INTRODUCTION

The cannabis plant has been used to treat a variety of ailments for many centuries and includes multiple species, of which Cannabis indica and Cannabis sativa are best known1. Δ9-Tetrahydrocannabinol (THC) is the major psychoactive ingredient, and cannabidiol is a non-intoxicating ingredient. Cannabis sativa usually has a higher THC:CBD ratio than Cannabis indica. Thus, sativa strains often have more psychotropic effects whereas indica strains are more sedating2. As of July 2020, 33 states and the District of Columbia have medical cannabis laws and 11 states and the District of Columbia have recreational cannabis laws. Due to the recent change in cannabis laws, CBD consumer sales have skyrocketed; they are expected to increase from half a billion in 2018 to $1.8 billion in 20223. As CBD has gained more popularity and expanded unregulated use, its drug–drug interactions remain largely unknown. CBD is known to interact with cytochrome P450 drug metabolizing enzymes, and this affects co-administration of CBD with other pharmaceutical drugs that are also inhibited or metabolized by these enzymes4. The consequence of the lack of information on drug–drug interactions is an inadequate knowledge of their potential adverse reactions when consumed together. Interactions, either additive or synergistic, or contraindications are largely undescribed and are a major health concern. As evidenced from drug interaction databases such as the Medscape Drug Interaction Checker, which healthcare professionals and researchers primarily use to check for drug interactions, searches for CBD interactions typically yield few results. Therefore, a comprehensive detailed review is warranted to provide insight into this topic.

METHODS

We conducted a detailed online literature search of the databases Pubmed and Google Scholar (1975 to March 2020), along with the drug interaction databases Medscape Drug Interaction Checker and Drug Bank using the terms, cannabidiol (or CBD) with interactions (n = 19,943), narcotics (n = 4070); anti-depressants (n = 440); AED (1246); alcohol (n = 1810); drug. In addition, CBD with specific drug names (acetaminophen (n = 1776) and morphine (6034), for example) were also searched. The results regarding drug interactions from the search were extracted and summarized by 1 author (PB). This review’s focus is not just limited to adverse effects but also any possible effects that could be attributable to CBD–drug interactions by simultaneous use either prescribed or consumed nonmedically. When examining CBD’s interactions with nicotine, there were several references available on cannabis or marijuana as a whole plant with nicotine/smoke, but none for CBD and nicotine/smoke. Cannabis/marijuana plant–drug interactions are beyond the scope of this review.

CANNABIDIOL’S MECHANISM OF ACTION

CBD is a non-psychotomimetic phytocannabinoid that has broad range of possible therapeutic effects including anxiolytic, antidepressant, anticonvulsant, neuroprotective, anti-inflammatory and immunomodulatory properties without any stimulant or convulsant properties5. CBD attenuates brain damage associated with neurogenerative or ischemic conditions. It affects synaptic plasticity and facilitates neurogenesis. The mechanism of these effects involves multiple pharmacological targets6. In animal models, CBD (a) blocks or reduces the spread of generalized seizures induced by maximal electroshock or γ-aminobutyric acid (GABA)–inhibiting drugs, (b) blocks simple partial seizures induced by the topical application of convulsant metals on the cortex, and (c) increases the seizure threshold for electrical kindling. CBD increased the potency of AEDs in animal models of partial and generalized motor seizures, but inhibited the action of AEDs in animal models of absence seizures7. CBD attenuated GABA release from ventral pallidum neurons, restoring the normal function of this system in psychotic patients8. CBD can also increase adult neurogenesis in mice, and this effect has been shown to be dependent on CB1 receptors9. CBD can act as a serotonin 1A receptor (5HT1A) agonist. Aripiprazole, an atypical antipsychotic, acts as a partial agonist at this receptor, an effect that could, together with its actions on D2 and 5-HT2A receptors, contribute to the therapeutic effects of this drug.

