ACOFP Blog

Jacob Lenz, OMS-IV | A.T. Still University – Kirksville College of Osteopathic Medicine
2022 Namey/Burnett Preventive Medicine Writing Award Submission

Sponsored by the ACOFP Foundation, with winners selected by the ACOFP Health & Wellness Committee, the Namey/Burnett Preventive Medicine Writing Award honors the memory of Joseph J. Namey, DO, FACOFP, and John H. Burnett, DO, FACOFP—dedicated advocates for osteopathic medicine—and recognizes the best preventive medicine blog posts submitted by osteopathic family medicine students and residents.

The public view of marijuana has shifted dramatically over the past decade as states rapidly move toward cannabis legalization. Simultaneously, among individuals aged 12 years and older, there was an increase in marijuana users from 25.8 million in 2002 to 48.2 million in 2019.¹ As marijuana becomes more readily available to individuals for both medicinal and recreational purposes, now is the time for physicians to have open discussions with patients about their cannabis usage and not circumvent the topic. While the health effects and indications of marijuana are still under review, the purpose of this article is to summarize recent peer-reviewed findings on the topic to help open the discussion on cannabis in the exam room.

Pharmacokinetics

The pharmacokinetics of cannabis are still under study; however, an increase in the number of states legalizing cannabis has opened the door for a boost in research. Recent advances in research instrumentation and governance have led to a better understanding of the endocannabinoid system (ECS). The ECS consists of receptors, endocannabinoids (eCBs), interacting enzymes and genes for the receptors and enzymes.² Endocannabinoids are found naturally in the body and have a role in most “physiological, behavioral, immunological and metabolic functions.”² Cannabinoids, on the other hand, are found in the cannabis plant with a variety of biologically active compounds and act on the same receptors.

Cannabinoid receptors (CBR) are G-protein coupled receptors that primarily interact via Gi/o signaling.^2,3 The distribution of CBR1 and CBR2 throughout the body differ, with an expression of CBR1 primarily in the central nervous system (CNS) and CBR2 in the peripheral nervous system (PNS) and immune system.^2,3 Cannabinoids further interact with the transient receptor potential of vanilloid (TRPV), also activated by capsaicin; the transient receptor potential of ankyrin (TRPA), also activated by menthol; and serotonin receptors (5HT2).^2,3 The two most heavily studied eCBs are anandamide and 2-arachidonoylglycerol that act as partial and full agonists to CBR, respectively, and activate TRPV1.²

Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most studied extracts of the cannabis plant. THC is a partial agonist at the CBRs.² On the other hand, CBD has a low affinity for CBRs, with possible allosteric roles not wholly understood.³ Both THC and CBD activate TRPV2 and TRPA1 receptors, which shed light on their possible role in pain management.²

THC is a lipophilic compound metabolized in the liver primarily into 11-hydroxy-THC, a psychogenic compound, and 11-nor-9-carboxy-THC with no psychogenic properties; the latter can be detected in urine for drug screening purposes.² THC’s bioavailability varies depending on the individual’s body composition. THC consumed via inhalation rapidly enters the bloodstream, while ingested THC takes 1–2 hours before detectable levels can occur.²

Cannabis appears to operate similarly to opioid analgesia by modulating the central pain pathways.^4,5 Via CBR1s, cannabinoids reduce pre and post-synaptic neurotransmission in the spinal cord and dorsal root ganglion.^4–6 Decreased neurotransmission attenuates ascending messages from primary nociceptors.^4–6 CBR1s also modify pain through the descending inhibitory pathways in the periaqueductal gray and raphe nucleus and the limbic system.⁵ The brain receptor density of CBR1s is sparse in the pons and medulla oblongata, unlike with opioid receptors; this finding may help explain the absence of cardiovascular or respiratory depression during cannabis intoxication.²

What benefits are observed from cannabis use?

