At its November 2017 meeting, the World Health Organization (WHO) Expert Committee on Drug Dependence (ECDD) concluded that, in its pure state, CBD does NOT appear to have abuse potential or cause harm. In humans, CBD exhibits no effects indicative of any abuse or dependence potential and is generally well tolerated with a good safety profile.
The comprehensive review of 132 studies by Bergamaschi et al. describes the safety profile of CBD, mentioning several properties: catalepsy is not induced and physiological parameters are not altered (heart rate, blood pressure, and body temperature). Moreover, psychological and psychomotor functions are not adversely affected. The same holds true for gastrointestinal transit, food intake, and absence of toxicity for nontransformed cells (1).
At lower doses, it has physiological effects that promote and maintain health, including antioxidative, anti-inflammatory, and neuroprotection effects. For instance, CBD is more effective than vitamin C and E as a neuroprotective antioxidant and can ameliorate skin conditions such as acne (1).
Systematic reviews concluded that CBD generally has a low risk of clinically significant drug-interactions (7). Cannabinoids are weak inhibitors of cytochrome P450 (CYP). CBD inhibits CYP2C19, 3A4 and 3A5, although this can be observed ONLY at doses higher than clinically used (8). Most drug interactions are an effect of the concurrent use of other agents’ depression of the central nervous system. Clinically significant interactions are rare, and it may be combined practically with any medicine (9).
Chronic use and high doses up to 1,500 mg/day of CBD are reportedly well tolerated in humans (1).
PRECAUTIONS
Anti-arrhythmics
Quinidine, sold as Quin-G, Cardioquin, Quinora, Quinidex Extentabs, Quinaglute Dura-Tabs, Quin-Release, a class I antiarrhythmic agent (Ia) medication, is metabolized in the liver by CYP3A4. CBD has been shown to inhibit this enzyme system and may increase blood concentration of these medications and can increase the risk of serious side effects, such as serious arrhythmias.
Anthistamines
Antihistamines such as Chlorpheniramine are metabolized in the liver by CYP3A4. CBD has been shown to inhibit this enzyme system and may increase blood concentration of Antihistamines.
Antibiotics
Macrolides such as Erythromycin (not Azithromycin) is metabolized in the liver by CYP3A4. CBD has been shown to inhibit this enzyme system and may increase blood concentration of Erythromycin.
In contrast Clarithromycin and Telithromycin are very strong inhibitors of the CYP3A4 enzymes and this may lead to slower CBD degradation and can consequently lead to higher CBD doses that are longer pharmaceutically active.
Anticoagulants
The majority of these medications are metabolized by CYP3A4 and CYP3A5 enzymes. CBD can inhibit both of these enzymes, thus CBD may increase the Warfarin levels for example. We highly advise you consult with your Doctor before starting CBD while on a blood thinner. Monitoring the INR levels is highly recommended.
Anticonvulsants
In a number of trials with CBD in children with severe epilepsy, Clobazam concentrations increased when CBD was co-administered and dosage of Clobazam had to be reduced in some patients in one study.(Geffrey et al., 2015; Devinsky et al., 2018b).
Gaston and colleagues performed a safety study in adults and children in which CBD was administered with commonly-used anti-epileptic drugs (AEDs) (Gaston et al., 2017). Most changes in AED concentration were within acceptable ranges, but abnormal liver function tests were reported in those taking Valproate, and authors emphasized the importance of continued monitoring of AED concentrations and liver function treatment with CBD.
Antidepressants
CYP2D6 and CYP3A4 metabolizes many antidepressants, so CBD may increase serum concentrations of SSRIs, such as citalopram (Celexa), escitalopram (Lexapro), fluvoxamine (Luvox), paroxetine (Paxil), Prozac, and sertraline (Zoloft), Tricyclic antidepressants (Amitriptyline), SARIs (Trazadone), and Aminoketone Antidepressants (Bupropion). Caution is advised.
Anti-fungals
Anti-fungals are metabolized in the liver by CYP3A4. CBD has been shown to inhibit this enzyme system and may increase blood concentration these classes of medications.
In contrast, Ketoconazole, an antifungal and a very strong CYP3A4 inhibitor, can double the CBD peak plasma concentrations.
Anti-hypertensive
Calcium Channel Blockers are metabolized in the liver by CYP3A4. CBD has been shown to inhibit this enzyme system and may increase blood concentration of these medications.
Beta blockers are metabolized in the liver by CYP2D6. CBD has been shown to inhibit this enzyme system and may increase blood concentration of these medications.
Anti-nausea
Zofran is metabolized by CYP2D6 and CYP3A4. CBD inhibits both of these enzymes and so can increase the amount of Zofran that enters your bloodstream.
Anti-psychotics
Typical and Atypical Antipsychotics such as Haloperidol, Seroquel, and Zyprexa are metabolized in the liver by CYP3A4. CBD has been shown to inhibit this enzyme system and may increase blood concentration of these medications.
Benzodiazepines
Benzodiazepines such as Alprazolam, Clobazam, Clonazepam, Diazepam, Midazolam and Triazolamare are metabolized in the liver by CYP3A4. CBD has been shown to inhibit this enzyme system and may increase blood concentration of these medications and can increase the risk of serious side effects, such as CNS depression.
