PMID- 36559092 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20221225 IS - 1999-4923 (Print) IS - 1999-4923 (Electronic) IS - 1999-4923 (Linking) VI - 14 IP - 12 DP - 2022 Nov 25 TI - Adverse Effects of Oral Cannabidiol: An Updated Systematic Review of Randomized Controlled Trials (2020-2022). LID - 10.3390/pharmaceutics14122598 [doi] LID - 2598 AB - (1) Background: With the massive demand for the use and commercialization of medicinal cannabidiol (CBD) products, new randomized clinical trials (RCTs) are being published worldwide, with a constant need for safety and efficacy evaluation. (2) Methods: We performed an update on a systematic review published in 2020 that focused on analyzing the serious adverse effects (SAEs) of CBD in RCTs and its possible association with drug interactions. We also updated the report of the most prevalent CBD adverse effects (AEs). We systematically searched EMBASE, MEDLINE/PubMed, and Web of Science without language restriction for RCTs that reported adverse effects after repeated oral CBD administration for at least one week in healthy volunteers or clinical samples published from January 2019 to May 2022. The included studies were assessed for methodological quality by the Quality Assessment of Controlled Intervention Studies tool. The present review is registered on PROSPERO, number CRD42022334399. (3) Results: Twelve studies involving 745 randomized subjects analyzed were included (range 1.1-56.8 y). A total of 454 participants used CBD in the trials. The most common AEs of CBD were mild or moderate and included gastrointestinal symptoms (59.5%), somnolence (16.7%), loss of appetite (16.5%), and hypertransaminasemia (ALT/AST) (12.8%). Serious adverse effects include mainly hypertransaminasemia with serum levels elevations greater than three times the upper limit of the normal (6.4%), seizures (1.3%), and rash (1.1%). All SAEs reported in the studies were observed on CBD as an add-on therapy to anticonvulsant medications, including clobazam and valproate. (4) Conclusion: Recent RCTs involving oral CBD administration for at least a week suggest that CBD has a good safety and tolerability profile, confirming previous data. However, it can potentially interact with other drugs and its use should be monitored, especially at the beginning of treatment. FAU - Souza, Jose Diogo R AU - Souza JDR AD - Department of Neurosciences and Behavior, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, Brazil. FAU - Pacheco, Julia Cozar AU - Pacheco JC AD - Department of Neurosciences and Behavior, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, Brazil. FAU - Rossi, Giordano Novak AU - Rossi GN AUID- ORCID: 0000-0002-1952-1207 AD - Department of Neurosciences and Behavior, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, Brazil. FAU - de-Paulo, Bruno O AU - de-Paulo BO AD - Department of Neurosciences and Behavior, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, Brazil. FAU - Zuardi, Antonio W AU - Zuardi AW AD - Department of Neurosciences and Behavior, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, Brazil. AD - National Institute for Science and Technology-Translational Medicine, Ribeirao Preto 14049-900, Brazil. FAU - Guimaraes, Francisco S AU - Guimaraes FS AD - Department of Neurosciences and Behavior, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, Brazil. AD - Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, Brazil. FAU - Hallak, Jaime E C AU - Hallak JEC AD - Department of Neurosciences and Behavior, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, Brazil. AD - National Institute for Science and Technology-Translational Medicine, Ribeirao Preto 14049-900, Brazil. FAU - Crippa, Jose Alexandre AU - Crippa JA AUID- ORCID: 0000-0001-9520-6746 AD - Department of Neurosciences and Behavior, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, Brazil. AD - National Institute for Science and Technology-Translational Medicine, Ribeirao Preto 14049-900, Brazil. FAU - Dos Santos, Rafael G AU - Dos Santos RG AUID- ORCID: 0000-0003-2388-4745 AD - Department of Neurosciences and Behavior, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto 14049-900, Brazil. AD - National Institute for Science and Technology-Translational Medicine, Ribeirao Preto 14049-900, Brazil. LA - eng PT - Journal Article PT - Review DEP - 20221125 PL - Switzerland TA - Pharmaceutics JT - Pharmaceutics JID - 101534003 PMC - PMC9782576 OTO - NOTNLM OT - CBD OT - adverse effects OT - cannabidiol OT - drug interaction OT - safety COIS- JC was a consultant and/or has received speaker fees and/or sits on the advisory board and/or receives research funding and/or receives speaker fees from Janssen-Cilag, Torrent Pharm, Prati-Donaduzzi, Mantecorp, ArtMed, PurMed Global, and BSPG Pharm over the past 3 years. JC, JH, and AZ are coinventors of the patent "Fluorinated CBD compounds, compositions and uses thereof. Pub. No.: WO/2014/108899. International Application No.: PCT/IL2014/050023," Def. US number Reg. 62193296; 29 July 2015; INPI on 19 August 2015 (BR1120150164927; Mechoulam R, Zuardi AW, Kapczinski F, Hallak JEC, Guimaraes FS, Crippa JAS, Breuer A). Universidade de Sao Paulo (USP) has licensed this patent to Phytecs Pharm (USP Resolution No. 15.1.130002.1.1) and has an agreement with Prati-Donaduzzi to "develop a pharmaceutical product containing synthetic CBD and prove its safety and therapeutic efficacy in the treatment of epilepsy, schizophrenia, Parkinson's disease, and anxiety disorders". JC, JH, and AZ are coinventors of the patent "Cannabinoid-containing oral pharmaceutical composition, method for preparing and using same", INPI on 16 September 2016 (BR 112018005423-2). The other authors report no conflict of interest. EDAT- 2022/12/24 06:00 MHDA- 2022/12/24 06:01 PMCR- 2022/11/25 CRDT- 2022/12/23 01:56 PHST- 2022/10/17 00:00 [received] PHST- 2022/11/17 00:00 [revised] PHST- 2022/11/22 00:00 [accepted] PHST- 2022/12/23 01:56 [entrez] PHST- 2022/12/24 06:00 [pubmed] PHST- 2022/12/24 06:01 [medline] PHST- 2022/11/25 00:00 [pmc-release] AID - pharmaceutics14122598 [pii] AID - pharmaceutics-14-02598 [pii] AID - 10.3390/pharmaceutics14122598 [doi] PST - epublish SO - Pharmaceutics. 2022 Nov 25;14(12):2598. doi: 10.3390/pharmaceutics14122598.