Safety and side effects of cannabidiol, a Cannabis sativa constituent

Machado Bergamaschi, Mateus; Helena Costa Queiroz, Regina; Waldo Zuardi, Antonio; Alexandre S. Crippa, Jose

doi:10.2174/157488611798280924

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

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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CBD does not produce psychotropic effects, probably because of its low affinity for CB1 receptors.
“Unlike THC, CBD does not produce psychotropic effects and this is probably because of its low affinity for CB1 receptors 55– 57.”
From Psychosocial and pharmacological interventions for the treatment of cannabis use disorder (2018) · cites this paper as [57]
Acute and chronic administration of CBD by various routes to healthy volunteers and patients with different clinical conditions did not induce significant adverse effects.
“According to comprehensive reviews, acute and chronic administration of CBD by various routes (oral, inhaled, intravenous) to healthy volunteers and patients with different clinical conditions did not induce significant adverse effects (50, 51), especially because a conversion of oral cannabidiol to THC seems not to occur in humans (52).”
From Translational investigation of the therapeutic potential of Cannabidiol (CBD): Toward a new age (2018) · cites this paper as [50]

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Influence of cannabidiol on delta‐9‐tetrahydrocannabinol effects
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Interactions between THC and cannabidiol in mouse models of cannabinoid activity
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Tryptophan as a Link between Psychopathology and Somatic States
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Toxicity of short-term administration of cannabinoids to rhesus monkeys
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The effect of cannabinoids on intestinal motility and their antinociceptive effect in mice
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A metabolic interaction in vivo between cannabidiol and Δ1‐tetrahydrocannabinol
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Repeated treatment with cannabidiol but not Δ9-tetrahydrocannabinol has a neuroprotective effect without the development of tolerance
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Psychoactive cannabinoids reduce gastrointestinal propulsion and motility in rodents.
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Uso terapêutico dos canabinoides em psiquiatria
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Cannabidiol-induced apoptosis in primary lymphocytes is associated with oxidative stress-dependent activation of caspase-8
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A comparative study on cannabidiol-induced apoptosis in murine thymocytes and EL-4 thymoma cells
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Interaction between cannabidiol (CBD) and ∆9-tetrahydrocannabinol (THC): influence of administration interval and dose ratio between the cannabinoids
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Delayed treatment with cannabidiol has a cerebroprotective action via a cannabinoid receptor‐independent myeloperoxidase‐inhibiting mechanism
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The interplay of cannabinoid and NMDA glutamate receptor systems in humans: preliminary evidence of interactive effects of cannabidiol and ketamine in healthy human subjects
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Effect of cannabidiol on sepsis‐induced motility disturbances in mice: involvement of CB1receptors and fatty acid amide hydrolase
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The Potent Emetogenic Effects of the Endocannabinoid, 2-AG (2-Arachidonoylglycerol) Are Blocked by Δ9-Tetrahydrocannabinol and Other Cannnabinoids
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Cannabidiol was ineffective for manic episode of bipolar affective disorder
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Comparative metabolism of cannabidiol in dog, rat and man
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Inhibition of cyclosporine and tetrahydrocannabinol metabolism by cannabidiol in mouse and human microsomes
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Interaction of cannabidiol and alcohol in humans
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Nonpsychoactive Cannabidiol Prevents Prion Accumulation and Protects Neurons against Prion Toxicity
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The Effect of Cannabidiol on Mouse Hepatic Microsomal Cytochrome P450-Dependent Anandamide Metabolism
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γ-Irradiation Enhances Apoptosis Induced by Cannabidiol, a Non-psychotropic Cannabinoid, in Cultured HL-60 Myeloblastic Leukemia Cells
Gallily, R., Even-Chen, T., Katzavian, G., Lehmann, D., Dagan, A., & Mechoulam, R. (2003) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/1042819031000103917 · Cited by 62 · see citing works
Cannabidiol inhibits the hyperphagia induced by cannabinoid-1 or serotonin-1A receptor agonists
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Selective inactivation of mouse liver cytochrome P-450IIIA by cannabidiol.
