Cannabidiol (CBD)

Side Effects and Drug Interactions

Cannabidiol (CBD) has promise for many medical applications although they are not yet well defined nor are the mechanisms by which it works well understood. When taking CBD one must be aware of potential side effects and drug interactions CBD may have with other medications.

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Cannabidiol (CBD):

 

 

The medical information on this site is provided as a resource for information only, and is not to be used or relied upon for any diagnostic or treatment purposes and is not intended to create any patient-physician relationship.  Readers are advised to seek professional guidance regarding the diagnosis and treatment of their medical concerns.

 

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CBD: Side Effects

CBD has been determined to be safe, with no fatal overdoses on record. It is generally well tolerated with minimal or mild side effects only. CBD does not affect motor function or memory and does not appear to have the potential for physical dependence (e.g. withdrawal and tolerance), nor is it associated with abuse or addiction.

The side effects of CBD are mild and include:

  • Low blood pressure
  • Dry mouth
  • Light-headedness
  • Drowsiness.

 

 

CBD: Safety

CBD offers great therapeutic potential but remains poorly studied. Human CBD short-term studies illustrate low toxicity and only mild adverse effects. However, it is unknown what side effects may be caused by prolonged use. It is important to note that there are few to no long term studies on CBD administration in healthy people even though short term trials show CBD to be safe and well tolerated. Studies also do not assess prolonged use in chronically ill people who often take medications continuously for many years. Even animal studies only evaluate chronic CBD treatment for up to several months, which may mimic prolonged use in people, but differences cannot be excluded.

There is no evidence for CBD to have abuse or dependence potential, and there is no evidence of public health related problems associated with the use of pure CBD.

 

 

 

CBD: Drug Interactions

Cannabinoids and Opioids

There appears to be a synergistic analgesic (pain-relieving) benefit when cannabinoids are added to opioid treatment for pain in which there is a greater-than-additive benefical effect with the addition of cannabinoids. Studies indicate a trend towards reduced use of opioids when patients taking opioids add cannabinoids to their regimen. It is not uncommon for patients started on cannabinoids to be able to taper down or off opioids.

 

Interestingly, animal studies suggest that cannabinoids may reduce the development of tolerance to the analgesic benefits of opioids, resulting in less need for opioid dose escalation.

 

There is no enhancement of cardiorespiratory suppression from opioids with the addition of cannabinoids due to the very low density of cannabinoid (CB) receptors in brainstem cardiorespiratory centers. There does not appear to be any significant interactions with opioids regarding a cannabinoid effect on the metabolism of most opioids.

 

CYP2D6

However, there is research showing that CBD may inhibit CYP2D6, one of the liver enzymes responsible for metabolizing tramadol and codeine. Because the analgesic benefits from tramadol and codeine come from their active metabolites resulting from CYP2D6 metabolism, these two opioids may be less effective if taken with CBD.

 

P-glycoprotein (P-gp) Transporters

Another way in which medications may interact with one another is through their effect on drug transport systems, especially the P-glycoprotein (P-gp) system. The P-gp transporters transport medications and metabolites out of the central nervous system and brain through the blood-brain barrier into the blood. The activity of P-gp transporters can significantly impact the effect of drugs such as morphine, oxycodone and methadone on the brain by reducing their levels in the brain. Early findings indicate that CBD significantly inhibits P-gp-mediated drug transport, suggesting CBD could potentially increase brain levels of morphine and other opioids that are P-gp substrates thus enhancing their impact. CBD may also influence the absorption and disposition of other coadministered compounds that are P-gp substrates.

 

UDP-glucuronosyltransferase (UGT) family of enzymes

The UDP-glucuronosyltransferase (UGT) family of enzymes found in the liver and kidneys play an important role in the metabolism of medications. These enzymes attach glucoronide to medications to facilitate their elimination. The interaction between UGTs and cannabinoids have not yet been thoroughly examined but a recent 2021 study evaluated the potential of Δ9-THC, CBD, and cannabinol (CBN), and their major metabolites, to inhibit the activity of UGT enzymes.

The highest inhibition was seen by CBD against the glucuronidation activity of UGTs 1A9, 2B4, 1A6, and 2B7 but strong inhibition of UGT1A9 and UGT2B7 was also found with THC and CBN. Regarding the metabolites of these cannabinoids, there was weak or no inhibition was found.

