Cited by 559Cannabis and Cannabinoid ResearchPhytochemistry Medicinal Plant ApplicationsForensic Toxicology and Drug Analysis

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Safety and Side Effects of Cannabidiol, a Cannabis sativa Constituent

Machado Bergamaschi, Mateus, Helena Costa Queiroz, Regina, Waldo Zuardi, Antonio, Alexandre S. Crippa, Jose·2011·Current Drug Safety

DOI 10.2174/157488611798280924

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Abstract

Cannabidiol (CBD), a major nonpsychotropic constituent of Cannabis, has multiple pharmacological actions, including anxiolytic, antipsychotic, antiemetic and anti-inflammatory properties. However, little is known about its safety and side effect profile in animals and humans. This review describes in vivo and in vitro reports of CBD administration across a wide range of concentrations, based on reports retrieved from Web of Science, Scielo and Medline. The keywords searched were "cannabinoids", "cannabidiol" and "side effects". Several studies suggest that CBD is non-toxic in non-transformed cells and does not induce changes on food intake, does not induce catalepsy, does not affect physiological parameters (heart rate, blood pressure and body temperature), does not affect gastrointestinal transit and does not alter psychomotor or psychological functions. Also, chronic use and high doses up to 1,500 mg/day of CBD are reportedly well tolerated in humans. Conversely, some studies reported that this cannabinoid can induce some side effects, including inhibition of hepatic drug metabolism, alterations of in vitro cell viability, decreased fertilization capacity, and decreased activities of p-glycoprotein and other drug transporters. Based on recent advances in cannabinoid administration in humans, controlled CBD may be safe in humans and animals. However, further studies are needed to clarify these reported in vitro and in vivo side effects.

