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The pharmacology of (−)-trans-Δ⁹-tetrahydrocannabinol, or THC, is probably the most well-studied of any controlled substance. THC has both psychoactive and peripheral physiologic effects in man, but it is best known as the component of marijuana that causes a “high”. THC is the most common phytocannabinoid (plant-derived cannabinoid) in cannabis drug products, but it is produced in the plant via a gene that also directs the production of cannabidiol (CBD), the most prevalent non-psychoactive cannabinoid. THC acts in the human body via both endocannabinoid receptors and other mechanisms. THC’s activity at the CB1 and CB2 receptors explains its impact on pain, spasticity, mood, appetite, and sedation.1 Through non-ECS mechanisms, THC is also a bronchodilator, a neuroprotective antioxidant, an antipruritic in cholestatic jaundice, and an anti-inflammatory agent.2

THC was listed as a Schedule I substance in 1971, meaning that in the opinion of regulators, THC has high abuse potential with no accepted medical use. Medications in this schedule may not be prescribed, dispensed, or administered. Other substances listed as Schedule I include heroin, ecstasy, and gamma hydroxybutyric acid (GHB).3 The entire cannabis plant remains under Schedule I by US federal law.4 There is, however, a synthetic form of THC approved by the FDA as an appetite stimulant for people with HIV/AIDS and for nausea relief for people receiving cancer chemotherapy; the pharmaceutical formulation is called dronabinol. A similar drug, nabilone, carries a similar anti-nausea indication. These drugs were studied and approved before we had the more potent appetite stimulants and anti-nausea treatments that we have today, and so the comparisons to “conventional therapy” when approved might no longer be considered valid. These are the only forms of THC that are legal under Federal law in the US; in the individual states that have legalized medicinal or recreational cannabis, the Feds have elected not to vigorously enforce the law as long as both state rules are followed unless it is felt that someone is abusing or gaming the system.5

In nature, THC is found inside the dried resin glands of the female cannabis flower, but as an acid, THC-A, which itself has no psychoactive effects in humans before modification (by heating). In the plant, THC and other cannabinoids most likely serve a protective function against bacteria, viruses, and parasites. THC-A becomes THC when it is decarboxylated by heat—when lighting a marijuana cigarette, heating a bowl, or cooking it. Heat removes a carbon atom from THC-A; the acid cannot bind with human ECS receptors because of its shape, while THC is the right fit.

Acute exposure to THC typically leads to the following effects:

  • a general feeling of euphoria or relaxation—”being high”—that may result from ECS stimulation that increases dopamine response in the brain6
  • changes in perception, creating a distorted illusion of time and space; colors may seem more vivid, music may seem more rich, and emotions may seem more profound
  • impairment of memory and concentration ability, inattentiveness
  • impaired psychomotor coordination with slower than average response times, impaired balance and posture—all making driving under the influence of THC potentially hazardous
  • heavy-body sensation
  • increased heart rate, increased breathing rate, and decreased blood pressure
  • red eyes
  • dry mouth
  • THC also produces sensory perception changes; colors may seem brighter, music more vivid, and emotions more profound. Some people experience feelings of paranoia.

The onset of these effects varies by individual and by dose (tolerance), and also by method of administration. Smoking THC leads to such sensations within minutes, while ingesting cooked cannabis may delay onset for as long as a couple hours.

There are also potential adverse effects of THC use acutely—primarily anxiety, paranoia, and fear. While these can happen in any user, they are more likely with novice users, in the elderly, and with higher doses. Those higher levels of exposure are more commonly encountered today, as In the last 30 years, the amount of THC has increased in many illicit strains and some state-licit strains developed for recreational dispensaries, from 3-4% to upwards of 20%.7–9 Higher concentrations of THC can be particularly problematic for elderly users, who never used THC or perhaps last used it many years ago, and have now had it recommended by a physician, only to experience acute psychosis.8,10–12 It is really important that medicinal use of THC follow the mantra of “start low, go slow” for dosing, to offer some protection against these events. At the other extreme of age, the broader availability of THC, particularly as edibles that may appear attractive to toddlers and older kids, has also led to a dramatic increase in acute pediatric psychosis traced to THC ingestion.13 Besides psychiatric adverse effects, “cannabis hyperemesis” can be a troublesome acute complication of THC use.14

More chronic use of THC can be problematic in different ways. While addictive potential varies significantly among individuals, and THC is clearly not as addictive of some other drugs of abuse, the usual cited risk of “cannabis use disorder” with regular use is around 15% of users.15 The risk of addiction and other long-term behavioral sequalae correlate to age of onset and frequency of use. This is particularly important in adolescence and up to age 25 or so, when the brain remains relatively “plastic.”15–17

Another issue with chronic THC abuse that has been debated for years is whether or not THC causes schizophrenia. The current thinking is that causation is probably not direct, but that the use of cannabis may “unmask” sub-clinical schizophrenia in susceptible patients.18,19 The evidence is sufficiently suggestive of such a relationship that, as a physician authorized in my state to recommend medicinal cannabis, I will not give THC to a patient who has a strong family history of schizophrenia or psychosis, and who does not already have “safe” experience with cannabis.

