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BROCK BAKEWELL, MPH
ARI GREIS, DO
ASIF ILYAS, MD, MBA, FACS
SUMMARY POINTS
THC and CBD behave in a dynamic and dose-dependent manner.
THC and CBD may modulate one another; with CBD potentially decreasing the negative side effects of THC.
The predominant delivery route for recreational use of cannabis is through inhalation methods (smoking or vaporization). In contrast, medical cannabis users may use a combination of oral, inhaled and/or topical routes of delivery.
INTRODUCTION
Medical cannabis, also known as medical marijuana, has been used for its medicinal qualities for centuries worldwide. 1 Today in the US, cannabis is a Schedule I drug under the federal controlled substance act. However, it has received increased attention over the last few decades for its therapeutic abilities to alleviate pain symptoms and potentially treat other medical conditions. 2 As a result, 33 states and the District of Colombia have legalized medical cannabis. The many bioactive compounds in cannabis are known as cannabinoids, which bind to cannabinoid receptors (CB1 and CB2) on cell membranes. These cannabinoid receptors typically bind endogenous cannabinoids (anandamide and 2- arachidonoylglycerol).2 CB1 receptors are mainly found in the central and peripheral nervous systems; CB2 receptors are primarily found on immune cells. 3 Two of the main exogenous cannabinoids are Δ9 ‐ tetrahydrocannabinol (THC) and cannabidiol (CBD). THC has intoxicating properties targeting the CB1 receptors; CBD, a non-intoxicating cannabinoid, appears to not bind directly to either CB1 or CB2 receptors, and acts as an antagonist at CB1 receptors making CBD an appealing option for medical use.4 This Research Brief will aim to outline the most current recommendations for dosing, concentrations, and delivery routes of medical cannabis.
DOSING
Dosing of cannabis has been widely variable across numerous studies2 , in part due to the relationship between THC and CBD, and subsequent variations in concentrations. The effects of THC vary depending on its route of administration. Smoking or vaping THC causes a maximum plasma concentration within minutes and psychotropic effects within seconds to a few minutes. 5 These effects peak after 15 to 30 minutes and lessen within two to three hours. After oral ingestion, the same psychotropic effects occur within 30 to 90 minutes, and reach their maximum effect after 2 to 3 hours, and persist for about 4 to 12 hours, depending on the dose. 5 One review of 165 clinical pharmacology studies attempted to normalize the dose of THC. It defined a low dose as less than 7 mg, a medium dose as 7–18 mg, and a high dose as greater than 18 mg.6 Unlike THC, CBD has shown fewer side effects at much higher dosages. Dosing for CBD appears to be safe at doses of 25mg/kg and may be safe at even higher doses because it has limited effects on measured vital signs. 7 While most studies have looked at each cannabinoid separately, one study stated that each compound affected the vaporization efficiency of the other in a dynamic and dose-dependent manner. 8 Much like many other medications slow titration at low doses is preferred to determine a patient’s tolerance, especially in naïve cannabis patients. Small micro does of 2-3mg of THC oral can be taken at bed time to help reduce negative side effects. This dose can be increased by 1.25– 2.5 mg THC at bedtime every 2 days until the desired effect is obtained. In event of side effects, the dose can be reduced to the previous better tolerated dose. 9
CONCENTRATIONS
Concentrations of THC and CBD in cannabis, through plant hybridization, have significantly changed over the last few decades. The THC content in 1995 was estimated at 4% and increased to 12% in 2014. The increased THC level has also been paired with decreasing CBD concentrations from 28% to 15%, extending the potency of THC-rich marijuana approximately 80 times. 10 In most cases there is zero CBD in flower and vape oils in dispensary menus. The increase in THC concentration can cause psychotic symptoms and anxiety. However, CBD appears to modulate THC thus reducing the adverse side effects of THC. 11 There have not yet been enough research studies conducted to assess the effects of varied ratios of THC:CBD. Moreover, there have been mixed results in some studies with small sample sizes; therefore, more research is needed to assess appropriate concentrations for therapeutic use. 12
DELIVERY ROUTES
Cannabinoids can be administered in many different methods: oral, topical, inhalation, cooking with oil or butter, or made into tea. 13 Smoking and vaporization allow THC to be transferred from lungs to bloodstream rapidly due to cannabinoid lipophilicity. 14 Vaporization is preferred over smoking because it reduces exposure to the byproducts of combustion and possible carcinogens present in smoking, allowing for the decrease in adverse respiratory syndromes. 13 Oral mucosal sprays have been approved in Canada and several European countries.2 Other administration routes include rectal, sublingual, transdermal, eye drops, and aerosols. However, all of these routes have been subjected to limited research, and therefore few conclusions can be drawn about their efficacy at this time. Despite the lack of scientific evidence for efficacy topical cannabinoids, even ones containing THC, are not intoxicating and can be used as needed in addition to the other routes of delivery. Table 1 lists the typical routes of medical cannabis delivery. Table 2 lists the variables to consider in medical cannabis delivery.