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Rodríguez-Muñoz, M., Onetti, Y., Cortés‐Montero, E., Garzón, J., & Sánchez‐Blázquez, P. (2018) · Molecular Brain · doi:10.1186/s13041-018-0395-2 · Cited by 127
Isolation, Purification, and Antimicrobial Characterization of Cannabidiolic Acid and Cannabidiol from Cannabis sativa L.
Martinenghi, L. D., Jønsson, R., Lund, T., & Jenssen, H. (2020) · Biomolecules · doi:10.3390/biom10060900 · Cited by 130
Complementary Therapies in Parkinson Disease: a Review of Acupuncture, Tai Chi, Qi Gong, Yoga, and Cannabis
Deuel, L. M., & Seeberger, L. (2020) · Neurotherapeutics · doi:10.1007/s13311-020-00900-y · Cited by 131
Cannabidiol as a Potential Treatment for Anxiety and Mood Disorders: Molecular Targets and Epigenetic Insights from Preclinical Research
Melas, P. A., Scherma, M., Fratta, W., Cifani, C., & Fadda, P. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22041863 · Cited by 127
“Specifically, studies on the safety and tolerability of CBD demonstrate no significant side effects with oral doses up to 1500 mg/day or with intravenous doses of 30 mg [3].”
Background
Low doses of widely consumed cannabinoids (cannabidiol and cannabidivarin) cause DNA damage and chromosomal aberrations in human-derived cells
Russo, C., Ferk, F., Mišík, M., Ropek, N., Nersesyan, A. K., Mejri, D., Holzmann, K., Lavorgna, M., Isidori, M., & Knasmüller, S. (2018) · Archives of Toxicology · doi:10.1007/s00204-018-2322-9 · Cited by 121
Is the cardiovascular system a therapeutic target for cannabidiol?
Stanley, C. P., Hind, W. H., & O’Sullivan, S. E. (2012) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.2012.04351.x · Cited by 121
A Novel Self-Emulsifying Drug Delivery System (SEDDS) Based on VESIsorb® Formulation Technology Improving the Oral Bioavailability of Cannabidiol in Healthy Subjects
Knaub, K., Sartorius, T., Dharsono, T., Wacker, R., Wilhelm, M. G., & Schön, C. (2019) · Molecules · doi:10.3390/molecules24162967 · Cited by 119
Pharmacokinetics and Tolerability of Multiple Doses of Pharmaceutical-Grade Synthetic Cannabidiol in Pediatric Patients with Treatment-Resistant Epilepsy
Wheless, J. W., Dlugos, D., Miller, I., Oh, D. A., Parikh, N., Phillips, S. E., Renfroe, J. B., Roberts, C. M., Saeed, I., Sparagana, S. P., et al. (2019) · CNS Drugs · doi:10.1007/s40263-019-00624-4 · Cited by 127
Preliminary Investigation of the Safety of Escalating Cannabinoid Doses in Healthy Dogs
Vaughn, D. M., Kulpa, J., & Paulionis, L. (2020) · Frontiers in Veterinary Science · doi:10.3389/fvets.2020.00051 · Cited by 119
“The interaction depends on whether CBD is administered prior to THC (pharmacokinetic interaction more likely) or concurrently with THC (pharmacodynamic interaction more likely) (7, 34, 39) and also on the dose ratio of the compounds (39, 40).”
Background
Cannabidiol, a Major Non-Psychotropic Cannabis Constituent Enhances Fracture Healing and Stimulates Lysyl Hydroxylase Activity in Osteoblasts
Kogan, N. M., Melamed, E., Wasserman, E., Raphael-Mizrahi, B., Breuer, A., Stok, K. S., Sondergaard, R. E., Escudero, A. V. V., Baraghithy, S., Attar-Namdar, M., et al. (2015) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.2513 · Cited by 115
“Multiple experimental and clinical trials have portrayed CBD as a safe agent,((50)) suggesting further studies in humans to assess its usefulness for improving fracture healing.”
Background
Cardioprotective effect of cannabidiol in rats exposed to doxorubicin toxicity
Fouad, A. A., Albuali, W. H., Al-Mulhim, A. S., & Jresat, I. (2013) · Environmental Toxicology and Pharmacology · doi:10.1016/j.etap.2013.04.018 · Cited by 116
Self‐initiated use of topical cannabidiol oil for epidermolysis bullosa
Chelliah, M. P., Zinn, Z. A., Khuu, P., & Teng, J. M. C. (2018) · Pediatric Dermatology · doi:10.1111/pde.13545 · Cited by 114
“There are also many studies that have demonstrated the protective function of cannabinoids in acute and chronic inflammatory diseases,(5,6) although long-term safety and effects of its use have not been studied.(7,8) Within the epidermis itself, CB agents have been shown to indirectly inhibit proliferation of cultured…”
Background
Marijuana: Current Concepts†
Greydanus, D. E., Hawver, E. K., Greydanus, M. M., & Merrick, J. (2013) · Frontiers in Public Health · doi:10.3389/fpubh.2013.00042 · Cited by 112
Cannabidiol as a potential treatment for psychosis
Davies, C., & Bhattacharyya, S. (2019) · Therapeutic Advances in Psychopharmacology · doi:10.1177/2045125319881916 · Cited by 121
Cannabidiol for neurodegenerative disorders: A comprehensive review
Bhunia, S., Kolishetti, N., Yndart, A., Vashist, A., & Nair, M. G. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.989717 · Cited by 121
“, 2020), its nonpsychoactive nature, and well-tolerated pharmacological behavior (Bergamaschi et al., 2011).”
Background
A reliable and validated LC-MS/MS method for the simultaneous quantification of 4 cannabinoids in 40 consumer products
