Cannabis, Drug interactions, Pharmacokinetics, Topiramate/cannabis, Trazodone/cannabis

Clinical Due Diligence: Drug Interactions with Cannabis and Cautions for Practitioners

A Clinician’s Perspective

By David G Knox, MD

With spreading legalization of Cannabis sativa and the increasing popularity of cannabidiol (CBD) especially, there is increasing concern about the concomitant use of cannabis with prescription medications. Cannabis is a poly-pharmaceutical botanical comprised of well over 400 pharmacologically active compounds, many with potential for drug interactions.

Cannabis Pharmacokinetics

In order to understand drug interactions with cannabis, we need a basic working understanding of cannabis pharmacokinetics, which is the study of the absorption, distribution, metabolism, and excretion of cannabinoids in the human body. While simple in theory, cannabis pharmacokinetics are complicated by the plant itself. Hundreds of chemically distinct varieties (chemovars) of cannabis currently exist, of which phytocannabinoids and terpenes are hallmark constituents. These varied phytochemical compositions, or chemical profiles, add complexity to pharmacokinetic determination. Each of the constituents follows its own kinetic pathway, but this may be affected by all of the others. Of these 400+ known compounds found in cannabis, we have limited information about the pharmacokinetics of just a few. Much of what we do know is based on the studies done on the pharmacodynamics of the best known phytocannabinoids, CBD and THC.¹

The rate of cannabis absorption, bioavailability, and duration of activity are dependent on the route of administration, chemical profile, product concentration, and amount consumed. Bioavailability refers to the fraction of an administered dose of a substance that reaches the systemic circulation and is then measurable as serum concentration. The data shown in Figure 1 are based on the pharmacodynamic study of THC and show the variability across the different routes of administration. The bioavailability of CBD, other cannabinoids, and terpenes have not been studied as well as THC; and there are some differences between the different cannabinoids. A number of other factors also play a role, which results in this broad range of bioavailability, as shown in Figure 1.

Figure 1. Absorption of Cannabis as a Function of Route of Administration

The overall bioavailability of an administered dose of cannabis has a broad range and is relatively low regardless of the method used, but the duration of action is quite variable between methods.

Distribution in the body is also somewhat dependent on the route of administration; but once cannabinoids enter the serum, there is rapid redistribution, primarily into highly vascularized tissues, including the brain, liver, and kidneys. As the cannabinoids are strongly lipophilic, overall redistribution is predominantly into fat. A smaller proportion of cannabinoids and their metabolites bind to serum protein.

Excretion is relatively slow, due to the high volume of distribution, with 80-90% being eliminated within five days. Most excretion is through feces (>65%) and through urine (20%).^2-4

The majority of our understanding about drug interactions comes from studies on the metabolism of cannabinoids in the body. Cannabinoid metabolism occurs to a small degree in multiple tissues and organs, but predominantly occurs in the liver. Microsomal hydroxylation and subsequent oxidation are catalyzed by cytochrome P450 enzymes, which are also responsible for the metabolism of most chemicals and hundreds of pharmaceutical drugs that enter into systemic and hepatic circulation. Chemicals and drugs may be neutral substrates, inhibitors, or inducers of CYP450 enzymes. Neutral substrates are simply metabolized by the enzyme, while inhibitors reduce enzymatic activity, preventing or decreasing the metabolism of its substrates and thus increasing the concentration of the substrate and duration of its effect. Inducers increase the activity of the enzyme, enhancing the metabolism of its substrates and thus decreasing the substrates’ concentration and duration of effect. Note that THC and CBD are non-neutral substrates.⁵

THC:CYP450 Interaction

THC is metabolized by isoenzymes CYP3A4 and CYP2C9. THC is first hydroxylated to 11-OH-THC, then oxidized to water soluble THC-COOH (11-nor-9-carboxy-THC) and other inactive metabolites. This is an area where route of administration matters. Noting the rapid redistribution of cannabinoids into fat and other tissues, only about 10-20% of inhaled THC is converted to 11-OH-THC. When ingested, however, THC first enters the portal circulation and, as a result, nearly 100% may be metabolized to 11-OH-THC. This active metabolite binds more strongly to CB1 receptors than THC does and can enhance euphorigenic or intoxicating effects by up to 10-fold.⁶ (This also means a higher risk of adverse or toxic effects.)

