Question
What medicines may probably work together with marijuana?
 | Response from Sarah T. Melton PharmD |
Twenty-six states and the District of Columbia at the moment have laws broadly legalizing marijuana in some type.[1] But, no matter authorized standing, leisure and medicinal use of marijuana is frequent throughout the United States. With this growing availability and in addition the growing efficiency of marijuana,[2] it is crucial for each customers and healthcare professionals to concentrate on the potential drug interactions related to marijuana use.
Tetrahydrocannabinol (THC) is the main psychoactive cannabinoid present in marijuana.[2] Cannabidiol (CBD) can be present in excessive concentrations in marijuana however just isn't psychoactive; it has an antagonistic impact at the cannabinoid receptors and seems to dam a few of the results of THC.[3] Cannabinol (CBN) is a comparatively weak psychoactive cannabinoid current in very small portions inside the marijuana plant however is one in every of the main metabolites of THC.[4] The marijuana plant comprises greater than 50 different cannabinoids, however artificial medicines permitted by the US Food and Drug Administration (eg, dronabinol and nabilone) comprise solely THC with none CBD. The pharmacologic impact of those merchandise might differ from that of pure cannabis.[5]
Data are restricted relating to the potential drug interactions related to marijuana use; nonetheless, unstudied interactions will be theorized primarily based on the metabolism of the main cannabinoids in marijuana.
CYP450 Enzymes
Cytochrome P450 (CYP450) enzymes are chargeable for the metabolism of most chemical substances and medicines that enter the human physique. Humans have roughly 60 CYP genes. CYP450 enzymes happen primarily in liver cells the place drug metabolism happens.
Chemicals or medicine could also be substrates, inhibitors, or inducers of CYP450 enzymes. Substrates are substances which might be metabolized by the enzyme. Inhibitors cut back the exercise of the enzyme, stopping the metabolism of its substrates and thus growing the substrate focus and impact. Inducers, on the different hand, improve the exercise of the enzyme, enhancing the metabolism of its substrates and thus lowering the substrate focus and impact.[6]
The CYP1A2, CYP3A4, CYP2C9, and CYP2C19 enzymes are identified to be affected by marijuana use.[7,8]
CYP1A2
Smoking marijuana recurrently is believed to trigger induction of the CYP1A2 enzyme, which can lower serum concentrations of 1A2 substrates.[9] One research reported that theophylline clearance was 48% better in people who smoked greater than 2 joints weekly.[10] Marijuana can be anticipated to have an identical impact on different 1A2 substrates.
Other 1A2 substrates. Aminophylline, caffeine, clozapine, duloxetine, estradiol, estrogens, flutamide, fluvoxamine, frovatriptan, lidocaine, melatonin, mexiletine, mirtazapine, olanzapine, propranolol, ramelteon, rasagiline, ropinirole, tizanidine, triamterene, zolmitriptan.
CYP3A4
The CYP3A4 enzyme is concerned in the metabolism of each THC and CBD.[7] Therefore, 3A4 inhibitors might improve serum concentrations of those cannabinoids, whereas 3A4 inducers might lower the serum concentrations. In one research carried out in the United Kingdom, rifampin (3A4 inducer) decreased the focus of THC by 40% and CBD by 20%. In the similar research, ketoconazole (3A4 inhibitor) was discovered to extend the focus of THC by 20%.[11] It can be anticipated that different 3A4 inhibitors and inducers would produce an identical impact.
Strong 3A4 inducers. Carbamazepine, enzalutamide, fosphenytoin, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, St. John's wort.
Strong 3A4 inhibitors. Clarithromycin, darunavir, grapefruit juice, itraconazole, ketoconazole, lopinavir, mifepristone, nefazodone, nelfinavir, ombitasvir, paritaprevir, ritonavir, posaconazole, saquinavir, telaprevir, telithromycin, verapamil, voriconazole.
CYP2C9
In addition to CYP3A4, CYP2C9 is the different identified enzyme chargeable for metabolism of THC.[7] In a research of sufferers who had been poor metabolizers of 2C9, THC concentrations had been discovered to be threefold increased than in these with regular 2C9 perform.[12] While no identified research have regarded particularly at the results of 2C9 inhibitors and inducers on THC concentrations, they might be anticipated to have related results as the 3A4 inhibitors and inducers.
Strong 2C9 inducers. Barbiturates, carbamazepine, phenytoin, rifabutin, rifampin, rifapentine, St. John's wort.