REFFERENCES
1. Hui-Lin Li. An archaeological and historical account of cannabis in china. Economic botany. 1974;28(4):437-448. https://www.jstor.org/stable/4253540.
2. Borgelt LM, Franson KL, Nussbaum AM, Wang GS. The pharmacologic and clinical effects of medical cannabis. Pharmacotherapy. 2013;33(2):195-209. https://search.datacite.org/works/10.1002/phar.1187. doi: 10.1002/phar.1187.
3. Nagarkatti P, Pandey R, Rieder SA, Hegde VL, Nagarkatti M. Cannabinoids as novel antiinflammatory drugs. Future Medicinal Chemistry. 2009;1(7):1333-1349. https://doi.org/10.4155/fmc.09.93. doi: 10.4155/fmc.09.93.
4. Klein TW. Cannabinoid-based drugs as anti-inflammatory therapeutics. Nature reviews. Immunology. 2005;5(5):400-411. https://search.datacite.org/works/10.1038/nri1602. doi: 10.1038/nri1602.
5. Grotenhermen F. Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokinet. 2003;42(4):327-360. https://search.datacite.org/works/10.2165/00003088- 200342040-00003. doi: 10.2165/00003088-200342040-00003.
6. Zuurman L, Ippel AE, Moin E, van Gerven, Joop M. A. Biomarkers for the effects of cannabis and THC in healthy volunteers. British Journal of Clinical Pharmacology. 2009;67(1):5-21. https://search.datacite.org/works/10.1111/j.1365-2125.2008.03329.x. doi: 10.1111/j.1365- 2125.2008.03329.x.
7. Iffland K, Grotenhermen F. An update on safety and side effects of cannabidiol: A review of clinical data and relevant animal studies. Cannabis and cannabinoid research. 2017;2(1):139- 154. https://search.datacite.org/works/10.1089/can.2016.0034. doi: 10.1089/can.2016.0034.
8. Solowij N, Broyd SJ, van Hell HH, Hazekamp A. A protocol for the delivery of cannabidiol (CBD) and combined CBD and ∆9-tetrahydrocannabinol (THC) by vaporisation. BMC pharmacology & toxicology. 2014;15(1):58. https://www.ncbi.nlm.nih.gov/pubmed/25319497. doi: 10.1186/2050-6511-15-58.
9. MacCallum CA, Russo EB. Practical considerations in medical cannabis administration and dosing. European journal of internal medicine. 2018;49:12-19. https://search.datacite.org/works/10.1016/j.ejim.2018.01.004. doi:
10.1016/j.ejim.2018.01.004. 10. Elsohly MA, Mehmedic Z, Foster S, Gon C, Chandra S, Church JC. Changes in cannabis potency over the last two decades (1995-2014) - analysis of current data in the united states. Biological psychiatry. 2016;79(7):613-619.
11. Morgan CJ, Freeman TP, Schafer GL, Curran HV. Cannabidiol attenuates the appetitive effects of Δ9-tetrahydrocannabinol in humans smoking their chosen cannabis. Neuropsychopharmacology (New York, N.Y.). 2010;35(9):1879-1885. https://search.datacite.org/works/10.1038/npp.2010.58. doi: 10.1038/npp.2010.58.
12. Freeman AM, Petrilli K, Lees R, et al. How does cannabidiol (CBD) influence the acute effects of delta-9-tetrahydrocannabinol (THC) in humans? A systematic review. Neuroscience and biobehavioral reviews. 2019;107:696-712. https://search.datacite.org/works/10.1016/j.neubiorev.2019.09.036. doi: 10.1016/j.neubiorev.2019.09.036.
13. Bridgeman MB, Abazia DT. Medicinal cannabis: History, pharmacology, and implications for the acute care setting. P&T (Lawrenceville, N.J.). 2017;42(3):180-188. https://www.ncbi.nlm.nih.gov/pubmed/28250701.
14. Hartman RL, Brown TL, Milavetz G, et al. Controlled cannabis vaporizer administration: Blood and plasma cannabinoids with and without alcohol. Clinical chemistry (Baltimore, Md.). 2015;61(6):850-869. https://www.ncbi.nlm.nih.gov/pubmed/26019183. doi: 10.1373/clinchem.2015.238287.