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Δ9-Tetrahydrocannabinol and cannabidiol modulate mitogen-induced tryptophan degradation and neopterin formation in peripheral blood mononuclear cells in vitro
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Cannabinoids reduce fertility of sea urchin sperm
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Marijuana extracts possess the effects like the endocrine disrupting chemicals
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Failure of cannabinoid compounds to stimulate estrogen receptors
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Effects on Cell Viability
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Induction and genetic regulation of mouse hepatic cytochrome P450 by cannabidiol
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THE ORAL ACTIVITY OF Δ′‐TETRAHYDROCANNABINOL AND ITS DEPENDENCE ON PROSTAGLANDIN E2
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Inhibition of hepatic microsomal cytochrome P450 by cannabidiol in adult male rats.
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In Vitro Effects of Cannabinoids on Follicular Function in the Rat1
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Cannabidiol lacks the vanilloid VR1-mediated vasorespiratory effects of capsaicin and anandamide in anaesthetised rats
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Cannabinol and cannabidiol in combination: Temperature, open-field activity, and vocalization
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Effects of psychoactive and nonpsychoactive cannabinoids on the hypothalamic-pituitary axis of the adult male rat
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Macrophages, cytokines, and HIV
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Changes in the conditioned emotional response of rats, induced by delta 9-thc, cbd and mixture of the two cannabinoids
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Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders.
Devinsky, O., Cilio, M. R., Cross, H., Fernandez‐Ruiz, J., French, J., Hill, C., Katz, R., Di Marzo, V., Jutras‐Aswad, D., Notcutt, W. G., et al. (2014) · Epilepsia · doi:10.1111/epi.12631 · Cited by 1,000 · see citing works
“) in both acute and chronic administration.(50) Limited safety data exist for long-term use in humans, although there have been many patient-years of exposure to nabiximols following approval in many European countries and Canada.”
Background
Cannabidiol as a Potential Treatment for Anxiety Disorders
Blessing, E., Steenkamp, M. M., Manzanares, J., & Marmar, C. R. (2015) · Neurotherapeutics · doi:10.1007/s13311-015-0387-1 · Cited by 717 · see citing works
“A review of potential side effects in humans found that CBD was well tolerated across a wide dose range, up to 1500 mg/day (orally), with no reported psychomotor slowing, negative mood effects, or vital sign abnormalities noted [20].”
Background
An update on safety and side effects of cannabidiol: a review of clinical data and relevant animal studies
Iffland, K., & Grotenhermen, F. (2017) · Cannabis & Cannabinoid Research · doi:10.1089/can.2016.0034 · Cited by 645 · see citing works
“One can often argue that what the studies call ‘‘chronic’’ CBD administration only differs to acute treatment, because of repeated administration of CBD. Nonetheless, we also included these studies with repeated CBD treatment, because we think that compared to a one-time dose of CBD, repeated CBD regimens add value an…”
BackgroundResultInfluential
A Systematic Review on the Pharmacokinetics of Cannabidiol in Humans
Millar, S., Stone, N. L., Yates, A. S., & O’Sullivan, S. E. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.01365 · Cited by 567 · see citing works
“CBD has attracted significant interest due to its anti-inflammatory, anti-oxidative and anti-necrotic protective effects, as well as displaying a favorable safety and tolerability profile in humans (Bergamaschi et al., 2011), making it a promising candidate in many therapeutic avenues including epilepsy, Alzheimer’s d…”
Background
Labeling Accuracy of Cannabidiol Extracts Sold Online
Bonn‐Miller, M. O., Loflin, M., Thomas, B. F., Marcu, J. P., Hyke, T., & Vandrey, R. G. (2017) · JAMA · doi:10.1001/jama.2017.11909 · Cited by 532 · see citing works
Drug–drug interaction between clobazam and cannabidiol in children with refractory epilepsy
Geffrey, A. L., Pollack, S. F., Bruno, P. L., & Thiele, E. A. (2015) · Epilepsia · doi:10.1111/epi.13060 · Cited by 496 · see citing works
“A review of 132 papers analyzing CBD use alone in humans and animals reported an average elimination half-life of 24 h.(18) Because the trial subjects have refractory epilepsy, many are taking multiple concomitant AEDs.”