This inhibition of UGT activity by CBD, THC and CBN may play an important role in drug-drug interactions. Major cannabinoids found in the plasma of cannabis users inhibit several UDP-glucuronosyltransferase (UGT) enzymes, including UGT1A6, UGT1A9, UGT2B4, and UGT2B7. This study identified the potential of cannabinoids to inhibit all the major kidney UGTs as well as the two most abundant UGTs present in liver. This study suggests that as all three major kidney UGTs are inhibited by cannabinoids, greater drug- drug interaction effects might be observed from co-use of cannabinods and therapeutics that are cleared renally.

See: Cannabinoids and Opioids

 

Smoking – Tobacco and Marijuana

Smoking marijuana and tobacco both induce CYP1A2 through activation of the aromatic hydrocarbon receptors, and this effect between the two products is additive. Of note: this effect is based on the smoke associated with the smoking of marijuana or tobacco, not the drugs in the smoke.  As a result of this CYP1A2 enzyme being induced, in other words more CYP1A2 enzyme is manufactured, medications that are metabolized by CYP1A2 will be broken down faster, blood levels will be decreased and the therapeutic effects of the drug will be reduced. CYP1A2 is the enzyme responsible for metabolizing such drugs as caffeine, tizanidine (Zanaflex), duloxetine (Cymbalta), methadone, olanzapine (Zyprexa) and melatonin.

 

When one suddenly stops smoking either tobacco, marijuana or both, the induction effect is quickly reversed and the levels of CYP 1A2 enzyme rapidly return to previous levels (downregulation) over a few days. When this occurs in an individual chronically taking one of the medications metabolized by CYP 1A2, the blood levels of this medication may quickly rise leading to the potential for increased side effects and toxicity from the medication.

 

This is especially significant in medications that have a narrow therapeutic index such as tizanidine (Zanaflex), in which even small increases in blood levels may be associated with increased side effects. It is therefore important to reduce doses of these medications in the first few days after suddenly stopping smoking either tobacco, marijuana or both to avoid possible toxicity from the medication. Due to body size and gender-related variables, this reduction is especially warranted in small females.

 

While the CYP 1A2 enzyme is not a major enzyme in the metabolism of methadone, it has been reported that methadone levels can dangerously increase with smoking cessation. As a rule of thumb, it has been recommended that a stepwise daily methadone dose reduction of approximately 10% be engaged until the fourth day after smoking cessation.

 

Alcohol and Benzodiazepines

The combination of cannabinoids with alcohol and benzodiazepines may increase sedation and cognitive impairment.

 

NSAIDS (Non-Steroid Anti-inflammatory Drugs)

It has been reported that NSAIDs such as ibuprofen and naproxen, particularly indomethacin, can partially antagonize the effects of THC, although the mechanism responsible is not fully understood.

 

Anticholinergic drugs (tricyclic antidepressants (TCAs) and some muscle relaxers)

Medications with anticholinergic activity such as amitriptyline (Elavil) and doxepin, and muscle relaxers such as cyclobenzaprine (Flexeril) may increase the psychoactive side effccts of cannabinoids.

 

CBD and Piperine

Blood levels and duration of action of CBD may be increased if CBD is accompanied by ingestion of piperine, an alkaloid found in black pepper (Piper nigrum). Piperine has been found to reduce metabolic breakdown of CBD in the intestines and the liver. Furthermore, piperine may suppress the elimination of CBD (and THC) from the brain by inhibiting the P-gp transporter mechanism involved, leading to prolonged effects of CBD and THC.

 

 

 

Metabolism of CBD

The way in which many drug interactions occur is through their impact on how a drug is metabolized. Understanding how CBD is metabolized provides insight as to how other drugs may interact with CBD.

CBD is extensively metabolised in the liver, primarily to 7-OH-CBD which is then metabolised further into as many as 100 metabolites that are excreted in feces and urine. Seven CYP enzymes have been identified as metabolising CBD: CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5, but the two main ones are CYP3A4 and CYP2C19.

 

Although research is lacking, the metabolites formed from CBD are believed to be present in the body at pharmacologically significant concentrations. Pharmacological studies of CBD metabolites are scarce but suggest biological activities not directly related to CB receptors. The pharmacological effects observed with CBD may be attributed at least in part to its metabolites.