Inhibitors of CYP3A4 slightly increase serum THC concentration and duration of activity. Inducers of CYP3A4 slightly decrease serum THC concentration and duration of activity. (See Figure 2)

THC itself is a CYP1A2 inducer, hastening metabolism of its substrates and decreasing serum concentrations of many drugs. The degree of induction is dependent on the route and amount of THC consumed. THC and CBN have also been seen to confer a small degree of inhibition on other CYP isoenzymes.^6,7

Figure 2: CYP and Cannabis Interactions

CBD:CYP450 Interaction

CBD is metabolized by CYP3A4, CYP2C9, and CYP2C19. (See Figure 3) CBD is oxidized to 7-OH-CBD and 6-OH-CBD. CBD is a potent competitive inhibitor of CYP3A4 and CYP2D6, which are responsible for metabolizing another 25% of all pharmaceutical drugs. As a competitive inhibitor, it displaces other substrates at the site of enzymatic activity, slowing the metabolism of many other substrates including THC. The degree of inhibition is dependent on the route and amount of CBD consumed, with high doses more likely to cause significant interactions.^8,9

Figure 3. Examples of Cannabis and CYP450 Interactions

This brief review of pharmacology provides many clues as to how certain drugs may interact with the presence of cannabinoids, but how does this translate to clinical practice? Multiple studies have been conducted on patients reviewing potential drug interactions with cannabis use. Some of these studies have shown^3,4,10:

• THC and CBD increased coumadin levels and INR. A single case of INR >10 with high cannabis use has been reported.

• CBD increases serum levels of seizure medications, including the metabolite des-methyl-clobazam while decreasing clobazam levels.

• Smoked cannabis decreases serum theophylline.

• Cannabis may increase serum levels of blood pressure medications e.g. carvedilol, HCTZ, lisinopril, and valsartan, with a potential for decreased heart rate and hypotension.

• No significant (i.e. only minor) interactions were seen with co-administration of antiretrovirals (indinavir or nelfinavir), or chemotherapeutic agents (docetaxel or irinotecan).

Of note, increases in serum levels of drugs tested were rarely outside of therapeutic windows, with the exception of clobazam, where higher levels of its metabolite bear the potential for increased side effects. The vast majority of patients do not experience side effects when taking cannabis in conjunction with other common medications. There has been little cause for concern over a long period of concomitant use in a significant population of cannabis users. This may be a reflection of dose, as CBD inhibition shown in the lab was primarily a function of higher CBD concentrations than would be seen in typical patient use. Interactions may be more of a concern with high doses of oral CBD (600 mg or more).^7.11

Many interactions of the cannabinoids with other drugs are not based on their metabolic interactions, but on their activity on similar receptor systems. Additive CNS depressant effects are seen with alcohol, barbiturates, and benzodiazepines, but notably not with opioids. Concomitant use of cannabis with anticholinergics can enhance tachycardia and hypertension. Case studies have suggested that combining cannabis with SSRIs can induce hypomania (elevated mood with symptoms e.g. racing thoughts, decreased sleep, grandiose thoughts, talkativeness).^11,12

Clinical Pearls and Precautions

Understanding dynamic drug-drug interactions is critical to optimizing medical management and safety when co-administering any medication. This is especially true when a co-administered drug has a narrow therapeutic window or major adverse side effect potential. Again, while most pharmaceuticals are made of a single substrate, cannabis does pose challenges as a poly-pharmaceutical botanical substance.

So, what is the clinical approach to co-administration of cannabis and medical management?

Clinical pragmatism:

• Rely on the standard of care and biochemistry.

• Know your CYPs and the effects of their strongest substrates.

• Monitor serum markers and other relevant labs more closely; e.g. INR, anti-epileptic or chemotherapeutic drug levels, and LFTs.

• Make dose adjustments as necessary.

Integrate your fundamental knowledge and principles of endocannabinology:

• Review the chemical profiles of cannabis products: chemovars should be characterized by analytical chemistry, i.e. which cannabinoids, ratios and concentrations, terpenes, etc. are present.

• Advise your patients to begin with micro-dosing (using a fraction of 1-5 mg /dose) and consider the best route of administration. Doses can then be titrated slowly and weaned back as needed.

• The dose and route of administration influences bioavailability, which in turn influences cannabinoid-CYP engagement.

• Combining methods with topicals may lower the dose needed by ingestion.

• Monitor the subjective and objective effects of cannabis use reported by patients.

• Know the common signs of THC overconsumption (e.g. red eyes, dry mouth, reduced tear flow, cough & bronchitis, dysphoria, anxiety, panic, transient tachycardia, hypotension, hyperemesis).

• Remember the potency of 11-OH-THC with its potential for increasing adverse side effects.

• When using other drugs with cannabis, interactions can be reduced by staggering the timing of administration. Also, other drug doses can be adjusted: e.g. cannabis can reduce opioid dose requirements.

• When in doubt about any potential interaction, look it up or confer with a pharmacist for further guidance.