Meng, Q., Buchanan, B., Zuccolo, J., Poulin, M.-M., Gabriele, J. P., & Baranowski, D. C. (2018) · PLoS ONE · doi:10.1371/journal.pone.0196396 · Cited by 110
Access to cannabidiol without a prescription: A cross-country comparison and analysis
McGregor, I. S., Cairns, E. A., Abelev, S. V., Cohen, R., Henderson, M., Couch, D., Arnold, J. C., & Gauld, N. J. (2020) · International Journal of Drug Policy · doi:10.1016/j.drugpo.2020.102935 · Cited by 114
The effects of herbal medicine on epilepsy
Liu, W., Ge, T., Pan, Z., Leng, Y., Lv, J., & Li, B. (2017) · Oncotarget · doi:10.18632/oncotarget.16801 · Cited by 104
“), no significant adverse effects were seen in both acute and chronic medication [61].”
Background
ASRA Pain Medicine consensus guidelines on the management of the perioperative patient on cannabis and cannabinoids
Shah, S., Schwenk, E. S., Sondekoppam, R. V., Clarke, H. A., Zakowski, M. I., Lynn, R. R., Yeung, B., Nicholson, K., Schwartz, G. S., Hooten, W. M., et al. (2023) · Regional Anesthesia & Pain Medicine · doi:10.1136/rapm-2022-104013 · Cited by 113
“40”
Cannabidiol for the treatment of cannabis withdrawal syndrome: a case report: CBD and cannabis withdrawal
Crippa, J. A. S., Hallak, J. E. C., Machado-de-Sousa, J. P., Queiroz, R. H. C., Bergamaschi, M., Chagas, M. H. N., & Zuardi, A. W. (2013) · Journal of Clinical Pharmacy and Therapeutics · doi:10.1111/jcpt.12018 · Cited by 101
“CBD has proven to be a safe drug with no significant adverse effects in humans, even with chronic use(24) and in high doses.(12,25,26) Based on these findings, we investigated the effects of CBD in a subject with cannabis dependence and a history of cannabis withdrawal syndrome.”
BackgroundSelf-citation
The Effect of Cannabidiol on Ischemia/Reperfusion-Induced Ventricular Arrhythmias
Gonca, E., & Darıcı, F. (2014) · Journal of Cardiovascular Pharmacology and Therapeutics · doi:10.1177/1074248414532013 · Cited by 106
The heterogeneity and complexity of Cannabis extracts as antitumor agents
Baram, L., Peled, E., Berman, P., Yellin, B., Besser, E., Benami, M., Louria‐Hayon, I., Lewitus, G. M., & Meiri, D. (2019) · Oncotarget · doi:10.18632/oncotarget.26983 · Cited by 100
“The two most wellknown and heavily researched of these compounds are (-)-Δ9-trans-tetrahydrocannabinol (Δ9-THC), a principal psychotropic ingredient in the plant [2, 3], and cannabidiol (CBD) [4].”
Background
Cannabidiol as a potential treatment for psychosis
Schubart, C. D., Sommer, I. E., Fusar‐Poli, P., de Witte, L. D., Kahn, R. S., & Boks, M. P. (2013) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2013.11.002 · Cited by 105
No Acute Effects of Cannabidiol on the Sleep-Wake Cycle of Healthy Subjects: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study
Linares, I. M. P., Guimarães, F. S., Éckeli, Á. L., Crippa, A. C. S., Zuardi, A. W., Souza, J. D. S., Hallak, J. E. C., & Crippa, J. A. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00315 · Cited by 100
“…Pharmacology | www.frontiersin.org 5 April 2018 | Volume 9 | Article 315 the literature on the few significant side effects resulting from the administration of CBD to humans in a wide range of doses, administered chronically or acutely (Bergamaschi et al., 2011b; Kerstin and Grotenhermen, 2017).”
BackgroundInfluential
Cannabidiol Is a Novel Modulator of Bacterial Membrane Vesicles
Kosgodage, U. S., Matewele, P., Awamaria, B., Kraev, I., Warde, P., Mastroianni, G., Nunn, A. V. W., Guy, G. W., Bell, J. D., Inal, J. M., et al. (2019) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2019.00324 · Cited by 98
An ethnobotanical study of medicinal plants used to treat skin diseases in northern Pakistan
Malik, K., Ahmad, M., Zafar, M. N., Ullah, R., Mahmood, H. M., Parveen, B., Rashid, N., Sultana, S., Shah, S. N., & Lubna (2019) · BMC Complementary and Alternative Medicine · doi:10.1186/s12906-019-2605-6 · Cited by 112
Cannabidiol as a Therapeutic Alternative for Post-traumatic Stress Disorder: From Bench Research to Confirmation in Human Trials
de Bitencourt, R. M., & Takahashi, R. N. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00502 · Cited by 108
“Although CBD is considered safe (Bergamaschi et al., 2011), the long-term effects were not evaluated in this study and need to be better elucidated (Shannon and Opila-Lehman, 2016).”
BackgroundInfluential
Emerging evidence for the antidepressant effect of cannabidiol and the underlying molecular mechanisms
Silote, G. P., Sartim, A. G., Sales, A. J., Eskelund, A., Guimarães, F. S., Wegener, G., & Joca, S. R. L. (2019) · Journal of Chemical Neuroanatomy · doi:10.1016/j.jchemneu.2019.04.006 · Cited by 98
Effects of short-term cannabidiol treatment on response to social stress in subjects at clinical high risk of developing psychosis
Appiah‐Kusi, E., Petros, N., Wilson, R. J., Colizzi, M., Bossong, M. G., Valmaggia, L., Mondelli, V., McGuire, P. K., & Bhattacharyya, S. (2020) · Psychopharmacology · doi:10.1007/s00213-019-05442-6 · Cited by 93