Background
A Phase I, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose, Multiple Dose, and Food Effect Trial of the Safety, Tolerability and Pharmacokinetics of Highly Purified Cannabidiol in Healthy Subjects
Taylor, L., Gidal, B. E., Blakey, G. E., Tayo, B., & Morrison, G. (2018) · CNS Drugs · doi:10.1007/s40263-018-0578-5 · Cited by 471 · see citing works
Cannabidiol Adverse Effects and Toxicity
Huestis, M. A., Solimini, R., Pichini, S., Pacifici, R., Carlier, J., & Busardò, F. P. (2019) · Current Neuropharmacology · doi:10.2174/1570159x17666190603171901 · Cited by 479 · see citing works
Cannabidiol, neuroprotection and neuropsychiatric disorders
Campos, A. C., Fogaça, M. V., Sonego, A. B., & Guimarães, F. S. (2016) · Pharmacological Research · doi:10.1016/j.phrs.2016.01.033 · Cited by 446 · see citing works
“In ddition, it does not change heart rate, blood pressure or body emperature, does not induce catalepsy, and does not alter psy- PRESS Research xxx (2016) xxx–xxx chomotor or psychological functions like THC [40].”
BackgroundInfluential
Cannabidiol for the Reduction of Cue-Induced Craving and Anxiety in Drug-Abstinent Individuals With Heroin Use Disorder: A Double-Blind Randomized Placebo-Controlled Trial
Hurd, Y. L., Spriggs, S. A., Alishayev, J., Winkel, G. H., Gurgov, K., Kudrich, C., Oprescu, A. M., & Salsitz, E. A. (2019) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2019.18101191 · Cited by 344 · see citing works
“Consistent with previous reports (27, 28), no serious adverse events were noted in association with CBD administration throughout the duration of the trial.”
Translational investigation of the therapeutic potential of Cannabidiol (CBD): Toward a new age
Crippa, J. A., Guimarães, F. S., Campos, A. C., & Zuardi, A. W. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02009 · Cited by 308 · see citing works
Cannabidiol: A Potential New Alternative for the Treatment of Anxiety, Depression, and Psychotic Disorders
García-Gutiérrez, M. S., Navarrete, F., Gasparyan, A., Austrich-Olivares, A., Sala, F., & Manzanares, J. (2020) · Biomolecules · doi:10.3390/biom10111575 · Cited by 306 · see citing works
Trends in use, pharmacology, and clinical applications of emerging herbal nutraceuticals
Williamson, E. M., Liu, X., & Izzo, A. A. (2019) · British Journal of Pharmacology · doi:10.1111/bph.14943 · Cited by 315 · see citing works
Human Metabolites of Cannabidiol: A Review on Their Formation, Biological Activity, and Relevance in Therapy
Ujváry, I., & Hanuš, L. (2016) · Cannabis and Cannabinoid Research · doi:10.1089/can.2015.0012 · Cited by 302 · see citing works
Acute Effects of a Single, Oral dose of d9-tetrahydrocannabinol (THC) and Cannabidiol (CBD) Administration in Healthy Volunteers
Martín‐Santos, R., Crippa, J. A. S., Batalla, A., Bhattacharyya, S., Atakan, Z., Borgwardt, S., Allen, P., Seal, M. L., Langohr, K., Farré, M., et al. (2012) · Current Pharmaceutical Design · doi:10.2174/138161212802884780 · Cited by 298 · see citing works
“CBD is pharmacologically active and can have anticonvulsant, sedative, anxiolytic [3,4,17,18] and antipsychotic effects [4, 19-25].”