 

 

 

CBD: Drug-Metabolic Interactions

The major cannabanoids, THC and CBD are both metabolized in the liver by the CYP450 enzymes 2C9, 2C19 and 3A4. Drugs that inhibit these enzymes may enhance or prolong the effects of THC and CBD. Whether people with genetic variants of these enzymes may experience altered effects from cannabinoids is not known. In one study, potential drug–drug interactions of THC/CBD oro-mucosal spray (Sativex, nabiximols) in combination with CYP450 inducers and inhibitors were assessed using various dose regimens. The antibiotic rifampicin, an inducer of CYP3A4, significantly reduced the peak plasma concentration of CBD, while the antifungal ketoconazole, a CYP3A4 inhibitor, nearly doubled the peak plasma concentration of CBD.  However, the moderate CYP2C19 inhibitor omeprazole (Prilosec), a proton-pump inhibitor used to treat gastroesophageal reflux disease (GERD), did not significantly alter the pharmacokinetics of CBD.

 

CBD has been identified as a potent inhibitor of CYP2D6 which may have significant impact on the metabolism of medications that are broken down by CYP2D6, including hydrocodone (Norco, Vicodin, Zohydro, Hysingla). As such, use of CBD especially at high doses with tramadol, codeine or hydrocodone may significantly reduce the analgesic effectiveness of these opioids.

 

Limited evidence also suggests that CBD may significantly inhibit CYP2C19, the enzyme  responsible for metabolizing many medications including:

  1. Anticoagulants such as clopidogrel (Plavix),
  2. Tricyclic antidepressants such as amitriptyline (Elavil)
  3. SSRI antidepressants including citalopram Celexa) and escitalopram (Lexapro)
  4. Proton pump inhibitors such as omeprazole (Prilosec) and pantoprazole (Protonix)
  5. Other drugs including indomethacin (Indocin), diazepam (Valium) and propranolol (Inderal).

 

As a result this may lead to elevated blood levels of these medications and their associated side effects.

 

 

 

Resources:

National Academy of Sciences

The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research

 

These lay-person websites appear to be good resources for exploring medical marijuana:

  1. www.GreenCamp.com
  2. www.Healer.com
  3. www.MedicalJane.com
  4. www.ProjectCBD.org

 

 

References:

Epidiolex (cannabidiol)

  1. FDA approves CBD drug – Epidiolex – The Washington Post

 

Marinol (dronabinol)

  1. Marinol – dronabinol

 

Cannabidiol (CBD)- Overviews

  1. CANNABIDIOL (CBD) Pre-Review Report WHO 2017
  2. Cannabidiol – State of the art and new challenges for therapeutic applications. – 2017 PubMed – NCBI

 

CBD – Anxiety

  1. Overlapping Mechanisms of Stress-Induced Relapse to Opioid Use Disorder and Chronic Pain – Clinical Implications – 2016
  2. Cannabidiol Modulates Fear Memory Formation Through Interactions with Serotonergic Transmission in the Mesolimbic System – 2016
  3. Cannabidiol regulation of emotion and emotional memory processing: relevance for treating anxiety-related and substance abuse disorders. – PubMed – NCBI
  4. Review of the neurological benefits of phytocannabinoids – 2018
  5. Plastic and Neuroprotective Mechanisms Involved in the Therapeutic Effects of Cannabidiol in Psychiatric Disorders – 2017
  6. Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. – PubMed – NCBI
  7. Evidences for the Anti-panic Actions of Cannabidiol – 2017
  8. Cannabidiol, a Cannabis sativa constituent, as an anxiolytic drug – 2012
  9. Cannabidiol Reduces the Anxiety Induced by Simulated Public Speaking in Treatment-Naïve Social Phobia Patients – 2011

 

CBD – Interaction with THC

  1. Cannabidiol: a promising drug for neurodegenerative disorders? – PubMed – NCBI
  2. Oral Cannabidiol does not Alter the Subjective, Reinforcing or Cardiovascular Effects of Smoked Cannabis – 2015
  3. Taming THC – potential cannabis synergy and phytocannabinoid-terpenoid entourage effects – 2011
  4. A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. – PubMed – NCBI

 

CBD – Pain

  1. The non-psychoactive cannabis constituent cannabidiol is an orally effective therapeutic agent in rat chronic inflammatory and neuropathic pain. – PubMed – NCBI 2007
  2. Molecular Targets of Cannabidiol in Neurological Disorders – 2015
  3. Cannabidiol Modulates Fear Memory Formation Through Interactions with Serotonergic Transmission in the Mesolimbic System – 2016
  4. Cannabidiol enhances morphine antinociception, diminishes NMDA-mediated seizures and reduces stroke damage via the sigma 1 receptor – 2018
  5. Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model of neuropathic pain. – PubMed – NCBI – 2018
  6. Cannabidiol for Pain Treatment – Focus on Pharmacology and Mechanism of Action – 2020

 

