The Research

The major cannabinoid in hemp oil is cannabidiol (CBD) which is metabolized in the liver via hydroxylation by the CYP450 enzymes CYP2C9, CYP2C19, and CYP3A4.1  In animals, CBD has been shown to affect the metabolism of drugs that are metabolized by these and other CYP450 enzymes.1-6  This effect on other enzymes may not be a direct effect of CBD but of the covalent binding of a CBD metabolite to a hepatic microsomal P450.7   Even though there is significant risk of DDI’s with CBD, the clinical incidence and significance is much less than would be expected given this extensive range of metabolic interference.7,8  The answer to this dilemma can be found in the amount of CBD required to produce a DDI. 

Most of the data on DDI interactions has been performed in animals and, when extrapolated to humans, 90% absorption of an oral dose of over 5mg/kg of CBD would be needed to effect the concentration of a drug metabolized via the CYP2B6 pathway, the pathway which is affected by the lowest CBD intake.Much higher doses oral doses are reguired to effect the other CYP enzymatic pathways.9   At 30% absorption, a much more realistic oral absorption rate than 90%, 50 mg/kg would be necessary to affect any CYP pathway metabolism of a drug.  It is important to note that all of the above effects are changes in drug concentrations, which may not result in any clinically significant DDI’s.

These animal extrapolations and are similar to what has been found in humans that take Epidiolex, a CBD enriched hemp oil product approved by the FDA for treatment of some childhood epilepsies.   Dosages greater than 5mg/kg (2.27mg/pound) are needed to cause a change in the blood levels of some drugs metabolized via the CYP system and the severity of the effect increase with increasing dosages of CBD.10  This means a 150 pound person would need to take a minimum of 340mg/day of CBD to have a change in blood levels of another drug.   However, in this study10, all of the changes in blood levels were minimal and not outside the therapeutic range, except for Clobazam and Desmethylclobazam whose levels fell below the normal therapeutic range, however, there was no apparent worsening in epileptic activity.  This means that although there is a statistical finding of interaction, there was no adverse clinical significance of the interaction.  All patients in this study had increasing amount of CBD being given and all ended at a maximum dose of 50mg/kg (~24mg/lb. or 3400mg/day for a 150# person).  Even at this high dose, no adverse clinical reactions were reported.  This is not unexpected as no serious side effects have been reported in normal patients receiving up to 6000/day.11  Similar findings with CBD and Clobazam in low and high doses have been reported in other studies. 12-14  In as study of CBD artisan use (patients using CBD on their own) in patients with epilepsy, no adverse clinical DDI were found.15

Two cases of cannabis DDI’s have been reported with warfarin, one was a patient smoking marijuana and the other was a patient taking CBD for epilepsy.16,17  The first case may have been a THC induced DDI, while the second was probably a CBD-induced DDI.  In the second case17, the dose of CBD the person was taken when the DDI started occurring was 15mg/kg (33mg/pound), a very high CBD dose.  

The administration of CBD alone versus CBD in hemp oil that contains other cannabinoids may be a significant factor in minimizing clinical DDI effects.  The entourage effect of the other cannabinoids and compounds in the hemp oil seem to minimize the effect of CBD on the CYP450 enzymes.8,18,19   The magnitude of this effect is not known at this time, but the entourage effect of hemp oil in increasing the effectiveness of CBD in other disease states is well known.

 However, not all CBD induced changes in drug concentrations may be due to CBD interfering with the liver’s CYP450 enzyme system. In the study referenced above10, the blood level of Rufinamide, a drug not metabolized by the CYP450 system, was decreased when CBD, however, the level stayed well within the therapeutic range.  Again, a statistical finding with no clinical significance.

Bottom Line

High levels of CBD (>340mg/day) can cause interactions with the metabolism of some drugs but few clinical significant DDI’s have been reported.20  Low dose CBD does not seem to cause any interactions with other drugs.   American Shaman Water Soluble Hemp oil (ASWSHO) is a nano-technology treated hemp oil which most people take in the amounts of 5mg to 15mg twice a day and report great results.21  Ingestion at these low amounts should not result in any drug-drug interactions.   However, I highly recommend that all doctors follow their patients closely and monitor for interactions, regardless of the dosage, until more information is available.   

