symptoms, amisulpride, antipsychotic drugs, side effect profile, prodromal psychosis
- MeSH terms
- Amisulpride, Acute Disease, Adult, Amides, Arachidonic Acids, Cannabidiol, Double-Blind Method, Drug Therapy, Combination, Ethanolamines, Female, Humans, Male, Oleic Acids, Palmitic Acids, Psychiatric Status Rating Scales, Schizophrenia, Schizophrenic Psychology, Sulpiride, Antipsychotic Agents, Signal Transduction, Polyunsaturated Alkamides, Young Adult, Endocannabinoids
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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