Neurobiology of cannabis
After discovering the cannabinoid receptor in 1990, a plethora of basic science studies has taught us a great deal about the neuropharmacology of the two most active ingredients in cannabis—THC and CBD—which are pharmacologically complementary. In the early 1960s, when cannabis was widely used by our country’s youth, the leaves from the marijuana plant were derived from the original naturally occurring plants that had been harvested since approximately 3000 BC—Cannabis sativa.
In the original cannabis plant, the THC content was roughly 2%, with relatively equal amounts of CBD. Once THC was identified as the cannabinoid associated with the “high,” marijuana plant breeders genetically enriched subsequent generations of plants to have increased THC—up to 30%—and decreased CBD. The most potent form of THC is called “wax,” which is 50% pure THC. A 2016 article documented that the ratio of THC to CBD of illegally sold cannabis in the US increased from 14:1 to 80:1 between 1995 and 2014.2
Following the discovery of the first endogenous cannabinoid receptor in 1990, a second receptor was found: aptly named cannabinoid 1 receptor (CB1R) and cannabinoid 2 receptor (CB2R). CB1R is the primary receptor in the mammalian brain and is present in high concentrations in the hippocampus, hypothalamus, amygdala, basal ganglia, substantia nigra, and cerebellum. There are some CB2Rs in the brain as well, although their primary locations include the gastrointestinal system, the spleen, and immune cells such as the macrophages.
Two endogenous cannabinoids bind to these CB receptors, anandamide (AEA) and 2-arachidonoylglycerol (2-AG). Interestingly, unlike most neurotransmitters in the brain, AEA and 2-AG are synthesized postsynaptically “on demand” and diffuse upstream, across the synapse, and bind to presynaptic CB1 and CB2 receptors. This ultimately results in inhibition of the presynaptic release of glutamate, GABA, dopamine, norepinephrine, serotonin, and acetylcholine. (For more details on this pathway see Atakan,3 and Maccarrone et al.4)
Benefits of legalization
One of the most compelling arguments for the legalization of cannabis is the ability to regulate its production, composition, and distribution. Illegally obtained cannabis has unpredictable content: concentrations of THC and CBD can vary widely; and there is no quality control to inform the user of the potency and ratios of THC to CBD. When purchased illegally, the “cannabis” may actually contain “cannabimimetic agents.” Two well-known examples are K-2 and Spice, which are sprayed onto dry plant matter. These synthetic chemicals mimic THC but bind much more potently to CB1R and can cause serious adverse effects, including psychosis.
Cannabis sold at state certified dispensaries is quantitatively assayed for contents, including defined percentages of CBD versus THC. This allows for a high degree of predictability of the cannabis product being purchased, and the possibility to titrate the amount to find the optimal dose for a person’s preferred effect. Dispensaries will also only sell cannabis products to individuals aged 21 or older. The consumer-dispenser interface also allows for accurate information on the risks, benefits, and adverse effects. It also provides a venue for educating the public about the serious and in some cases irreversible brain damage that cannabis can cause to the developing brains of children, adolescents, and young adults as well as the adverse effects to the fetus in pregnant women.
1. National Academies on Sciences, Engineering and Medicine. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. 2017. http://www.nap.edu/24625. Accessed March 13, 2019.
2. ElSohly MA, Mehmedic Z, Foster S, et al. Changes in cannabis potency over the last 2 decades (1995-2014): analysis of current data in the United States. Biol Psychiatry. 2016;79:613-619.
3. Atakan Z. Cannabis, a complex plant: different compounds and different effects on individuals. Ther Adv Psychopharmacol. 2012;2:241-254.
4. Maccarrone M, Guzmán M, Mackie K, et al. Programming of neural cells by (endo) cannabinoids: from physiological rules to emerging therapies. Nature Rev. 2014;12:786-801.
5. Andrade C. Cannabis and neuropsychiatry, 2: the longitudinal risk of psychosis as an adverse outcome. J Clin Psychiatry. 2016;77:e739-e742.
6. McGuire P, Robson P, Cubala WJ, et al: Cannabidiol (CBD) as an adjunctive therapy in schizophrenia: a multicenter randomized controlled trial. Am J Psychiatry. 2018;175:225-231.
7. Harvey PD. Smoking cannabis and acquired impairments in cognition: starting early seems like a really bad idea. Am J Psychiatry. 2019;176:90-91.
8. Meier MH, Caspi A, Ambler A, et al: Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc Natl Acad Sci USA. 2012;109:E2657-E2664.