Other potential long-term effects of THC/cannabis use may include:

  • permanent alterations in memory; like most long-term sequelae related to THC use, this correlates to length and intensity of exposure
  • lung irritation/chronic bronchitis; this is actually not the THC, but the delivery mechanism. Let me be doctor-ish, please: SMOKING IS BAD
  • apathy/amotivational behavior, which typically is associated with tolerance to the effects of THC20

With all this information and all this knowledge, we still know all too little about the potential medicinal benefits of THC. Substantial research is being conducted all over the world to determine beneficial effects of THC that would outweigh the liabilities listed above. Particularly in hospice/end-of-life care, the anxiolytic and euphoric effects of the drug outweigh any concerns about addiction or cumulative effect. An admittedly incomplete list of diseases and symptoms for which there is biologic plausibility for a therapeutic effect of THC includes21:

  • glaucoma
  • multiple sclerosis (with CBD)
  • movements disorders (Parkinson’s, Tourette’s)
  • inflammatory bowel diseases
  • anorexia
  • persistent nausea and vomiting (as with cancer chemotherapy)
  • chronic neuropathic pain
  • chronic non-cancer-associated pain
  • cancer-related pain
  • headaches
  • PTSD
  • opioid abuse

Clearly much more study is required to explore the use of THC for these problems, in which “conventional” therapies often fall short.22

Resources

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2. Russo EB, Marcu J. Cannabis Pharmacology: The Usual Suspects and a Few Promising Leads. Adv Pharmacol San Diego Calif. 2017;80:67-134. doi:10.1016/bs.apha.2017.03.004
3. Gabay M. The Federal Controlled Substances Act: Schedules and Pharmacy Registration. Hosp Pharm. 2013;48(6):473-474. doi:10.1310/hpj4806-473
4. Drug Scheduling. https://www.dea.gov/drug-scheduling. Accessed February 23, 2020.
5. DEA Must Stop Interfering With Legal Medical Marijuana Dispensaries, Federal Court Rules. Time. https://time.com/4080110/dea-medical-marijuana-california-ruling/. Accessed February 23, 2020.
6. Bloomfield MAP, Ashok AH, Volkow ND, Howes OD. The effects of Δ9-tetrahydrocannabinol on the dopamine system. Nature. 2016;539(7629):369-377. doi:10.1038/nature20153
7. 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. Biol Psychiatry. 2016;79(7):613-619. doi:10.1016/j.biopsych.2016.01.004
8. Stuyt E. The Problem with the Current High Potency THC Marijuana from the Perspective of an Addiction Psychiatrist. Mo Med. 2018;115(6):482-486.
9. Daily use of powerful pot linked to severe mental disorders, European study finds. NBC News. https://www.nbcnews.com/storyline/legal-pot/daily-use-high-potency-marijuana-linked-higher-rates-psychosis-study-n985151. Accessed February 24, 2020.
10. Di Forti M, Marconi A, Carra E, et al. Proportion of patients in south London with first-episode psychosis attributable to use of high potency cannabis: a case-control study. Lancet Psychiatry. 2015;2(3):233-238. doi:10.1016/S2215-0366(14)00117-5
11. Barkus E. High-potency cannabis increases the risk of psychosis. Evid Based Ment Health. 2016;19(2):54. doi:10.1136/eb-2015-102105
12. Nebhinani. Late-life psychosis: An overview. http://www.jgmh.org/article.asp?issn=2348-9995;year=2014;volume=1;issue=2;spage=60;epage=70;aulast=Nebhinani. Accessed February 24, 2020.
13. Vo KT, Horng H, Li K, et al. Cannabis Intoxication Case Series: The Dangers of Edibles Containing Tetrahydrocannabinol. Ann Emerg Med. 2018;71(3):306-313. doi:10.1016/j.annemergmed.2017.09.008
14. Mahmad AI, Jehangir W, Littlefield JM, John S, Yousif A. Cannabis hyperemesis syndrome: A case report review of treatment. Toxicol Rep. 2015;2:889-890. doi:10.1016/j.toxrep.2015.05.015
15. Hasin DS. US Epidemiology of Cannabis Use and Associated Problems. Neuropsychopharmacology. 2018;43(1):195-212. doi:10.1038/npp.2017.198
16. Abush H, Ghose S, Van Enkevort EA, et al. Associations between adolescent cannabis use and brain structure in psychosis. Psychiatry Res Neuroimaging. 2018;276:53-64. doi:10.1016/j.pscychresns.2018.03.008
17. Hawkridge S. Age of Opportunity: lessons from the new science of adolescence. J Child Adolesc Ment Health. 2018;30(1):61-66. doi:10.2989/17280583.2018.1480166
18. Radhakrishnan R, Wilkinson ST, D’Souza DC. Gone to Pot – A Review of the Association between Cannabis and Psychosis. Front Psychiatry. 2014;5. doi:10.3389/fpsyt.2014.00054
19. Shrivastava A, Johnston M, Terpstra K, Bureau Y. Cannabis and psychosis: Neurobiology. Indian J Psychiatry. 2014;56(1):8-16. doi:10.4103/0019-5545.124708
20. Lac A, Luk JW. Testing the Amotivational Syndrome: Marijuana Use Longitudinally Predicts Lower Self-Efficacy Even After Controlling for Demographics, Personality, and Alcohol and Cigarette Use. Prev Sci Off J Soc Prev Res. 2018;19(2):117-126. doi:10.1007/s11121-017-0811-3
21. Mouhamed Y, Vishnyakov A, Qorri B, et al. Therapeutic potential of medicinal marijuana: an educational primer for health care professionals. Drug Healthc Patient Saf. 2018;10:45-66. doi:10.2147/DHPS.S158592
22. Priority Considerations for Medicinal Cannabis-Related Research | Cannabis and Cannabinoid Research. https://www.liebertpub.com/doi/abs/10.1089/can.2019.0045. Accessed February 24, 2020.

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