Medicinal cannabis use is at an all-time high in the United States. From 2016 to 2020 alone, the number of patients enrolled in a state medical marijuana program quadrupled, according to a study published in Annals of Internal Medicine. As many as 8 million Americans use medical cannabis routinely to treat a chronic condition, per estimates from the National Organization for the Reform of Marijuana Laws.

As cannabis grows in popularity, healthcare professionals may find more and more patients turning to them with specific questions about medical cannabis use. But to answer these questions and support their patients, healthcare professionals need education and training on the topic, as well as clinical guidelines that provide evidence‐based information about efficacy, safety, and appropriate dosage of medical cannabis products.

A 2022 study, in which 26 healthcare professionals who dealt with chronic pain patients were interviewed, found that the vast majority reported being not ready or comfortable to answer patients’ questions regarding medical cannabis. They also felt unable to issue a written authorization for a patient to possess medical cannabis.

Until these gaps in education are addressed, healthcare professionals will continue to be limited in their ability to make treatment recommendations about medical cannabis for their patients. This blog should serve as a resource for healthcare professionals, including physicians, pharmacists and nurses, who wish to counsel patients on potential drug interactions between cannabis and other drugs.

I. Understanding Cannabis Pharmacology
The endocannabinoid system (ECS) is made of three different components: endocannabinoids, receptors, and enzymes.

The endocannabinoids are molecules that are already in our body that are similar to cannabinoids that are found in cannabis. Endocannabinoids help to keep our internal functions running smoothly. Receptors are the binding sites for endocannabinoids to signal the ECS to activate. The effects vary depending on where the receptor is and which endocannabinoid binds to it. Enzymes break down endocannabinoids after the function is carried out.

Overall, the ECS helps maintain homeostasis. It can help regulate our immune system, reduce inflammation, and promote healing. Cannabis plays a part in the ECS since cannabinoids like THC, short for delta-9-tetrahydrocannabinol, bind to receptors, which in turn activates the ECS. THC is the main psychoactive ingredient in the cannabis plant, and it’s what gives users a “high” feeling.

For example, THC binds to CB1 and CB2 receptors. CB1 receptors (CB1R) are primarily found in the central nervous system and this binding site can lead to psychoactive effects such as euphoria, perception changes, and increase in appetite. CB1R is concentrated in the forebrain, the region most responsible for cognition. CB1R levels fluctuate over a lifetime, with the peak between 15 and 17 years of age. CB2 is found in the peripheral nervous system and immune systems which can help reduce inflammation and pain. THC-dominant chemovars can be used for pain relief, nausea, appetite stimulation, and muscle relaxation but could cause side effects of anxiety, dry mouth, impaired memory and coordination.

CBD, which is short for cannabidiol, is different from THC because it does not bind directly to the receptors. Instead, it inhibits enzymes from breaking down endocannabinoids that are currently found circulating in the body. CBD is not psychoactive, and is thus easier to find in the U.S. than THC. While they both have the same molecular formula (21 carbon atoms, 30 hydrogen atoms, and two oxygen atoms), the way the atoms are arranged is different. This difference is why THC and CBD have distinct chemical properties and unique effects on your body.

II. Common Prescription Drug Interactions with Cannabis
When using THC, it is important to monitor for drug interactions. Cytochrome enzymes, which are called CYP for short, are a family of enzymes responsible for a majority of drug metabolism occurring in the liver. THC is primarily metabolized in the body by an enzyme in this family: CYP3A4. About a quarter of drugs are metabolized by this same enzyme. Because cannabis is a potent CYP3A4 inhibitor, it can cause an increase in the concentration of drugs metabolized by this enzyme. This fact is important because patients who are using medical cannabis are often patients who have concurrent comorbid conditions and who are on other prescription drugs.

An increase in the concentration of certain medications can mean an increase in their effect. For an antibiotic, this may mean an increase in risk of diarrhea. For a blood pressure medication, this may mean an increase in risk of falling because your blood pressure dangerously drops too low. For a diabetes medication, an increase in concentration can increase hypoglycemia and risk of dangerous low blood sugars. Medications can also be toxic at certain doses. An increase in the concentration can increase risk of toxicity. Medications that have a narrow therapeutic range (levothyroxine, warfarin, digoxin) are medications that can be affected most by increases or decreases in concentrations

We will take a closer look at a few common drugs that are extensively metabolized by this CYP3A4 family. These include calcium channel blockers (amlodipine, nifedipine), macrolide antibiotics, benzodiazepines, certain statins (notably atorvastatin and rosuvastatin), HIV medications (in particular, the protease inhibitor class), and steroids. Warfarin (Coumadin), a common blood thinner, also interacts with THC by inhibition of CYP2C9, which metabolizes warfarin. This can cause higher levels of warfarin in the blood and potential increase in INR and/or risk of bleeding.