Cannabis-derived products are used for a wide range of patient-determined ailments. Some of the most common self-reported indications for cannabis are pain, nausea, depression, anxiety, multiple sclerosis, cancer, epilepsy, cachexia and glaucoma—an ever-expanding list that grows longer with time.^2,3

While small in number, a few FDA-approved cannabis-derived drugs are currently available on the market. Dronabinol (Marinol® capsule, Syndros® liquid) is a synthetic THC indicated for nausea and vomiting of chemotherapy and an appetite stimulator in AIDS cachexia. Nabilone (Cesamet®, capsule) is available for similar indications as dronabinol but is structurally distinct as a synthetic analog of THC.³ Cannabidiol (Epidiolex®, highly concentrated CBD oil >98%) was recently approved in 2018 for use in two rare pediatric seizure disorders: Lennox-Gastaut and Dravet syndromes.^3,7 However, practically all cannabis users, medical and recreational, are not consuming FDA-approved cannabis products. In the United States, studies on cannabis effects have been limited due to the disparity in products available to researchers and what is available to everyday consumers from dispensaries or street purchases.³

Cannabis has been used for more than 5,000 years to treat pain.² Chronic pain is the most common indication for cannabis usage; one report out of Colorado revealed severe pain as the indication for almost 94% of their medical marijuana cardholders.⁸ However, there is conflicting evidence on the types of pain cannabis can alleviate.^2,3,6 Neuropathic pain appears to respond to THC, with higher concentrations leading to a more robust response.² However, side effects vastly increase as the THC:CBD ratio increases.² CBD has been shown to be effective for inflammatory pain due to its poorly understood anti-inflammatory effects.² Of note, cannabis consumption may reduce the usage of other pain medications, evidenced by a study conducted in Michigan that showed a 64% reduction of opioids in marijuana consumers.⁹ While clinical trials support cannabis as effective in treating pain, little is known on its effective dose, route of administration or side effects of commonly used products.³

What adverse effects have been seen from cannabis use?

The cannabis available on today’s markets is not the same as the cannabis procurable in the 1970s. Legalization has led to an explosion in horticulturists genetically breeding plants to create various strands with increased potency. In the past 20 years, potency in various strains has risen from 4% to 12%; furthermore, THC extracts from these strands can reach concentrations over 70% in weight or volume.^3,10 Increased availability and concentration of cannabis products leads to greater pediatric overdose compilations from accidental ingestion.³

THC is widely regarded as the psychoactive component and is postulated to exert its influence via CBR1 in the brain.³ With a dose-dependent relationship, increases in THC content in cannabis products lead to more potent intoxication and psychogenic effects in individuals.^3,11 Recent evidence has shown THC products with high dose CBD reduce the intoxicating effects (low THC:CBD ratio).¹⁰ These findings are essential in leading the way to recommendations for safe THC:CBD ratios for medicinal and recreational cannabis products. Regardless of the form or ratio, physicians should warn patients who consume cannabis products of the dangers of driving intoxicated due to the “increased risk of motor vehicle crashes.”³

Cannabis is the second most commonly smoked substance in the United States.¹² Therefore, primary care physicians need to understand the effects of inhaled cannabis on the lungs. Hesitation in counseling patients on cannabis reveals provider uncertainty in juxtaposition to the current era of advocating for smoking cessation. Research on individuals who smoke marijuana alone has been difficult to gather as there is a high preponderance for marijuana smokers to additionally smoke cigarettes. A study conducted in Colorado showed individuals who used marijuana had 3.4 times greater odds of co-using tobacco.¹³ Studies have shown histopathologic changes in the bronchial mucosa, replacement of epithelial cells to mucous secreting cells, comparable to changes seen in tobacco smokers, giving insight to the increased chronic bronchitis symptoms seen in marijuana smokers.^3,12 However, these findings failed to support an increased risk of COPD or emphysema.¹² Evidence linking marijuana to lung cancer failed to show an increased risk, possibly due to THCs not well understood anticancer effects.^2–3 Further studies were unable to show significant evidence linking cannabis usage to other cancer such as head, neck, esophageal, or testicular.³ Thus, what appears to be the most significant risk factor for lung complications down the road may not be the impact of marijuana itself but rather the effects of the co-usage of marijuana and tobacco products.