In summary, clinically significant drug interactions with cannabis are not common, but we should remain informed and vigilant, and counsel our patients anyway—this is our clinical due diligence. Whether using a conventional pharmaceutical or a cannabis-derived product, dosing should start low and be titrated slowly. Match close monitoring with documentation. Always encourage patients to discuss their cannabis use with ALL of their pharmaceutical prescribers. Involved co-management of drug interactions and dosing adjustments are paramount for success in optimizing treatment for our patients.

References

1. Grotenhermen, F. Clinical Pharmacokinetics of Cannabinoids. Journal of Cannabis Therapeutics. January 2003.

2. Lynch T, Price A. The effect of cytochrome P450 metabolism on drug response, interactions and adverse effects. Am Fam Physician. 2007;76:391-396.

3. Sharma, P, et al. Chemistry, Metabolism and Toxicology of Cannabis: Clinical Implications. Iran J Psychiatry. 2012 Fall; 7(4):149-156

4. Ujvary I, Hanus L. Human metabolites of Cannabidiol: A Review on Their Formation, Biological Activity, and Relevance in Therapy. Cannabis Cannabinoid Res. 2016 Mar 1(1):90-101.

5. Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors and inducers of human drug metabolizing enzymes: a systemic review. Drug Mtab Rev. 2014;46:86-95

6. Watanabe K, et al. Cytochrome P450 enzymes involved in the metabolism of tetrahydrocannabinol and cannabinol by human hepatic microsomes. Life Sci. 2007; 80(15):1415-9 (ISSN: 0024-3205)

7. Stott C, et al. A phase I, open-label, randomized crossover study in three parallel groups to evaluate the effect of rifampicin, ketoconazole, and omeprazole on the pharmacokinetics of THC/CBD oromucosal spray in healthy volunteers. Springerplus. 2013;2:236.

8. Rong C, et al. drug-drug interactions as a result of co-adminstering delta-9-THC and CBD with other psychotropic agents. Expert Opinion on Drug Sa. 2018 Jan; 17(1);51-54.

9. Zendulka O, et al. Cannabinoids and Cytochrome P450 Interactions. Curr Drug Metab. 2016:17(3):206-26.

10. Fugh-Berman A, et al. Medical Cannabis: Adverse Effects and Drug Interactions. Government of the District of Columbia Department of Health.

11. Arellano AL, et al. Neuropsychiatric & General Interactions of Natural and Synthetic Cannabinoids with Drugs of Abuse and Medicines. CNS Neurol Disord Drug Targets. 2017; 16(5):554-566.

12. Iffland K, Grotenhermen F. An update on Safety & Side Effects of CBD: A Review of Clinical Data & Relevant Animal Studies. Cannabis Cannabinoid Res. 2017;2(1):139-154.

DVENT Academy 2019        

David G. Knox, MD, a graduate of the University of Washington School of Medicine, practiced as an emergency doctor for 38 years. As an emergency physician, he became aware of the toll caused by chronic pain and began to study endocannabinoids and the use of cannabinoid medicine as an alternative to opioids. He co-founded The American Cannabinoid Clinics, PC., with his wife, a board-certified anesthesiologist, and his physician daughters. Dr. Knox and colleagues counsel patients about safe and effective use of cannabinoid medicine that can be integrated with their primary care. http://www.americancannabinoidclinics.com/

Photo at http://www.americancannabinoidclinics.com/.

SIDEBAR

A Clinical Case of Drug: Drug Interactions

A 54-year-old female presents to her physician with symptoms of altered mental functioning, including somnolence and difficulty thinking clearly, to the degree that she had not been able to return to work for several weeks. She reports her symptoms began several months earlier but markedly worsened after a recent influenza-like illness. She had been seen in an urgent care setting with acute symptoms of cough, malaise, and body aches and was diagnosed with influenza A. She was prescribed oseltamivir for antiviral treatment, albuterol MDI, and prednisone for her respiratory symptoms, and was advised to use generic guaifenesin/dextromethorphan for cough control. She returned to urgent care five days later as she continued having severe cough with occasional vomiting, and she was prescribed Phenergan with codeine syrup. Her acute influenza symptoms subsided, but she continued to feel confused and sedated even two weeks later.

A review of symptoms also revealed a complaint of numbness on the left side of her face, raising her worry about a possible stroke or brain tumor. She also noted waves of a rapid pounding heart, night sweats, vivid dreams, and hearing voices singing.