MECHANISMS BEHIND CANNABIDIOL’S INTERACTIONS WITH OTHER MEDICATIONS

CBD is extensively metabolized by CYP450 enzymes in the liver, in particular by the isoforms CYP3A4 and CYP2C1910. Furthermore, CBD is able to inhibit CYP2C19, CYP2D6, and CYP2C9, and may inhibit members of the CYP3 family11,12, leading to potential pharmacologic interactions with other drugs13,14. In animal models, repetitive administration of CBD may induce members of the CYP2B family4. Studies in mice have shown that CBD inactivates cytochrome P450 isozymes in the short-term, but can induce them after repeated administration. This is similar to their induction by phenobarbital, thereby strongly suggesting a role for the 2b subfamily of isozymes of cytochrome P450. Another study showed this effect to be mediated by upregulation of mRNA for CYP3A, 2C, and 2B10 after repeated CBD administration15.

CBD is metabolized via the CYP3A4 enzyme, and approximately 60% of clinically prescribed medications are also metabolized through CYP3A4. In particular, drugs such as ketoconazole, itraconazole, ritonavir, and clarithromycin inhibit CYP3A416 and this could lead to the increased levels of CBD when consumed together. CBD may increase serum concentrations of cyclosporine, sildenafil, antihistamines, haloperidol, antiretrovirals, and some statins (atorvastatin and simvastatin but not pravastatin or rosuvastatin)17. Interaction of these drugs with CYP3A4 leads to slower CBD degradation and can consequently lead to higher CBD levels that are pharmaceutically active for long periods of time. In contrast, phenobarbital, rifampicin, carbamazepine, and phenytoin induce CYP3A4, causing reduced CBD bioavailability.

GPR55 (G protein-coupled receptor 55) is highly expressed in large dorsal root ganglion neurons (added now) and, upon activation by agonists (e.g., THC), increases intracellular calcium in these neurons that may lead to neuronal excitability18. CBD is reported to function as GPR55 antagonist and suppresses GPR55’s activities. The GPR55-dependent mechanism plays a major role in CBD’s anti-psychotic and anti-epileptic activities19. The therapeutic effects of CBD on inhibiting the neurotransmission in Dravet syndrome mouse model were mediated by its antagonism of GPR5520.

CBD inhibition of the BCRP (Breast Cancer Resistance Protein) efflux function in the placental cotyledon warrants further research of co-administration of CBD with known BCRP substrates such as nitrofurantoin, cimetidine, and sulfasalazine21.

The Medscape Drug Interaction Checker database22 was searched for CBD’s interactions with other drugs and the results are tabulated in Table 1.

Table 1 Cannabidiol–Psychoactive Drug Interactions22
Full size table

CB1 receptors are located in the central nervous system and CB2 receptors are mostly found in the peripheral system23. Due to the lipophilic nature of CBD and THC, these compounds bind to these receptors and exert several pharmacological activities. CBD is a CB1 antagonist, a negative allosteric modulator at CB2, and an agonist at the transient receptor potential cation channel subfamily V member 1 (TRPV1) and serotonin 1A (5-HT1A) receptors, resulting in anxiolytic, antipsychotic, anticonvulsant, antioxidant, analgesic, and immunomodulatory functions, some of which buffer the harmful effects of THC like psychosis24. In particular, CB1, TRPV1, and 5HT1A are thought to be related to psychosis, anxiety, and pain, respectively. As reported by several researchers, CBD appears to have minimal analgesic activity25. In addition, evidence supporting CBD’s efficacy in treating psychiatric disorders remain scarce26.

CBD acts through several different targets and acts as cannabinoid receptor 1 and 2 antagonist (Fig. 1a), G-protein-coupled receptor 12 inverse agonist (Fig. 1a), glycine receptor subunit alpha-3 potentiator, 5-hydroxytryptamine receptor 1A (Fig. 1a) and 2A agonist (Fig. 1b), 3A antagonist (Fig. 1c), prostaglandin G/H synthase 1 and 2 inhibitor (Fig. 1d), and cytochrome P450 1B1 (Fig. 1e)/3A5 (Fig. 1e)/2D6 (Fig. 1f)/3A7 (Fig. 1f)/1A2 (Fig. 1g) inhibitor as well. The drugs that act on these targets as agonists, partial agonists, antagonists, negative modulators, inducers, binders, activators, blockers, and substrates could have the potential to interact as they work on the same target and mechanisms27. The possible drug–drug interactions of CBD based on these known targets against potential medications are collectively listed as flow chart figures that could have high clinical significance and relevance. The double-headed arrows indicate that the interactions are possible on either side.