A common public view is that marijuana usage can help patients with their mental health and thus provide an alternative to the standard of care. Current studies observing patient outcomes discovered that marijuana use in psychiatric patients worsened depressive and anxiety symptoms, decreased psychiatry visits and increased suicide ideation compared to what was seen in non-users.^3,14,15 Research supports the theory of a dose-response relationship of cannabis and psychiatric symptoms, showing habitual users who consumed daily, began using earlier, and used higher potency products began experiencing psychotic disorders at a younger age versus non-using peers.¹⁶ European metadata analysis has shown a correlation in cannabis-induced psychotic disorders converting to schizophrenia and bipolar disorder with rates up to 47% depending on the nation.¹⁶ Evidence suggests a possible genetic risk for increased schizophrenia susceptibility due to cannabis usage; however, current markers are not definitive thus far.^2,16 While the data is still too limited to prove causality; it can aid physicians in their recommendations to patients with psychiatric conditions who ask about marijuana in conjunction with their treatment.

Literature on cognitive decline in habitual marijuana users presents conflicting evidence. Diminished capabilities in attention, learning, and memory have been moderately linked to acute cannabis usage, defined as <24 hours post-consumption.^2,3 Distorted memory processes are hypothesized to be due to mitochondrial cannabinoid receptors altering mitochondrial metabolism in axon terminals and dendrites to affect neurotransmission.² Despite data on the acute response of cannabis, debate on the long-term effects exists. A recent twin study published in 2020 concluded no statistical difference in cognition, matching previous twin study findings.¹⁷ Another study observing several factors, one being neurocognitive measures, in cancer patients’ medical cannabis use also reported no statistical difference in neurocognitive measures versus the control group one year out.¹⁸ With both studies, generalization of the data is limited due to small sample sizes, but this early data in the area helps provide clinicians with helpful insight when following patients who are habitual users.

Cannabis usage and family planning do not appear to go hand in hand, as the eCB system may have a significant role in human growth and development.² Both male and female fertility are affected by cannabis usage. In males, habitual cannabis usage has been shown to decrease sperm function and survival due to an unclear mechanism.² In pregnant women, there is limited data on cannabis effects due to its Schedule I status. Marijuana exposure in-utero has been strongly associated with fetal growth restriction.³ Data from additional small studies have hinted at a possible link to pregnancy loss; however, the pathogenesis is still under review.² THC has been shown to pass through the placenta and be secreted in breast milk.^2,3 Current research is uncertain regarding the role of prenatal marijuana exposure and future child outcomes; however, small studies have shown decreased standardized test scores, altered memory processing, and increased impulsive behavior.2 While present data cannot pinpoint a definitive cause and effect, the uncertainty may be best approached by abstaining from cannabis use during pregnancy.

Where does this take us?

Changes are occurring on both a state level, as seen in cannabis legalization during election cycles, and on a federal level through the 2018 Farm Bill. State cannabis legalization walks a legal gray area, as these products are forbidden under federal law. The 2018 Farm Bill introduced a significant change to the law by removing cannabis products with low concentrations of THC (≤0.3% per dry weight) from the definition of marijuana in the Controlled Substances Act.⁷ Notably, the 2018 Farm Bill did not mention CBD, leading to an industry misinterpretation of the change as all cannabis derivatives becoming legal, which is not the case.⁷ However, despite these changes, the products most patients are seeking still fall into the category of Schedule 1 (THC content >0.3%, or CBD products). The Schedule 1 status of most cannabis products creates a legal headache for physicians due to the unclear legal framework and lack of guidance from professional societies.¹⁹ While it is illegal to prescribe cannabis due to its Schedule I status, physicians circumvent this in states with medical marijuana laws by attesting that a patient has a qualifying diagnosis to allow them access to medicinal marijuana.¹⁹

Currently, there are no clear guidelines on dosing recommendations for medicinal marijuana. Consumption of cannabis products for the everyday consumer can commonly occur through an oral, inhalant or topical route. Standardized dosing of cannabis products should be implemented to help consumers and physicians interpret what a patient is consuming. Research has yet to reveal upper limits of THC or CBD to quantify a threshold for intoxication or overdose levels. Habituation occurs at CBRs, and individual dosing can change with chronic use.² For chronically using patients who refuse to quit, recommending a lower THC:CBD ratio may lead to fewer side effects and mental health exacerbations.