CBD – Pharmacodynamics

  1. Beyond the CB1 Receptor – Is Cannabidiol the Answer for Disorders of Motivation? – 2016
  2. Molecular Targets of Cannabidiol in Neurological Disorders – 2015

 

CBD – Pharmacokinetics

  1. Human Cannabinoid Pharmacokinetics – 2007
  2. A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. – PubMed – NCBI
  3. Human Metabolites of Cannabidiol – A Review on Their Formation, Biological Activity, and Relevance in Therapy 2016
  4.  A Comprehensive Review on Pharmacotherapeutics of Herbal Bioenhancers – 2012
  5. The effects of black pepper on the intestinal absorption and hepatic metabolism of drugs. – PubMed – NCBI – 2011
  6. Piperine-pro-nanolipospheres as a novel oral delivery system of cannabinoids: Pharmacokinetic evaluation in healthy volunteers in comparison to buc… – PubMed – NCBI – 2017
  7. A Systematic Review on the Pharmacokinetics of Cannabidiol in Humans
  8. Human Pharmacokinetic Parameters of Orally Administered Δ 9-Tetrahydrocannabinol Capsules Are Altered by Fed Versus Fasted Conditions and Sex Differences – PubMed

 

CBD – Metabolites

  1. Human Metabolites of Cannabidiol – A Review on Their Formation, Biological Activity, and Relevance in Therapy – 2016

 

CBD – Drug Interactions

  1. Cannabidiol, a Major Phytocannabinoid, As a Potent Atypical Inhibitor for CYP2D6 – 2011
  2. The Effect of CYP2D6 Drug-Drug Interactions on Hydrocodone Effectiveness – 2014 
  3. Characterization of P-glycoprotein Inhibition by Major Cannabinoids from Marijuana – 2006
  4. Beyond the CB1 Receptor – Is Cannabidiol the Answer for Disorders of Motivation? – 2016
  5. Pharmacokinetic Drug Interactions with Tobacco, Cannabinoids and Smoking Cessation Products. – PubMed – NCBI – 2016
  6. The pharmacokinetics and the pharmacodynamics of cannabinoids. – PubMed – NCBI – 2018
  7. Drug-drug interactions as a result of co-administering Δ9-THC and CBD with other psychotropic agents. – PubMed – NCBI – 2018
  8. Medicinal Cannabis—Potential Drug Interactions – 2019
  9. Inhibition of UDP-Glucuronosyltransferase Enzymes by Major Cannabinoids and Their Metabolites – PubMed – 2021
  10. The Potential for Pharmacokinetic Interactions Between Cannabis Products and Conventional Medications – PubMed – 2021

 