BackgroundResult
Potential Adverse Drug Events and Drug–Drug Interactions with Medical and Consumer Cannabidiol (CBD) Use
Brown, J. D., & Winterstein, A. G. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8070989 · Cited by 295 · see citing works
A Cross-Sectional Study of Cannabidiol Users
Corroon, J., & Phillips, J. A. (2018) · Cannabis and Cannabinoid Research · doi:10.1089/can.2018.0006 · Cited by 290 · see citing works
Diversity of molecular targets and signaling pathways for CBD
de Almeida, D. L., & Devi, L. A. (2020) · Pharmacology Research & Perspectives · doi:10.1002/prp2.682 · Cited by 264 · see citing works
Inverted U-Shaped Dose-Response Curve of the Anxiolytic Effect of Cannabidiol during Public Speaking in Real Life
Zuardi, A. W., Rodrigues, N. P., Silva, A. L., Bernardo, S. A., Hallak, J. E. C., Guimarães, F. S., & Crippa, J. A. S. (2017) · Frontiers in Pharmacology · doi:10.3389/fphar.2017.00259 · Cited by 294 · see citing works
“…previous studies with both anxiogenic (Crippa et al., 2004; Parente et al., 2005) and anxiolytic drugs including CBD (Crippa et al., 2004, 2011; Bergamaschi et al., 2011a) have shown that only the anxiety and sedation factors present changes during public speaking tasks, we used only the items…”
BackgroundMethodResultInfluential
Cannabidiol can improve complex sleep-related behaviours associated with rapid eye movement sleep behaviour disorder in Parkinson's disease patients: a case series
Chagas, M. H. N., Éckeli, Á. L., Zuardi, A. W., Pena-Pereira, M. A., Sobreira-Neto, M. A., Sobreira, E. T. A., Camilo, M. R., Bergamaschi, M. M., Schenck, C. H., Hallak, J. E. C., et al. (2014) · Journal of Clinical Pharmacy and Therapeutics · doi:10.1111/jcpt.12179 · Cited by 253 · see citing works
“Then, this hypothesis underscores the need for studies with larger therapeutic windows exploring the endocannabinoid system in regard to its neuroprotective potential, especially when we know that CBD is a safe, well-tolerated drug.(22) Before concluding, it is important to mention that this study is based on a small…”
Background
Cannabidiol (CBD) as a Promising Anti-Cancer Drug
Seltzer, E. S., Watters, A. K., MacKenzie, D., Granat, L. M., & Zhang, D. (2020) · Cancers · doi:10.3390/cancers12113203 · Cited by 252 · see citing works
“Unlike other controlled substances, patients do not seem to develop a tolerance for CBD [131].”
Background
Cannabinoids in the Treatment of Epilepsy
Friedman, D. J., & Devinsky, O. (2015) · New England Journal of Medicine · doi:10.1056/nejmra1407304 · Cited by 243 · see citing works
Clinicians’ Guide to Cannabidiol and Hemp Oils
VanDolah, H. J., Bauer, B. A., & Mauck, K. F. (2019) · Mayo Clinic Proceedings · doi:10.1016/j.mayocp.2019.01.003 · Cited by 239 · see citing works
“Safety and Adverse Effects No rigorous safety studies have been done on “full-spectrum” phytocannabinoid oils because these products are relatively new, but the separate ingredients have been examined somewhat, generally with no major adverse effects noted.(87,88) Cannabidiol doses up to 300 mg/d have been used safely…”
Method
Does Cannabidiol Protect Against Adverse Psychological Effects of THC?
Niesink, R. J. M., & van Laar, M. (2013) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2013.00130 · Cited by 241 · see citing works
“Based on an extensive literature review, Bergamaschi and colleagues concluded that CBD, to the extent that it has been studied, is a substance with low toxicity (27).”
Background
Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential
Yuan, M., Yang, B., Rothschild, G., Mann, J. J., Sanford, L. D., Tang, X., Huang, C., Wang, C., & Zhang, W. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01519-z · Cited by 246 · see citing works
“394 CBD ’ s therapeutic potential for reducing depression-like behavior has been shown, since it interacts with a wide range of brain molecules 395,396 .”
Background
In vivo Evidence for Therapeutic Properties of Cannabidiol (CBD) for Alzheimer's Disease
Watt, G., & Karl, T. (2017) · Frontiers in Pharmacology · doi:10.3389/fphar.2017.00020 · Cited by 227 · see citing works
“…into the clinical setting could be realized relatively quickly: CBD Frontiers in Pharmacology | www.frontiersin.org 5 February 2017 | Volume 8 | Article 20 is readily available, appears to only have limited side effects (Bergamaschi et al., 2011) and is safe for human use (Leweke et al., 2012).”
Background
Effects of cannabidiol interactions with Wnt/&beta;-catenin pathway and PPAR&gamma; on oxidative stress and neuroinflammation in Alzheimer's disease
Vallée, A., Lecarpentier, Y., Guillevin, R., & Vallée, J.-N. (2017) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gmx073 · Cited by 226 · see citing works
“CBD does not change blood pressure or temperature of body and does not induce psychomotor psychological function like THC [22].”