The patient’s past medical history was most notable for migraine headaches since adolescence, for which she uses sumatriptan prn; six months prior, after a series of recurrent migraines, she was prescribed Topiramate XR, 150 mg daily, as prophylaxis. She has a history of mild asthma, usually associated with respiratory illness as noted above. She has some osteoarthritis complaints. Her history also includes major depression, but she has felt stable on a prescription of fluoxetine, 60 mg daily, for years. Patient denied medication allergies but reports experiencing prolonged oversedation with trazodone she had tried for insomnia.

She denied any use of alcohol or other drugs but does report that she has been taking CBD after a friend advised her of the results she had experienced with CBD for her arthritis. Patient was taking a dropperful of CBD tincture three times a day, although she did not know the exact dose it contained.

Physical exam revealed vital signs of Height 5’4”, weight 163 lbs, Temperature of 36.9°C,

Pulse 107, BP 143/86 and O2 saturation of 95%. HEENT showed injected oropharynx, but no sinus pain or tenderness. Heart sounds were rapid but regular without murmur. Lungs showed faint basilar rales and wheezing but good air movement. The abdomen was benign to palpation. The neurologic exam showed slight nystagmus and subjective numbness to the left side of the face, but there was no facial droop and cranial nerves otherwise appeared normal. Some unsteadiness of gait was noted, but motor strength was 5/5 bilaterally. She was fully oriented but exhibited slowness in her responses to questions and commands.

A full evaluation was commenced with lab and imaging studies. EKG showed sinus tachycardia, otherwise a normal tracing. CXR was negative for infiltrates. Unenhanced CT scan of the head was normal. WBC was slightly elevated at 13.7 but no anemia found. BUN was high at 36 mg/dL but the remainder of her CMP was normal. T4 and TSH also were normal. Urine drug screen was negative. Serum level of topiramate was significantly elevated at 73 mcg/ml (Therapeutic range 5-20 mcg/ml).

Discussion: This patient has experienced adverse effects from several possible drug:drug interactions. Topiramate is the most significant of the drugs involved, and it frequently can cause cognitive slowing as a side effect even at therapeutic levels. It was originally prescribed for seizures, but recently it is often used for migraine prophylaxis. Topiramate and trazodone are metabolized in the liver primarily by the CYP3A4 isoenzyme. Patients can exhibit different expressions of the CYP3A4 gene, which can account for differences in drug efficacy or toxicity, and many drugs affect enzymatic function. In general, it takes five full half-lives of a substance to be cleared from the body; Topiramate XR has a 57-hour half-life (compared to 25 hours for immediate release formulations), so normal clearance could take nearly 12 days. Clearance could be much longer with impaired metabolism or dehydration with an acute illness.

CBD has been noted to be an inhibitor of CYP3A4 as discussed in the accompanying article and could play a significant role in prolonging an elevated serum level of topiramate. As noted, it is not uncommon for patients to not know the actual dose of cannabinoids they are taking, due to uncertain source, or lack of testing or labeling. Commercial tinctures may range from 300 to 3000 mg in a 30 ml bottle, so her 1 ml dropperful could range from 10 to 100 mg per dose, with significant inhibition at the high end. Fluoxetine is predominantly an inhibitor of CYP2D6 but is also a modest inhibitor of CYP3A4. This additive inhibitory effect likely resulted in decreased topiramate clearance, with the elevated levels causing the patient’s protracted sedation and cognitive dysfunction.

Other potential interactions may be due to dextromethorphan and/or promethazine, both of which are metabolized by the CYP2D6 isoenzyme. Both of these drugs could have elevated levels due to inhibition of this enzyme by fluoxetine. High levels of dextromethorphan can cause neurologic symptoms such as dystonia, fatigue, drowsiness, dizziness and nystagmus, and auditory hallucinations as this patient experienced. Promethazine has significant anticholinergic activity and is frequently sedating and can affect memory and cognition. Codeine is also metabolized by CYP2D6 and can cause drowsiness.

Clinical course: After recognizing these interactions, the patient was advised to discontinue her Topiramate XR and CBD. With subsidence of her flu symptoms, she had quit her cough medications. She also decreased her fluoxetine dose to 30 mg/day. At a one-week follow-up, her topiramate levels remained elevated, consistent with slower than normal metabolism. At one month, the patient had complete resolution of all of her presenting symptoms.

This case scenario reveals the risk of inadequate history taking and consideration of possible drug interactions, as may happen in a busy ER or urgent care setting treating a seemingly simple flu-like illness. This patient’s history of oversedation with trazodone gives a hint of possible low metabolism via CYP3A4 and prior unreported use of CBD turns out to be a significant contributor to her presentation. Acute illness and the other drugs prescribed reveal the increased risks with polypharmacy. Early recognition of these issues may have avoided the need for an extensive workup with neuroimaging and other studies to rule out CNS pathology.