Figure 1
figure 1figure 1figure 1figure 1figure 1figure 1figure 1

a Target-mediated drug–drug interactions of cannabidiol with cannabinoid and 5-hydroxytryptamine 1A receptors27. b Target-mediated drug–drug interactions of cannabidiol with 5-hydroxytryptamine 2A receptors27. c Target-mediated drug–drug interactions of cannabidiol with 5-hydroxytryptamine 3A receptors27. d Target-mediated drug–drug interactions of cannabidiol with prostaglandin G/H synthase 1 and 2 inhibitors27. e Target-mediated drug–drug interactions of cannabidiol with Cytochrome P450 1B1 and 3A5 inhibitor27. f Target-mediated drug–drug interactions of cannabidiol with Cytochrome P450 2D6 and 3A7 inhibitor27. g Target-mediated drug–drug interactions of cannabidiol with Cytochrome P450 1A2 inhibitor27. The red dotted lines indicate CBD’s mechanism/actions as listed in red boxes. The blue double-headed arrows indicate the possible targets and interactions of CBD with other targets/mechanisms as listed in blue boxes. Green single-headed arrows indicate the drugs that act on these targets, as listed in green boxes. Such drugs may have additive/synergistic or antagonistic effects if given concomitantly with CBD.

Full size image

However, the interactions presented in these figures are predicted from in vitro evidence, preclinical animal data or from their reported mechanism of actions, and their translation into clinical activities have not been established. These interactions could be concentration dependent and may require very high concentration of CBD and the other drug for any interaction to occur. Complexities in drug bioavailability, bio-absorption, pharmacokinetics in humans may also play a major role in CBD–drug interactions. Therefore, these reported interactions warrant further detailed research in human trials for accuracy and clinical significance.

CANNABIDIOL INTERACTIONS

CBD’s interaction with AEDs and antidepressants is a topic of interest for physicians because of the possibility of simultaneous consumption of both. CBD has been reported to interact with several anticonvulsants, including diazepam, lamotrigine, and phenytoin28,29; sedative drugs including barbiturates such as phenobarbital and hexobarbital30; and narcotics such as codeine and morphine.

Cannabidiol’s Interaction with Anti-epileptic Drugs

CBD has clear interactions with multiple AEDs, including clobazam, stiripentol, and valproate. CBD inhibits CYP2C19 and CYP3A4, which catalyze the metabolism of N-desmethylclobazam (nCLB), an active metabolite of clobazam11,31,32,33. The inhibition of these enzymes by CBD leads to the accumulation of nCLB, which is about 20–100% as potent as clobazam34; therefore, monitoring of clobazam and nCLB levels is necessary when these medications are used concomitantly14. A highly purified CBD oral solution has been approved in the USA for seizures associated with Lennox-Gastaut and Dravet syndromes in patients aged ≥ 2 years, for which AEDs are commonly used. A recent trial investigated the impact of CBD on steady-state pharmacokinetics of clobazam (and nCLB), stiripentol, and valproate35. The study also examined the reciprocal effect of these drugs on CBD’s safety and tolerability and its major metabolites (7-hydroxy-cannabidiol [7-OH-CBD] and 7-carboxy-cannabidiol [7-COOH-CBD]) when co-administered. Concomitant CBD had significant effect on nCLB exposure (with 3.4-fold Cmax (maximum concentration) and AUC (area under the concentration-time curve)), and little effect on clobazam or stiripentol exposure, while no clinically relevant effect on valproate exposure was observed. Stiripentol decreased 7-OH-CBD exposure by 29% and 7-COOH-CBD exposure by 13%. CBD was moderately well-tolerated when co-administered with AEDs35. The most common side effects of CBD are diarrhea and sedation36. There was also an increased incidence of aspartate aminotransferase and alanine aminotransferase elevations while taking CBD, with concomitant valproate37.