BackgroundInfluential
Endocannabinoid system and mood disorders: Priming a target for new therapies
Micale, V., Marzo, V. D., Šulcová, A., Wotjak, C. T., & Drago, F. (2012) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2012.12.002 · Cited by 222 · see citing works
A critical review of the antipsychotic effects of cannabidiol: 30 years of a translational investigation
Waldo Zuardi, A., Alexandre S. Crippa, J., E.C. Hallak, J., Bhattacharyya, S., Atakan, Z., Martin-Santos, R., K. McGuire, P., & Silveira Guimaraes, F. (2012) · Current Pharmaceutical Design · doi:10.2174/138161212802884681 · Cited by 222 · see citing works
“CBD administration across a wide range of concentrations, did not detect important side or toxic effects [12].”
BackgroundResult
Cannabidiol presents an inverted U-shaped dose-response curve in a simulated public speaking test
Linares, I. M., Zuardi, A. W., Pereira, L. C., Queiroz, R. H., Mechoulam, R., Guimarães, F. S., & Crippa, J. A. (2019) · Brazilian Journal of Psychiatry · doi:10.1590/1516-4446-2017-0015 · Cited by 241 · see citing works
Oral Cannabidiol does not Alter the Subjective, Reinforcing or Cardiovascular Effects of Smoked Cannabis.
Haney, M., Malcolm, R. J., Babalonis, S., Nuzzo, P. A., Cooper, Z. D., Bedi, G., Gray, K. M., McRae-Clark, A., Lofwall, M. R., Sparenborg, S., et al. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2015.367 · Cited by 206 · see citing works
“…(300–600mg) alone has been reported to produce mild sedative and anxiolytic effects in some studies (Zuardi et al, 1993; Crippa et al, 2004, 2011; Bergamaschi et al, 2011a, b), whereas most report no measurable psychoactivity (Benowitz et al, 1980; Borgwardt et al, 2008; Bhattacharyya et al,…”
Background
Review of the neurological benefits of phytocannabinoids
Maroon, J. C., & Bost, J. (2018) · Surgical Neurology International · doi:10.4103/sni.sni_45_18 · Cited by 208 · see citing works
“[92] This improved safety profile may be a result of its lack of direct agonist properties at cannabinoid receptors.[4]”
Background
Cannabidiol reduces cigarette consumption in tobacco smokers: Preliminary findings
Morgan, C. J. A., Das, R., Joye, A., Curran, H. V., & Kamboj, S. K. (2013) · Addictive Behaviors · doi:10.1016/j.addbeh.2013.03.011 · Cited by 194 · see citing works
Cannabidiol enhances consolidation of explicit fear extinction in humans
Das, R., Kamboj, S. K., Ramadas, M., Yogan, K., Gupta, V., Redman, E., Curran, H. V., & Morgan, C. J. A. (2013) · Psychopharmacology · doi:10.1007/s00213-012-2955-y · Cited by 191 · see citing works
The Effects of Cannabinoids on Pro- and Anti-Inflammatory Cytokines: A Systematic Review of In Vivo Studies
Henshaw, F., Dewsbury, L. S., Lim, C. K., & Steiner, G. (2021) · Cannabis and Cannabinoid Research · doi:10.1089/can.2020.0105 · Cited by 157 · see citing works
Plastic and neuroprotective mechanisms involved in the therapeutic effects of cannabidiol in psychiatric disorders
Campos, A. C., Fogaça, M. V., Scarante, F. F., Joca, S. R. L., Sales, A. J., Gomes, F. V., Sonego, A. B., Rodrigues, N. S., Galve-Roperh, I., & Guimarães, F. S. (2017) · Frontiers in Pharmacology · doi:10.3389/fphar.2017.00269 · Cited by 175 · see citing works
“The pre-clinical and clinical studies available so far indicate that CBD has a good safety record (Bergamaschi et al., 2011b).”
Background
Dosage, Efficacy and Safety of Cannabidiol Administration in Adults: A Systematic Review of Human Trials
Larsen, C., & Shahinas, J. (2020) · Journal of Clinical Medicine Research · doi:10.14740/jocmr4090 · Cited by 170 · see citing works
“The comprehensive review by Bergamaschi et al included animal and clinical studies reporting a favorable safety profile of CBD in humans [42].”