Parallel to tobacco cessation, discontinuation of chronic cannabis consumption abruptly makes relapse almost certain. For heavy or chronic cannabis users, success has been found with psychotherapy; however, even with psychotherapy, up to 80% of these patients still relapse.²⁰ Currently, there are no approved medications for cannabis use disorder or withdrawal. However, dronabinol and gabapentin in early trials have been shown to be beneficial.^20,21

Regardless of current federal laws regarding cannabis, its usage has grown tremendously. While significant research needs to be done to learn about the full effects of the various plant derivatives, staying up to date on the most recent findings is key to making thought-out helpful recommendations to patients.

References

1. Substance Abuse and Mental Health Services Administration. Key Substance Use and Mental Health Indicators in the United States: Results from the 2019 National Survey on Drug Use and Health (HHS Publication No. PEP20-07-01-001, NSDUH Series H-55). Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration; 2020.
2. Bukiya AN, ed. Recent Advances in Cannabinoid Physiology and Pathology. Vol 1162. Springer International Publishing; 2019. doi:10.1007/978-3-030-21737-2
3. NASEM. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. National Academies Press (US); 2017. doi:10.17226/24625
4. Palazzo E, Luongo L, Novellis V de, Rossi F, Maione S. The role of cannabinoid receptors in the descending modulation of pain. Pharmaceuticals (Basel). 2010;3(8):2661–2673. doi:10.3390/ph3082661
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7. Abernethy A. Hemp Production and the 2018 Farm Bill. U.S. Food and Drug Administration. July 25, 2019. Accessed November 21, 2021. https://www.fda.gov/news-events/congressional-testimony/hemp-production-and-2018-farm-bill-07252019
8. Light MK, Orens B, Lewandowski, Pickton T. Market size and demand for marijuana in Colorado. The Marijuana Policy Group. Published online 2014. Cited by: NASEM. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. National Academies Press (US); 2017. doi:10.17226/24625
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10. Solowij N, Broyd S, Greenwood L-M, et al. A randomized controlled trial of vaporized Δ9-tetrahydrocannabinol and cannabidiol alone and in combination in frequent and infrequent cannabis users: acute intoxication effects. Eur Arch Psychiatry Clin Neurosci. 2019;269(1):17–35. doi:10.1007/s00406-019-00978-2
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16. Pearson NT, Berry JH. Cannabis and psychosis through the lens of DSM-5. Int J Environ Res Public Health. 2019;16(21). doi:10.3390/ijerph16214149
17. Ross JM, Ellingson JM, Rhee SH, et al. Investigating the causal effect of cannabis use on cognitive function with a quasi-experimental co-twin design. Drug Alcohol Depend. 2020;206:107712. doi:10.1016/j.drugalcdep.2019.107712
18. Ware MA, Wang T, Shapiro S, Collet J-P, COMPASS study team. Cannabis for the management of pain: assessment of safety study (COMPASS). J Pain. 2015;16(12):1233–1242. doi:10.1016/j.jpain.2015.07.014
19. Finelli E. The Physician’s Role in Medicinal Marijuana Use. Physician’s Weekly. October 21, 2021. Accessed November 21, 2021. https://www.physiciansweekly.com/the-physicians-role-in-medicinal-marijuana-use
20. Brezing CA, Levin FR. The current state of pharmacological treatments for cannabis use disorder and withdrawal. Neuropsychopharmacology. 2018;43(1):173–194. doi:10.1038/npp.2017.212
21. Schlienz NJ, Lee DC, Stitzer ML, Vandrey R. The effect of high-dose dronabinol (oral THC) maintenance on cannabis self-administration. Drug Alcohol Depend. 2018;187:254–260. doi:10.1016/j.drugalcdep.2018.02.022