A pharmacodynamic animal study using maximal electroshock and audiogenic seizure models showed that CBD potentiated the anticonvulsant effects of phenytoin by twofold and discreetly potentiated the effect of phenobarbital. CBD also reduced the anticonvulsant properties of chlordiazepoxide, clonazepam, and ethosuximide29,38,39. A pharmacokinetic interaction between CBD and clobazam was reported with decreased clobazam serum levels noted after increasing CBD doses40. Another study suggests that CBD is effective in reducing seizure frequency and severity from baseline in adults and children with treatment-resistant epilepsy. According to this study, CBD has its own seizure-reducing efficacy and not affected by pharmacokinetic drug–drug interactions with other AEDs. The efficacy of AEDs can be modulated by CBD but CBD’s anti-epileptic efficacy is unaffected by AEDs41.

Socala et al.42 observed that CBD increased the activity of topiramate, oxcarbazepine, pregabalin, tiagabine, and gabapentin, but did not affect the anticonvulsant effect of lamotrigine and lacosamide. Increased anticonvulsant activity of AEDs was partly related to pharmacokinetic interactions with CBD because CBD increased serum and brain concentrations of these AEDs. Although CBD did not affect the anticonvulsant activity of lacosamide, pharmacokinetic interactions between these two drugs cannot be excluded as CBD increased the brain concentration of lacosamide and vice versa. Interestingly, cannabidiol attenuated the anticonvulsant activity of levetiracetam and this interaction is pharmacodynamic in nature because no changes in serum and brain concentrations of either levetiracetam or CBD were observed.

Cannabidiol’s Interaction with Antidepressants

CBD inhibits hepatic enzyme CYP2D6, and because of this inhibition, the serum concentrations of selective serotonin reuptake inhibitor (SSRIs), tricyclic antidepressants, antipsychotics, beta-blockers, and opioids may be increased as these antidepressants are metabolized by this enzyme. CBD can also affect metabolism of omeprazole and risperidone by CYP2D6 interactions43. CBD also interacts with monoamine oxidase inhibitors (MAOIs) like tranylcypromine, phenelzine, and isocarboxazid by inhibiting their metabolism and causing these substances to remain in the circulatory system for longer periods of time leading to unpleasant side effects44.

When sertraline, a SSRI, was administered in combination with CBD in mouse model of post-traumatic stress disorder, the combination produced synergistic action on cognitive and emotional disturbances (severe anxiety and aggressive behavior)45. The noradrenergic antidepressant, desipramine, when administered concurrently with CBD, at subtherapeutic doses of both, resulted in significant antidepressant like effects, thus implicating a synergistic or additive mechanism46.

Amitriptyline, a tricyclic antidepressant, is metabolized by cytochrome P450 isozymes CYP2D6, CYP2C19, CYP3A4, CYP1A2 and CYP2C9, and CBD inhibits these enzymes, which may increase adverse effects simultaneously (e.g., anticholinergic syndrome, drowsiness, and QT interval prolongation)47.

Additionally, gabapentin, pregabalin, citalopram, paroxetine, and mirtazapine are all metabolized by cytochrome enzymes that are known to be inhibited by CBD and co-administration of CBD with these medications may have adverse effects47.

Cannabidiol’s Interaction with Opioids

CBD has been shown to have divergent effects when co-administered with opioids. CBD’s interaction with morphine varied in different behavior models. For example, when the acetic acid stimulated stretching assay model was used, the combination showed synergistic effects. In the hot plate thermal nociceptive assay model, acetic acid decreased operant responding for palatable food model and sub-additive effects (an effect that is less than additive) were observed. These results suggest that distinct mechanisms of action underlie the interactions between CBD and morphine. Thus, the choice of appropriate combination therapies for the treatment of acute pain conditions may depend on the underlying pain type and stimulus modality48.