Strong 2C9 inhibitors. Amiodarone, cimetidine, clopidogrel, delavirdine, disulfiram, fluconazole, fluorouracil, gemfibrozil, metronidazole, phenytoin, sulfadiazine, sulfamethoxazole, tolbutamide, valproic acid, voriconazole.
CYP2C19
In addition to CYP3A4, CYP2C19 is the different identified enzyme chargeable for metabolism of CBD.[7] In one research, omeprazole (2C19 inhibitor) didn't improve serum concentrations of CBD.[13] Even with these surprising outcomes, 2C19 inhibitors and inducers must be assumed to have related results on CBD concentrations as the 3A4 inhibitors and inducers till additional research present a greater understanding.
Strong 2C19 inducers. Barbiturates, carbamazepine, phenytoin, primidone, rifampin, rifapentine, St. John's wort.
Strong 2C19 inhibitors. Chloramphenicol, cimetidine, clopidogrel, delavirdine, efavirenz, esomeprazole, felbamate, fluconazole, fluoxetine, fluvoxamine, isoniazid, modafinil, omeprazole, oxcarbazepine, ticlopidine, voriconazole.
Other Potential Drug Interactions With Marijuana
Central nervous system (CNS) depressants. Clear proof exists that THC can improve sedative, psychomotor, respiratory, and different results of CNS depressant medicine and alcohol.[14-16]
Anticholinergic brokers, cocaine, sympathomimetics. Cannabinoids are identified to trigger tachycardia. Several drug monographs and medical research have been revealed indicating that concomitant use of marijuana with anticholinergics, cocaine, or sympathomimetic brokers can additional improve tachycardic and hypertensive results of cannabinoids.[17-19]
Disulfiram and fluoxetine. At least two case reviews of people taking disulfiram and no less than one case report of a person taking fluoxetine whereas additionally utilizing marijuana point out a doable interplay inflicting signs of hypomania.[20-22] Prescribing info for nabilone and dronabinol additionally consists of this drug interplay to warn prescribers of the potential danger.[19,23]
Warfarin. A single revealed case report describes an interplay with a affected person taking warfarin who additionally recurrently smoked tobacco and marijuana. The affected person had a number of comorbidities and was taking no less than 10 different medicines. On no less than two events, the affected person's worldwide normalized ratio (INR) elevated to values over 10 with episodes of bleeding. The solely change reported for each events was a rise in the quantity and frequency of marijuana smoking.[24] Patients who take warfarin and use marijuana recurrently ought to obtain shut INR monitoring for any potential interplay.
Antiepileptic medicine (AEDs). A current research examined baseline serum AED ranges to determine drug-drug interactions between CBD and 19 AEDs throughout an open-label security research in 81 sufferers (39 adults, 42 youngsters) with refractory epilepsy.[25] As doses of CBD had been elevated, the researchers famous a rise in the serum ranges of topiramate (P<.01), rufinamide (P<.01), and desmethylclobazam (P<.01) and a lower in the ranges of clobazam (P<.01) in each grownup and pediatric sufferers. In grownup sufferers, a big improve in the serum ranges of zonisamide (P=.02) and eslicarbazepine (P=.04) was noticed with growing CBD dose. No different drug interactions amongst the 19 AEDs had been famous. The authors really helpful monitoring serum AED ranges in sufferers receiving CBD, as drug-drug interactions could also be correlated with adversarial occasions and laboratory abnormalities.
Be Aware and Educate Patients
Patients utilizing marijuana must be educated to keep away from medicine that have an effect on related CYP450 enzymes. When these medicine can't be prevented, and marijuana use is predicted to proceed, the affected person must be monitored carefully for potential drug interactions.
Smoking greater than two joints weekly is more likely to improve the danger for drug-related interactions.[5,10] No information exist monitoring large-scale marijuana use in the United States. However, in Washington, a state during which marijuana use is authorized, the common person is estimated to smoke two to a few joints per week.[26]
With rising legalization and use all through the nation, healthcare professionals should train heightened warning in the scenario of concomitant use of medicines and marijuana.
Dr Melton acknowledges the analysis help of Nasar Ansari, PharmD Candidate, and Tandy Branham, PharmD Candidate.
Follow Medscape Pharmacists on Twitter: @MedscapePharm
Stirring the Pot: Potential Drug Interactions With Marijuana
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