Another patient population that may experience significant drug interactions are transplant recipients. Many medications that are used to prevent organ transplant rejection interact with THC. Calcineurin inhibitors (cyclosporine and tacrolimus) and mTOR inhibitors (sirolimus and everolimus) are both metabolized by CYP3A4. Since THC can inhibit CYP3A4, it can cause an elevated concentration of these medications. Elevated levels of these medications can lead to toxicity, kidney damage, high blood pressure, and increased risk of infection by increasing the immunosuppressant qualities of these medications. Corticosteroids like prednisone or dexamethasone metabolism can also be affected by THC, although the pathway is not as well-defined. THC can alter the gastrointestinal absorption of antimetabolites such as mycophenolate and azathioprine by decreasing GI motility.

III. Common OTC Drug Interactions with Cannabis
THC may also interact with several common over the counter medications. Use with NSAIDs such as ibuprofen or aspirin can increase the risk of GI bleeds or ulcers since both NSAIDs and THC affect prostaglandin synthesis and inflammation. Antihistamines can contribute to the drying and drowsing effect of THC. On the flip side, THC can increase heart rate and blood pressure when taken in combination with pseudoephedrine or phenylephrine (as of the time of writing, phenylephrine is no longer a recommended treatment anymore for congestion).

Some supplements may also interact with THC. These include St. John’s Wort, melatonin, valerian root, and echinacea.

• St. John’s Wort is often used for mood and depression, while not being completely validated through evidence-based studies as an effective treatment. St. John’s Wort is primarily metabolized by CYP3A4 therefore by inducing CYP3A4 enzymes, THC is more readily metabolized and can lead to a reduction in the effects of THC. Higher doses may be needed to reach the desired effects.
• Melatonin and Valerian Root are commonly used as a sleep aid and to help regulate our circadian rhythms since melatonin is found naturally occurring in our bodies already. Melatonin and THC both have sedative properties. Combining THC with either of these can enhance the sedative effects leading to increased drowsiness and impairment of cognitive and motor functions. This combination should be used in caution, even if both THC and melatonin are being used for improved sleep to avoid excessive sedation and drowsiness. It is also good to be cautious when operating heavy machinery or driving if either are being used.
• Echinacea is commonly used as an immune support supplement. Echinacea may also inhibit CYP3A4 and CYP1A2 enzymes, both having responsibility in metabolizing THC. With the combination of Echinacea and THC, the effects of THC can be increased which can therefore cause an increase in the psychoactive, sedative, and cognitive effects of THC.

I mention this information not to deter patients from using THC or cannabis, but more so to highlight the importance of being able to openly discuss cannabis use with healthcare providers. Many of these drug interactions can be avoided with dose or timing adjustments, as well as medical guidance to minimize risks and enhance therapeutic outcomes

IV. Factors Influencing Drug Interactions with Cannabis
The route in which THC is consumed also plays a huge part in how much it interacts with your body and other medications.

• Inhalation: THC is rapidly absorbed into the lungs and enters the bloodstream almost immediately. This results in the quickest onset usually within minutes. Because of the quick onset, this also has the shortest duration and may require more frequent administration.
• Oral (edibles): Absorption is slower and not as consistent. Peak levels are usually reached within 1-3 hours. This has the greatest risk of interactions with other medications due to the metabolism of oral THC that primarily occurs in the liver. This is often a place that can lead to over-dosing of THC when people may not feel the effects quick enough and take an additional dose.
• Topical: There are minimal systemic absorption effects when applied topically and the effects are more local to the area applied to. This has the least risk of drug interactions or “high” sensations that are generally associated with THC.
• Individual variations also have a large effect on how THC is absorbed.
• Many people may have variances in the receptors of the ECS system which can cause some people to be more sensitive to THC, while others less sensitive.
• More research needs to be conducted, but there is some evidence that THC affects women differently than men. Additionally, individuals taking hormones like birth control or to affirm gender identity may be affected differently by THC. For example, some research shows women are more likely to experience physical symptoms associated with anxiety, like elevated heart rate, when consuming THC than men.
• Regular THC use can lead to tolerance where higher doses are needed to have the same effect. Higher doses of THC can cause greater drug interaction risks. Prolonged use can also lead to desensitization of the ECS receptors.

VI. Clinical Implications and Recommendations
Whether you are supportive, neutral, or against medical cannabis, all healthcare professionals must recognize that patients are using it, and although it may not have been included in our traditional training, we need to learn about it, be open-minded, and above all, be non-judgmental. Otherwise, our patients will turn to other, less reliable sources of information or they will continue to use it, and lie about it.

Patients must feel comfortable discussing their medical cannabis use with their healthcare providers. If healthcare providers are not aware of cannabis usage, they will be unable to monitor their patients. Dosing adjustments of either THC or a medication may be necessary based on side effects and effects to the body.

Education that interactions exist is important, especially for prolonged and chronic diseases. By understanding the way that THC works in our body as well as how the medications that we take work, we are able to better understand and enhance safety and treatment outcomes.

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Jana Lappin is a practicing clinical pharmacist as well as the Director of Clinical Outreach at Kentucky Cannabis Clinic, a service that provides state-licensed physicians to certify and renew patients through the state’s medical marijuana program.