CBD is shown to inhibit heroin (diamorphine) metabolism and 6-monoacetylmorphine hydrolysis in in vitro conditions, which may be of clinical relevance49. A double-blind, placebo-controlled, crossover study in healthy volunteers with concomitant use of CBD and fentanyl showed that CBD does not exacerbate adverse effects associated with fentanyl and co-administration was well tolerated50.

Cannabidiol’s Interactions with -Δ9 -Tetrahydrocannabinol (THC)

There are 565 chemical compounds and 120 phytocannabinoids (as of 2017) isolated from cannabis, including THC and CBD51. THC produces the main psychoactive effects of cannabis, while CBD does not appear to have similar effects. Studies conflict as to whether CBD attenuates or exacerbates the behavioral and cognitive effects of THC. This includes the effects of CBD on THC-induced anxiety52, psychosis53, and cognitive deficits54. In a mouse model of paclitaxel-induced neuropathic pain, CBD synergized the effects of THC in attenuating mechanical allodynia, pain from usually non-painful stimuli. Also, CBD attenuated oxaliplatin- but not vincristine-induced mechanical sensitivity55. CBD inhibited the acute effects of THC and decreased THC effects on brain regions involved in memory, anxiety, and body temperature regulation56.

On the basis of CBD:THC ratios in cannabis, individuals from different populations were directly compared on indices of the reinforcing effects of drugs, explicit liking, and implicit attentional bias to drug stimuli. When intoxicated, smokers of high CBD:THC strains showed reduced attentional bias to drug and food stimuli compared with smokers of low CBD:THC. Those smoking higher CBD:THC strains also showed lower self-rated liking of cannabis stimuli on both test days. These reports suggest that CBD has potential as a treatment for cannabis use disorder57.

As both THC and CBD are hepatically metabolized, the potential exists for pharmacokinetic drug interactions via inhibition or induction of enzymes or transporters. In a study on the co-administration of CBD with THC in 5:1 dose ratio, CBD did not alter the trajectory of enduring THC-induced anxiety nor tolerance to the pharmacological effects of THC. There was no evidence of CBD potentiation of the behavioral effects of THC whereas CBD:THC in 1:1 co-administration increased histone 3 acetylation (H3K9/14ac) in the VTA (ventral tegmental area are group of neurons in the mid-brain) and ΔFosB, a transcription factor expression in the nucleus accumbens. Increased histone 3 acetylation in the VTA region associated with addictive properties of drug abuse. These changes suggest that CBD might have some protective effects over THC’s adverse effects over these brain regions and the process of memory58.

Cannabidiol’s Interaction with Other Drugs

Pharmacodynamic interactions may occur if CBD is administered with other central nervous system depressant drugs and cardiac toxicity may occur via additive hypertension and tachycardia with sympathomimetic agents. More vulnerable populations, such as older patients, may benefit from the potential symptomatic and palliative benefits of cannabinoids but are at increased risk of adverse effects59.

Warfarin

A case study described a patient with CBD treatment for the management of epilepsy, ultimately necessitating a 30% reduction in warfarin dose to maintain therapeutic international normalized ratio (INR) values60,37 with excessive bleeding as side effects.

Cyclosporine and Tacrolimus

CBD has the potential to affect the immunosuppressant cyclosporine’s metabolism which may result in increased cyclosporine blood levels and an increase in its toxic side effects. Another study reported CBD’s interaction with the immunosuppressant tacrolimus with 3-fold increase in dose-normalized tacrolimus concentrations61.

Acetaminophen

Caution should be taken when CBD is used with medications with the potential to cause hepatic injury, such as acetaminophen. CBD carries a recommendation for lowered doses in patients with hepatic impairment62. In a recent animal study, co-administration of CBD at the dose of 116 mg/kg (human dose of CBD is 10 mg/kg) with acetaminophen (400 mg/kg) resulted in 37.5% mortality associated with liver injury. No mortality was observed in the CBD-alone or acetaminophen-alone groups. The co-administration led to greater activation of c-Jun N-terminal kinase (JNK). Surprisingly, these effects were not observed in mice with a higher dose of CBD (290 mg/kg CBD with mouse equivalent dose of 25 mg/kg). This shows an interesting paradoxical effect of CBD/APAP-induced hepatotoxicity63.