Background
Cannabidiol (CBD) use in psychiatric disorders: A systematic review
Bonaccorso, S., Ricciardi, A., Zangani, C., Chiappini, S., & Schifano, F. (2019) · NeuroToxicology · doi:10.1016/j.neuro.2019.08.002 · Cited by 170 · see citing works
Cannabidiol as a Promising Strategy to Treat and Prevent Movement Disorders?
Peres, F. F., Lima, A. C., Hallak, J. E. C., Crippa, J. A. S., Silva, R. H., & Abílio, V. C. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00482 · Cited by 160 · see citing works
“For a broad review of CBD’s side effects, see Bergamaschi et al. (2011) and Iffland and Grotenhermen (2017).”
Background
Cannabinoid therapies in the management of sleep disorders: A systematic review of preclinical and clinical studies
Suraev, A. S., Marshall, N. S., Vandrey, R. G., McCartney, D., Benson, M. J., McGregor, I. S., Grunstein, R. R., & Hoyos, C. M. (2020) · Sleep Medicine Reviews · doi:10.1016/j.smrv.2020.101339 · Cited by 162 · see citing works
Single-Dose Pharmacokinetics and Preliminary Safety Assessment with Use of CBD-Rich Hemp Nutraceutical in Healthy Dogs and Cats
Deabold, K. A., Schwark, W. S., Wolf, L., & Wakshlag, J. J. (2019) · Animals · doi:10.3390/ani9100832 · Cited by 161 · see citing works
Cannabidiol, a Cannabis sativa constituent, as an anxiolytic drug
Schier, A. R. D. M., Ribeiro, N. P. D. O., Silva, A. C. D. O. E., Hallak, J. E. C., Crippa, J. A. S., Nardi, A. E., & Zuardi, A. W. (2012) · Brazilian Journal of Psychiatry · doi:10.1590/s1516-44462012000500008 · Cited by 154 · see citing works
Effectiveness of Cannabidiol Oil for Pediatric Anxiety and Insomnia as Part of Posttraumatic Stress Disorder: A Case Report
Shannon, S. M., & Opila-Lehman, J. (2016) · The Permanente Journal · doi:10.7812/tpp/16-005 · Cited by 152 · see citing works
Cannabidiol protects an in vitro model of the blood–brain barrier from oxygen‐glucose deprivation via PPARγ and 5‐HT1A receptors
Hind, W. H., England, T. J., & O’Sullivan, S. E. (2015) · British Journal of Pharmacology · doi:10.1111/bph.13368 · Cited by 152 · see citing works
“CBD has an excellent tolerability profile (Bergamaschi et al., 2011) and is currently licensed to treat spasticity in multiple sclerosis (in combination with THC, as the medicine Sativex; GW Pharmaceuticals, Cambridge UK) in over 20 countries.”
Background
The Polypharmacological Effects of Cannabidiol
Castillo-Arellano, J. I., Canseco-Alba, A., Cutler, S. J., & León, F. (2023) · Molecules · doi:10.3390/molecules28073271 · Cited by 163 · see citing works
Reasons for cannabidiol use: a cross-sectional study of CBD users, focusing on self-perceived stress, anxiety, and sleep problems
Moltke, J., & Hindocha, C. (2021) · Journal of Cannabis Research · doi:10.1186/s42238-021-00061-5 · Cited by 148 · see citing works
“In contrast, females were more likely to use CBD for self-perceived anxiety and insomnia, reflecting the higher prevalence of both symptoms amongst women (McLean et al. 2011; Li et al. 2002).”
Background
Cannabidiol (CBD) Is a Novel Inhibitor for Exosome and Microvesicle (EMV) Release in Cancer
Kosgodage, U. S., Mould, R. R., Henley, A. B., Nunn, A. V. W., Guy, G. W., Thomas, E. L., Inal, J. M., Bell, J. D., & Lange, S. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00889 · Cited by 144 · see citing works
“001% DMSO, based on clinically relevant doses for CBD (Bergamaschi et al., 2011); while Cl-amidine (a kind gift from Prof P.”