“In contrast, cannabidiol (CBD), is a safe and well-tolerated (Bergamaschi et al. 2011a) constituent of cannabis and has antipsychotic (Iseger and Bossong 2015; Leweke et al. 2012; McGuire et al. 2017; Bhattacharyya et al. 2010) and anxiolytic (Bergamaschi et al. 2011b) properties.”
BackgroundResultInfluential
Cannabidiol increases survival and promotes rescue of cognitive function in a murine model of cerebral malaria
Campos, A. C., Brant, F., de Miranda, A. S., Machado, F. S., & Teixeira, A. L. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2014.12.051 · Cited by 96
“This assumption is reinforced by several reports suggest the use of CBD in humans (Bergamaschi et al. 2011; Demiracka et al. 2010, Zuardi et al. 1993).”
Result
Cannabidiol aqueous solubility enhancement: Comparison of three amorphous formulations strategies using different type of polymers
Koch, N., Jennotte, O., Gasparrini, Y., Vandenbroucke, F., Lechanteur, A., & Évrard, B. (2020) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2020.119812 · Cited by 92
Cannabis and Cannabis Edibles: A Review
Peng, H., & Shahidi, F. (2021) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.0c07472 · Cited by 92
A marijuana-drug interaction primer: Precipitants, pharmacology, and pharmacokinetics
Cox, E. J., Maharao, N. V., Patilea-Vrana, G., Unadkat, J. D., Rettie, A. E., McCune, J. S., & Paine, M. F. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.05.001 · Cited by 91
“These inaccuracies were addressed via in vitro-to-in vivo extrapolation using the predicted concentrations of THC and CBD in the intestine, as well as unbound plasma concentrations in the portal venous and systemic circulation, after administration of representative medical doses by various routes (Bergamaschi et al.,…”
Method
Cannabidiol, a Cannabis sativa constituent, inhibits cocaine-induced seizures in mice: Possible role of the mTOR pathway and reduction in glutamate release
Gobira, P. H., Vilela, L. R., Gonçalves, B. D. C., Santos, R. P. M., de Oliveira, A. C., Vieira, L. B., Aguiar, D. C., Crippa, J. A., & Moreira, F. A. (2015) · NeuroToxicology · doi:10.1016/j.neuro.2015.08.007 · Cited by 89
Molecular Targets of Cannabidiol in Experimental Models of Neurological Disease
Silvestro, S., Schepici, G., Bramanti, P., & Mazzon, E. (2020) · Molecules · doi:10.3390/molecules25215186 · Cited by 93
“Moreover, thanks to its liposolubility, CDB forms aggregates which can be released slowly into adipose tissue [72].”
Background
The endocannabinoid system as a target for addiction treatment: Trials and tribulations
Sloan, M. E., Gowin, J. L., Ramchandani, V. A., Hurd, Y. L., & Foll, B. L. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.05.031 · Cited by 94
Pharmacokinetic investigation of synthetic cannabidiol oral formulations in healthy volunteers
Izgelov, D., Davidson, E. M., Barasch, D., Regev, A., Domb, A. J., & Hoffman, A. (2020) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2020.06.021 · Cited by 88
Cannabidiol treatment reduces the motivation to self-administer methamphetamine and methamphetamine-primed relapse in rats
Hay, G. L., Baracz, S. J., Everett, N. A., Roberts, J., Costa, P. A., Arnold, J. C., McGregor, I. S., & Cornish, J. L. (2018) · Journal of Psychopharmacology · doi:10.1177/0269881118799954 · Cited by 84
Cannabidiol as a Novel Candidate Alcohol Use Disorder Pharmacotherapy: A Systematic Review
Turna, J., Syan, S. K., Frey, B. N., Rush, B. R., Costello, M. J., Weiss, M., & MacKillop, J. M. (2019) · Alcoholism Clinical and Experimental Research · doi:10.1111/acer.13964 · Cited by 89
Use of Cannabidiol for the Treatment of Anxiety: A Short Synthesis of Pre-Clinical and Clinical Evidence
Wright, M., Ciano, P. D., & Brands, B. (2020) · Cannabis and Cannabinoid Research · doi:10.1089/can.2019.0052 · Cited by 87
“In addition, chronic use and high doses of up to 1500 mg/ day are reportedly well tolerated in humans.(37) Thus far, CBD demonstrates no potential for abuse or dependence in humans.”
Background
Neuropharmacological Effects of the Main Phytocannabinoids: A Narrative Review
SANTOS, R. G. D., Hallak, J. E. C., & Crippa, J. A. S. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-57369-0_3 · Cited by 82
Evaluation of Serum Cytokines Levels and the Role of Cannabidiol Treatment in Animal Model of Asthma
Vuolo, F. S., Petronilho, F. C., Sonai, B., Ritter, C., Hallak, J. E. C., Zuardi, A. W., Crippa, J. A. S., & Dal‐Pizzol, F. (2015) · Mediators of Inflammation · doi:10.1155/2015/538670 · Cited by 80
Cannabinoids as Anticancer Drugs
Ramer, R., & Hinz, B. (2017) · Advances in pharmacology · doi:10.1016/bs.apha.2017.04.002 · Cited by 82
Cannabidiol-Associated Hepatotoxicity: A Systematic Review and Meta-Analysis
Lo, L. A., Christiansen, A. L., Eadie, L., Strickland, J. C., Kim, D. D., Boivin, M. R., Barr, A. M., & MacCallum, C. A. (2022) · Journal of Internal Medicine · doi:10.1111/joim.13627 · Cited by 92
Role of the Endocannabinoid System in the Pathophysiology of Schizophrenia
Fakhoury, M. (2016) · Molecular Neurobiology · doi:10.1007/s12035-016-9697-5 · Cited by 81