Capsazepine

Co-administration of CBD, together with a TRPV-1 antagonist, capsazepine, reduces L-DOPA-induced dyskinesia (LID) by acting on CB1 and PPARγ receptors and reducing the expression of the inflammatory markers cyclooxygenase-2 and nuclear factor-kappa B64. These interactions could play a significant role as L-DOPA remains the most effective pharmacotherapy for Parkinson’s disease.

Other reports also demonstrate the possible interactions of CBD with rufinamide, zonisamide, and eslicarbazepine—increased accumulation of these drugs in the blood with concomitant use of CBD and their levels should be closely monitored37.

In a recent publication, Wilson-Morkeh et al.47 listed the interactions of CBD with corticosteroids (CS), commonly used drugs in the field of rheumatology. Hydrocortisone and prednisolone, commonly used CS, are both metabolized by the cytochrome P450 enzyme CYP3A65. CBD, as potent inhibitor of CYP3A when with these steroids may decrease glucocorticoid clearance and increase risk of systemic CS-induced side effects as well66. In addition, CBD could potentially interact with naproxen, tramadol, celecoxib, etoricoxib, fluoxetine, and tofacitinib as these are metabolized in the liver by cytochrome P450 enzymes. Another widely used RA drug, baricitinib, could be an exception as it was cleared by kidneys with minimal mediation by CYP3A4, and thus, the CBD interaction could be minimal. Methotrexate (MTX), hydroxychloroquine (HCQ), sulfasalazine (SSZ), mycophenolate mofetil (MMF), mesalazine, adalimumab, etanercept, abatacept, infliximab, and rituximab belong to the class of DMARDs (“disease-modifying anti-rheumatic drugs”), and these drugs have not been shown to produce interactions with CBD47.

Cannabidiol’s Interactions with Alcohol

Although CBD’s effects on alcohol consumption are poorly understood, CBD is known to act as an agonist of the 5-HT1A receptors and results suggest that CBD can attenuate alcohol consumption and potentially protect against certain harmful effects of alcohol, such as liver and brain damage67. When CBD was injected 30 min prior to each alcohol binge episode, it protected against hepatic injury, as measured by an attenuation in multiple markers of liver injury and oxidative stress68. Similarly, when CBD was co-administered with ethanol to rats, CBD was able to attenuate alcohol-induced brain damage in the hippocampal and entorhinal cortices. Alcohol-induced cell death was reduced by approximately 60% in both hippocampal granular cells and the entorhinal cortical pyramidal cells69. In a clinical study, CBD, when consumed with alcohol, produced significant impairments of motor and psychomotor performances, overestimations of time production (estimation of alcohol content over various time periods) and subjective responses indicating some protective effects, including an accurate self-perception of one’s intoxication and deficits. CBD did not prevent enhanced locomotor response once alcohol sensitization had developed70. CBD also lowered blood alcohol levels71. The timing and dosage of CBD administration could influence alcohol pharmacokinetics. Long-term effects of CBD on alcohol-induced anxiety and impulsivity need further exploration67.

CONCLUSION

This review provides an insight into the possible and potential interactions of CBD with other classes of commonly used drugs based on the evidence and knowledge currently available. Despite the increased popularity of CBD as a medication for myriad medical conditions, the limited availability of applicable pharmacokinetic and pharmacodynamic information highlights the need to initiate prescribing CBD using a “start low and go slow” approach, carefully observing the patient for desired and adverse effects. Further clinical studies in the patient populations for whom prescribing may be considered are needed to derive a better understanding of these drugs and enhance safe and optimal prescribing. Given few existing case reports or clinical trials available on CBD’s interactions with other drugs, future research should address and characterize the mechanisms of these interactions. The growing popularity of CBD use and the lack of sufficient information on CBD drug–drug interactions make it imperative that we investigate the impact of CBD upon concomitant drug use in future randomized, controlled trials.