Background
From Cannabis sativa to Cannabidiol: Promising Therapeutic Candidate for the Treatment of Neurodegenerative Diseases
Cassano, T., Villani, R., Pace, L., Carbone, A., Bukke, V. N., Orkisz, S., Avolio, C., & Serviddio, G. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00124 · Cited by 148 · see citing works
“Compared to delta-9-THC, CBD possess a better safety profile and it is well tolerated when administered at animals and patients even at high doses (up to 1,500 mg/day) (Bergamaschi et al., 2011).”
Background
Cannabidiol Induces Cell Cycle Arrest and Cell Apoptosis in Human Gastric Cancer SGC-7901 Cells
Zhang, X., Qin, Y., Pan, Z., Li, M., Liu, X., Chen, X., Qu, G., Zhou, L., Xu, M., Zheng, Q., et al. (2019) · Biomolecules · doi:10.3390/biom9080302 · Cited by 141 · see citing works
Effects of acute cannabidiol administration on anxiety and tremors induced by a Simulated Public Speaking Test in patients with Parkinson’s disease
de Faria, S. M., de Morais Fabrício, D., Tumas, V., Castro, P. C., Ponti, M. A., Hallak, J. E., Zuardi, A. W., Crippa, J. A. S., & Chagas, M. H. N. (2020) · Journal of Psychopharmacology · doi:10.1177/0269881119895536 · Cited by 140 · see citing works
“…accordance with anxiolytic effects of CBD observed in studies using the SPST as an experimental model of anxiety in individuals with social anxiety (Bergamaschi et al., 2011b) and healthy volunteers (Linares et al., 2019; Zuardi et al., 1993), as well as during the Public Speaking in Real Life…”
BackgroundMethodSelf-citation
Effects of cannabidiol (CBD) in neuropsychiatric disorders: A review of pre-clinical and clinical findings
Elsaid, S., Kloiber, S. M., & Foll, B. L. (2019) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2019.06.005 · Cited by 136 · see citing works
Oral administration of cannabis with lipids leads to high levels of cannabinoids in the intestinal lymphatic system and prominent immunomodulation
Zgair, A., Lee, J.-B., Wong, J. C., Taha, D. A., Aram, J., Virgilio, D. D., Mcarthur, J., Cheng, Y.-K., Hennig, I., Barrett, D., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-15026-z · Cited by 117 · see citing works
Safety and Toxicology of Cannabinoids
Sachs, J., McGlade, E., & Yurgelun-Todd, D. A. (2015) · Neurotherapeutics · doi:10.1007/s13311-015-0380-8 · Cited by 127 · see citing works
The Endocannabinoid System and Cannabidiol's Promise for the Treatment of Substance Use Disorder
Chye, Y., Christensen, E., Solowij, N., & Yücel, M. (2019) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2019.00063 · Cited by 128 · see citing works
Cannabidiol Interactions with Medications, Illicit Substances, and Alcohol: a Comprehensive Review
Balachandran, P., ElSohly, M. A., & Hill, K. P. (2021) · Journal of General Internal Medicine · doi:10.1007/s11606-020-06504-8 · Cited by 126 · see citing works
Cannabidiol enhances morphine antinociception, diminishes NMDA-mediated seizures and reduces stroke damage via the sigma 1 receptor
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 122 · see citing works
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 124 · see citing works
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 · see citing works
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 124 · see citing works
“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 · see citing works
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 120 · see citing works
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 · see citing works
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 117 · see citing works
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 · see citing works
“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 · see citing works
“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 · see citing works
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 113 · see citing works
“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 · see citing works
Cannabidiol as a potential treatment for psychosis
Davies, C., & Bhattacharyya, S. (2019) · Therapeutic Advances in Psychopharmacology · doi:10.1177/2045125319881916 · Cited by 113 · see citing works
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 115 · see citing works
“, 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 107 · see citing works
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 106 · see citing works
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 · see citing works
“), 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 109 · see citing works
“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 · see citing works
“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 100 · see citing works
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 99 · see citing works
“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 100 · see citing works
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 99 · see citing works
“…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 · see citing works
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 105 · see citing works
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 98 · see citing works
“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 93 · see citing works
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 · see citing works
“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 93 · see citing works
“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 · see citing works
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 · see citing works
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 · see citing works
“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 · see citing works
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 90 · see citing works
“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 90 · see citing works
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 · see citing works
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 · see citing works
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 83 · see citing works
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 85 · see citing works
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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 › 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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