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Drug and Disease Interactions

There are two main categories of medical marijuana related drug reactions that have been studied so far. The first involve drugs that are highly protein bound. The second involve drugs metabolized by the CYP450 isoenzymes.  


Protein bound drugs:
 Medical marijuana, particularly THC, is highly protein bound. As a result, it can displace other highly protein bound medications due to its high affinity for a variety of proteins. Warfarin for example, is highly protein bound and when used with medical marijuana can lead to an increased risk of bleeding due to its increased bioavailability.


CYP450 Enzymes:
 The main isoenzymes involved in this interaction are 2C9, 3A4 and 2C19 but also 2D6 and 1A2. These enzymes metabolize THC, CNB and CBD which also interferes with the metabolism of medications and vice-versa. THC and CBN are primarily metabolized by isoenzymes 2C9 and 3A4 and CBD is metabolized by 2C19 and 3A4. This pathway is saturable and therefore has a limit to the amount it can metabolize at a given time. This can also lead to an increase of drug bioavailability.

 

Anticoagulations/INR: Due to the metabolism of warfarin by CYP450 enzymes, THC and CBD have been shown to increase warfarin levels and may, consequently, affect a patient’s INR and risk of bleeding. There is also evidence to suggest that marijuana itself, has anticoagulation properties. Therefore, it has the potential to work synergistically with other known anticoagulants.


Inducers:
 CYP450 inducers increase enzyme activity and drug metabolism which can lead to decreased effectiveness of medical marijuana and CYP450 metabolized medications. For example THC is a CYP1A2 inducer which can affect medications such as duloxetine, naproxen and cyclobenzaprine, by decreasing its availability to due increased metabolism. Similarly, Rifampin is a CYP3A4 inducer which decreases THC and CBD concentrations.


Inhibitors:
 On the contrary, CYP450 inhibitors can increase effects of drugs and medical marijuana by inhibiting the enzymes and slowing down drug metabolism leading to increased concentrations. For example, CBD is a CYP3A4 inhibitor which can lead to potentiated effects of medications such as macrolides, calcium channel blockers, benzodiazepines and antihistamines. Similarly, the effects of medical marijuana can be increased by medications that are inhibitors of CYP3A4. Ketoconazole for instance has been known to increase THC and CBD’s bioavailability up to almost 2-fold.

 

 

Table of Potential Cannabis Related Drug Interactions

Cannabis may increase the concentrations of these drugs  Rationale

Alprazolam

Amiodarone

Amitriptyline

Atorvastatin

Codeine

Cyclosporine

Diazepam

Diltiazem

Dronedarone

Midazolam (oral)

Oxycodone 

Paroxetine

Risperidone

Sildenafil

Tacrolimus

Tadalafil

Tramadol

Triazolam

Vardenafil

Verapamil

Warfarin
CBD is a potent inhibitor of CYP 3A4 and CYP 2D6 

 

  

Cannabis may decrease the concentration of these drugs Rationale 
Chlorpromazine

Clozapine

Cyclobenzaprine

Duloxetine

Granestron

Haloperidol

Lidocaine

Mirtazepine
Naproxen

Olanzapine

Ondansetron

Propranolol

Ropinerole

Theophylline

Tizanadine
THC is an inducer of CYP 1A2  

 

 

These drugs may increase the serum concentrations of THC/CBD
Rationale
Amiodarone

Cimetidine

Clarithromycin

Clobazam

Eslicarbazepine

Erythromycin

Flovoxamine

Fluconazole

Fluoxetine

Isoniazid

Itraconazole 

Ketoconazole

Metronidazole

Nefazodone

Omeprazole

Omeprazole

Phenytoin

Sulfamethoxazole/trimethoprim

Topiramate

Valproic Acid

Verapamil

Zonisamide 
CYP 3A4, 2C9 and 2C19 Inhibition 

 

 

These drugs may decrease the serum concentrations of THC/CBD Rationale 
Carbamazepine

Oxcarbazepine

Phenobarbital
Primidone

Rifampin

St John’s Wort

Panax Ginseng

CYP3A4, 2C9 and 2C19 induction

 

 

Other potential Interactions  Rationale

CNS Depressants

Opioids

Benzodiazepines

Barbiturates

Alcohol


Anticholinergic activity

Anticholinergic agents

First generation antipsychotics

First generation antihistamines
THC and CBD have been shown to increase warfarin levels; frequent cannabis use has been associated with increase INR

 

 

Antiplatelet, anticoagulant, herbal supplements Rationale
 Apixaban

Clopidgrel

Enoxaparin

Garlic

Ginger

Gingko balboa
Ginseng

Glucosamine

Prasugrel

Rivaroxiban

Ticagrelor

Warfarin
THC and CBD have been shown to increase warfarin levels; frequent cannabis use has been associated with increase INR

 

References:

1.       Information for Health Care Professionals: Cannabis and the Cannabinoids. Prepared by Health Canada; February 2013.

2.       Medical Cannabis: Adverse Effects and Drug Interactions. District of Columbia Department of Health. doh.dc.gov/dcrx 

3.       Melton ST, Stirring the Pot: Potential Drug Interactions With Marijuana. Medscape. https://www.medscape.com/viewarticle/881059 . Accessed 30 Jan 2019.

4.       Alsherbiny MA, Guang CL. Medical Cannabis-Potential Drug Interactions. Medicines 2019, 6, 3.

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