Authors: Machado Bergamaschi, M., Helena Costa Queiroz, R., Waldo Zuardi, A., & Alexandre S. Crippa, J.
Venue: Current Drug Safety
Publisher: Bentham Science Publishers Ltd.
Published: 2011-09-01
Volume: 6
Issue: 4
Pages: 237-249
ISSN: 1574-8863 (ISSN-L)
DOI: 10.2174/157488611798280924
OpenAlex: W2128076336
Cited by: 558
References: 122
Citations by year: 2026: 17 · 2025: 39 · 2024: 47 · 2023: 58 · 2022: 51 · 2021: 67 · 2020: 84 · 2019: 48 · 2018: 37 · 2017: 37 · 2016: 23 · 2015: 18 · 2014: 11 · 2013: 9 · 2012: 11
FWCI: 7.23
Type: journal article
Language: en
Open access: closed
Locations: Current Drug Safety (publishedVersion)
PubMed (publishedVersion)
Funders: Fundação de Amparo à Pesquisa do Estado de São Paulo
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
Conselho Nacional de Desenvolvimento Científico e Tecnológico
Topics: Health Sciences › Medicine › Pharmacology (medical) › Cannabis and Cannabinoid Research
Life Sciences › Agricultural and Biological Sciences › Plant Science › Phytochemistry Medicinal Plant Applications
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Forensic Toxicology and Drug Analysis
Keywords: cannabidiol, Cannabis sativa, drug safety, adverse effects, toxicity, hepatotoxicity, drug metabolism inhibition, P-glycoprotein, fertility, cell viability, tolerability
MeSH terms: Animals, Anti-Inflammatory Agents, Antiemetics, Cannabidiol, Cannabis, Cell Survival, Eating, Humans, Antipsychotic Agents, Anti-Anxiety Agents

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Safety and Side Effects of Cannabidiol, a Cannabis sativa Constituent

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