Medical Marijuana – Opioids

  1. Use-of-Prescription-Pain-Medications-Among-Medical-Cannabis-Patients
  2. It is premature to expand access to medicinal cannabis in hopes of solving the US opioid crisis – 2018
  3. Patterns of medicinal cannabis use, strain analysis, and substitution effect among patients with migraine, headache, arthritis, and chronic pain in a medicinal cannabis cohort – 2018
  4. Patterns and correlates of medical cannabis use for pain among patients prescribed long-term opioid therapy. – PubMed – NCBI
  5. Associations between medical cannabis and prescription opioid use in chronic pain patients – A preliminary cohort study – 2017
  6. The prevalence and significance of cannabis use in patients prescribed chronic opioid therapy: a review of the extant literature. – PubMed – NCBI
  7. The use of cannabis in response to the opioid crisis: A review of the literature. – PubMed – NCBI
  8. Medical Cannabis Laws and Opioid Analgesic Overdose Mortality in the United States, 1999–2010 – 2014
  9. Rationale for cannabis-based interventions in the opioid overdose crisis – 2017
  10. Cannabis and the Opioid Crisis – 2018
  11. Impact of co-administration of oxycodone and smoked cannabis on analgesia and abuse liability. – PubMed – NCBI
  12. Cannabinoid–Opioid Interaction in Chronic Pain
  13. Synergistic interactions between cannabinoid and opioid analgesics. – PubMed – NCBI
  14. FDA approves CBD drug – Epidiolex – The Washington Post
  15. Opioid transport by ATP-binding cassette transporters at the blood-brain barrier: implications for neuropsychopharmacology. – PubMed – NCBI – 2011
  16. Opioids and the Blood-Brain Barrier – A Dynamic Interaction with Consequences on Drug Disposition in Brain – 2017
  17. The pharmacokinetics and the pharmacodynamics of cannabinoids. – PubMed – NCBI – 2018
  18. Cannabinoids and Cytochrome P450 Interactions. – PubMed – NCBI – 2016
  19. Pharmacogenetics of Cannabinoids – 2017 Enhanced Brain Disposition and Effects of Δ9-Tetrahydrocannabinol in P-Glycoprotein and Breast Cancer Resistance Protein Knockout Mice. 2012
  20. Pharmacogenomics of methadone maintenance treatment. – PubMed – NCBI
  21. Relationship between ABCB1 polymorphisms and serum methadone concentration in patients undergoing methadone maintenance therapy (MMT). – PubMed – NCBI- 2016
  22. Impact of ABCB1 and CYP2B6 Genetic Polymorphisms on Methadone Metabolism, Dose and Treatment Response in Patients with Opioid Addiction – A Systematic Review and Meta-Analysis – 2014
  23. ABCB1 haplotype and OPRM1 118A > G genotype interaction in methadone maintenance treatment pharmacogenetics – 2012
  24. The opioid epidemic – a central role for the blood brain barrier in opioid analgesia and abuse – 2017
  25. Morphine and the blood-brain barrier – diffusion, uptake, or efflux? – 2017
  26. Cyclosporine-inhibitable Blood-Brain Barrier Drug Transport Influences Clinical Morphine Pharmacodynamics – 2013
  27. Methadone Treatment for Pain States – 2005
  28. Cyclosporine-inhibitable Cerebral Drug Transport Does not Influence Clinical Methadone Pharmacodynamics – 2014
  29. Targeting blood–brain barrier changes during inflammatory pain – an opportunity for optimizing CNS drug delivery – 2011
  30. Targeting Transporters – Promoting Blood-Brain Barrier Repair in Response to Oxidative Stress Injury – 2015
  31. Cannabidiol enhances morphine antinociception, diminishes NMDA-mediated seizures and reduces stroke damage via the sigma 1 receptor – 2018

Medical Marijuana –Misc

  1. A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. – PubMed – NCBI
  2. Cannabis and cannabis extracts – greater than the sum of their parts? – 2001
  3. Medical cannabis and mental health: A guided systematic review. 2016 – PubMed – NCBI
  4. Epidemiological characteristics, safety and efficacy of medical cannabis in the elderly. – PubMed – NCBI
  5. Cannabis-conclusions – 2017 National Academy of Sciences
  6. Cannabis-chapter-highlights – 2017 National Academy of Sciences
  7. Cannabis-report-highlights – 2017 National Academy of Sciences
  8. Clinical Endocannabinoid Deficiency (CECD): Can this Concept Explain Therapeutic Bene ts of Cannabis in Migraine, Fibromyalgia, Irritable Bowel Syndrome and other Treatment-Resistant Conditions?-2004
  9. Marijuana use and the risk of lung and upper aerodigestive tract cancers: results of a population-based case-control study. – PubMed – NCBI
  10. Cannabis use and cognitive function: 8-year trajectory in a young adult cohort. – PubMed – NCBI
  11. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. – PubMed – NCBI
  12. Cannabinoids and Cytochrome P450 Interactions. – PubMed – NCBI Pharmacogenetics of Cannabinoids – 2018
  13. Systematic review of systematic reviews for medical cannabinoids – 2018
  14. Adverse effects of medical cannabinoids – a systematic review – 2008
  15. Cannabimimetic effects modulated by cholinergic compounds. – PubMed – NCBI
  16. Antagonism of marihuana effects by indomethacin in humans. – PubMed – NCBI
  17. Pharmacokinetics and pharmacodynamics of cannabinoids. – PubMed – NCBI
  18. Clinical Pharmacodynamics of Cannabinoids – 2004
  19. Affinity and Efficacy Studies of Tetrahydrocannabinolic Acid A at Cannabinoid Receptor Types One and Two. – 2017
  20. Quality Control of Traditional Cannabis Tinctures – Pattern, Markers, and Stability – 2016
  21. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. – PubMed – NCBI
  22. Pharmacology of Cannabinoids
  23. Current-status-and-future-of-cannabis-research-Clin-Researcher-2015
  24. Medical Marijuana for Treatment of Chronic Pain and Other Medical and Psychiatric Problems – A Clinical Review – 2015

 

Medical Marijuana – Product Evaluation

  1. The Cannabinoid Content of Legal Cannabis in Washington State Varies Systematically Across Testing Facilities and Popular Consumer Products – 2018
  2. Quality Control of Traditional Cannabis Tinctures – Pattern, Markers, and Stability – 2016

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