 

Note:  The FDA has not approved CBD for the treatment of any diseases other than the approval of Epidiolex for the treatment of some specific pediatric epilepsies. 

References:

1.        Zendulka O, etal.  Cannabinoids and Cytochrome P450 Interactions. Curr Drug Metab. 2016;17(3):206-26.
2.        Arellano AL, etal. Neuropsychiatric and General Interactions of Natural and Synthetic Cannabinoids with Drugs of Abuse and Medicines.  CNS Neurol Disord Drug Targets. 2017;16(5):554-566.
3.        Arnold WR, Weigle AT, Das A.  Cross-talk of cannabinoid and endocannabinoid metabolism is mediated via human cardiac CYP2J2.  J Inorg Biochem. 2018 Jul;184:88-99.
4.        Yamaori S, etal.  Biochem Pharmacol. Characterization of major phytocannabinoids, cannabidiol and cannabinol, as isoform-selective and potent inhibitors of human CYP1 enzymes.  2010 Jun 1;79(11):1691-8.
5.        Yamaori S. etal.  Cannabidiol, a major phytocannabinoid, as a potent atypical inhibitor for CYP2D6.   Drug Metab Dispos. 2011 Nov;39(11):2049-56.
6.        Yamaori, S., et al. Differential inhibition of human cytochrome P450 2A6 and 2B6 by major phytocannabinoids Forensic Toxicol 2011;29: 17.
7.        Kosel B, etal.  The effects of cannabinoids on th pharmacokinetics of indinavir and nelfinavir.  AIDS 2002;16(4):543-50.
8.        Bergamaschi MM, et al. (2011) Safety and side effects of cannabidiol, a Cannabis sativa constituent. Curr Drug Saf. 2011 Sep 1;6(4):237-49.
9.        Iffand K, Grotenhermen F. (2017) An update of the safety and side effects of cannabidiol: a review of clinical data and relevant animals studies.  Cannabis Cannabinoid Res 2017;2.1
10.     Gaston TE, etal. (2017)   Interactions between cannabidiol and commonly used antiepileptic drugs.  Epilepsia. 2017 Sep;58(9):1586-1592.
11.     Taylor L, etal.  A phase 1, 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.  CNS Drugs 2018;32:1053-67.
12.     Devinsky O, etal. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome.  Neurology® 2018;90:e1204-e1211.
13.     Lattanzi S , etal.  Efficacy and Safety of Cannabidiol in Epilepsy: A Systematic Review and Meta-Analysis.  Drugs. 2018 Nov;78(17):1791-1804.
14.     Morrison G, etal.  A Phase 1, Open-Label, Pharmacokinetic Trial to Investigate Possible Drug-Drug Interactions Between Clobazam, Stiripentol, or Valproate and Cannabidiol in Healthy Subjects.  Clin Pharmacol Drug Dev. 2019 Feb 21.
15.     Porcari GS, etal.   Efficacy of artisanal preparations of cannabidiol for the treatment of epilepsy: Practical experiences in a tertiary medical center.   Epilepsy Behav. 2018 Mar;80:240-246.
16.     Damkier P, etal.   Interaction between warfarin and cannabis.   Basic Clin Pharmacol Toxicol. 2019 Jan;124(1):28-31.
17.     Grayson L, etal.  An interaction between warfarin and cannabidiol, a case report.  Epilepsy & Behav Case Reports 2017:9:10-11
18.     Stott CG, Ayerakwa L, Wright S, et al. (2007) Lack of human cytochrome P450 induction by Sativex. 17th Annual Symposium on the Canna- binoids. Saint-Sauveur, Quebec, Canada: International Cannabinoid Research Society. p 211.
19.     Stott CG, Guy GW, Wright S, et al. (2005) The effects of cannabis extracts Tetranabinex and Nabidiolex on human cytochrome P450-mediated metabolism. June 27 2005; Clearwater, FL. International Cannabinoid Research Association. p 163.
20.     Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review.  Drug Metab Rev. 2014 Feb;46(1):86-95.
20. Kaufmann, R.  (unpublished observations). April 5, 2019.

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