Furanocoumarins (Grapefruit)
Furanocoumarins contain in grapefruits that can inhibit the actions of some CYP3A4 enzymes in your small intestine and thus can reduce the enzymatic degradation of certain medications, thereby increasing its duration of action and effect.
CBD was found to be is a more potent inhibitor of cytochrome enzymes than the grapefruit compound Bergapten (the strongest of several grapefruit components that inhibit).
Thus, medications or natural medicinal products that carry a grapefruit interaction warning should NOT be taken with CBD without the knowledge, consent and strict supervision of your licensed healthcare provider.
HIV Antivirals
Antivirals such as Atazanavir, Cobicistat, Darunavir, Fosamprenavir, Indinavir, Nelfinavir, Ritonavir, and Saquinavir are metabolized in the liver by CYP3A4. CBD has been shown to inhibit this enzyme system and may increase blood concentration of these medications.
Immune Modulators
Ciclosporine and Tracrolimus are metabolized in the liver by CYP3A4. CBD has been shown to inhibit this enzyme system and may increase blood concentration of these medications.
Opiods
CYP2D6 metabolizes opioids (including codeine and Oxycodone) so CBD may increase serum concentrations of opiods.
Note, CBD was co-administered with i.v. Fentanyl (a high potency opioid) which was reported as safe and well-tolerated (Manini et al.,2015).
Sildenafil (Viagra)
Sildenafil, Tadalafil, and Vardenafil are metabolized in the liver by CYP3A4. CBD has been shown to inhibit this enzyme system and may increase blood concentration of these medications and can increase the risk of serious side effects, such as hypotension and fainting.
Sleep Aids
Zolpidem (Ambien) is extensively metabolized in the liver by CYP3A4 with CYP2D6 also playing a minor roll. As such, it may interact with CBD, possibly increasing unwanted side effects of this medication.
Statins
Statins such as Atorvastatin, Lovastatin and Simvastatin (not Pravastatin or Rosuvastatin) are metabolized in the liver by CYP3A4. CBD has been shown to inhibit this enzyme system and may increase blood concentration of these medications and can increase the risk of serious side effects, such as Rhabdomyolysis.
Steroids
Steroids such as Stradiol, Hydrocortisone, Dexamethasone, Progesterone and Testosterone are metabolized in the liver by CYP3A4. CBD has been shown to inhibit this enzyme system and may increase blood concentration of these medications.
Stimulants
Adderall and Vyvanse, are metabolized by CYP2D6. CBD has been shown to inhibit this enzyme system and may increase blood concentration of these medications.
CBD & Metabolism
Cytochrome P450 System
The majority of drugs are broken down by what’s called Cytochrome P450 (CYP450) enzymes. There are over 50,000 distinct enzymes in this group that are found in tissues throughout your entire body.
The Cp3a enzymes
CYP3A, a subfamily of the CYP450 system, is involved in the metabolism of more than 50% of drugs clinically used. The human CYP3A subfamily expressed in the liver consists of at least three members: CYP3A4 (the most abundant), CYP3A5 and CYP3A7.
How CBD may be metabolized
In vitro data were identified that characterize CYP450 enzymes as potential significant contributors to the primary metabolism of CBD via the Cyp3A4 and CYP2c19 enzyme systems (1,4).
CYP3A4 inhibitors & Inducers
Various medications, as well as furanocoumarins (found in grapefruit) and CBD (found in hemp), can inhibit the action of the CYP3A4 enzymes. Various medications, as well as CBD, may induce the CYP3A4 enzymes (i.e amplify its ability to work). To put it simply, anything that can inhibit or induce the CYP3A system can effect how we clear other prescription medications from the body.
Medications that can effect how CBD functions.
Various drugs such as Ketoconazol, Itraconazol, Ritonavir, and Clarithromycin are strong inhibitors of CYP3A4 enzymes. This may lead to slower CBD degradation and can consequently lead to higher CBD doses that are longer pharmaceutically active. In contrast, Phenobarbital, Rifampicin, Carbamazepine, and Phenytoin induce the CYP3A4 system, causing reduced bio-availability (i.e. less CBD in the bloodstream) (5).
CBD inhibits the CP450 system
The exact mechanism of how CBD effects your body's metabolism of other medications is not yet fully understood. However, research has shown that CBD is a potent inhibitor against human CYP3A and other CYP450 enzymes (2). It was also found to interact with CYP1A2, CYP2C8, CYP2C9. CYP2C19 and UGT1a9, UGT2b7 substrates in vitro.
CBD could induce the CYP450 system
In 2015, at the International Cannabinoid Research Society meeting, Dr. Kazuhito Watanabe disclosed preliminary research evidence that CBD may induce some CYP450 enzymes (3).
More CBD Pharmacokinetics Research is needed.
Studies of CBD inhibition and induction of major human CYP450 enzymes generally reflect a low risk of clinically significant drug interactions with most use, but specific human data is still lacking (4). At current, research supports that CBD inhibits the CYP3A4, CYP3A5 and CYP2D6 enzymes (5), which could potentially cause higher than normal amounts of common prescription medications in your bloodstream when taken with CBD.
Caution is also advised with concomitant use of CBD and substrates of UDP-glucuronosyltransferases UGT1A9 and UGT2B7, and other drugs metabolized by the CYP2C19 enzyme (5).
As a precaution, please always consult with a licensed health care provider before taking CBD with your prescription medication(s) as certain medications (some main ones listed above) may warrant medical supervision.