With marijuana legal in several states and medical marijuana available in many others, clinicians are confronted with the benefits, adverse effects, and addictability of cannabinoids. For a first look at these issues, let’s see what is known about cannabinoid neurobiology and the pharmacology of marijuana and synthetic cannabinoids.
Several hundred chemicals have been identified in the marijuana plant, of which around a hundred are active at cannabinoid receptors in the brain. Delta-9 tetrahydrocannabinol (THC) is the most psychoactive and is thought to be responsible for marijuana’s addicability. Another constituent of interest these days is cannabidiol. But research is in its early stages, and many other natural and synthetic cannabinoids are being studied.
The main cannabinoid receptors in the brain are CB1, which is involved in psychoactive and many other neurobiological effects, and the less numerous CB2, which is expressed mainly outside the central nervous system on immune-related cells, but also on some neurons. Both are G-protein coupled receptors and thus, like monoamines and opioids, exert slower neuromodulatory effects. CB1 receptors are among the most abundant such receptors in the brain. They are prominent in the cortex, basal ganglia, hippocampus, and cerebellum, and also in the gut. Of note, they, along with enzymes for synthesizing and breaking down endocannabinoids, are found in the dorsal raphe, where most serotonergic neurons are located, which suggests they modulate brain serotonergic activity. CB2 receptors are induced after tissue injury and during inflammation; in the brain they are primarily located on microglia and vascular elements but may be expressed by some neurons. As we shall see, most endogenous and exogenous cannabinoids are active at both CB1 and CB2 receptors.
The endogenous cannabinoids have interesting biological properties. 2-arachidonoyl glycerol (2-AG) and anandamide have been studied the most. They are neither small molecules, like acetylcholine and the monoamines, nor peptides like the endogenous opioids and many hormones. They are lipids whose precursors are in lipid membranes, available to be liberated quickly into the extracellular space. 2-AG is an important intermediate in the synthesis of other lipids, including prostaglandins. 2-AG and anandamide are broken down by several pathways, including COX-2, which is involved in prostaglandin synthesis. Another interesting feature of the endocannabinoid system is that they appear to function as retrograde messengers--they are released by post-synaptic neurons to modulate presynaptic neuronal activity. They may thus be important for short-term synaptic plasticity.
The endocannabinoid system, then, is widely distributed in the nervous system and other parts of the body, including the immune system. It functions in several ways that are quite different from more familiar neurotransmitter systems. Let’s now look at the pharmacological effects of endogenous, natural, and synthetic cannabinoids.
The endogenous ligand 2-AG is a full agonist of both the CB1 and CB2 receptors. Anandamide is a partial agonist. The THC found in marijuana is a terpenoid, different from endocannabinoids. TCH is a partial agonist of both cannabinoid receptors and may thus stimulate them while blocking the effects of endogenous cannabinoids. Dronabinol is synthetic THC; it is marketed in the U.S. as Marinol for nausea associated with chemotherapy and for weight loss in patients with AIDS and classified by the Food and Drug Administration as Schedule II. The THC analogue nabilone, marketed as Cesamet for similar indications, has better bioavailability. It is also Schedule II and is used off-label as adjunct therapy for chronic pain.
Another constituent of marijuana, cannabidiol, has low affinity for both CB1 or CB2 receptors; it may act via indirect CB1 antagonism, by effects on other cannabinoid receptors, antagonism of serotonin receptors, or other mechanisms. Synthetic cannabidiol, branded Epidiolox, is not available in the U.S. but is being studied for use in against seizures, tumors, pain, inflammation, psychosis, anxiety, and addiction. Cultivated strains of hemp with minimal THC and high cannabidiol contents are marketed as herbal supplements and special forms of medical marijuana. Sativex is a 1:1 combination of THC and cannabidiol approved in a few countries for muscle spasticity in multiple sclerosis; it is also being investigated in the U.S.
A long list of THC analogues are sold as “synthetic marijuana” under names like “Spice” and “K2.” Many are now Schedule I in the U.S., though illegal use and overdoses still occur.
THC concentrations in cultured marijuana have risen from 1-2% in the 1960’s to around 9% in recent years. Because cannabidiol appears to reduce the psychotropic effects of THC, commercially available marijuana is often engineered with ratios of THC to cannabidiol as high as 80:1, but medically-marketed marijuana is now available with nominally lower ratios.
What guidance does this fascinating cannabinoid neuropharmacology provide for clinical work? This first-pass review of basic cannabinoid science has not addressed many important questions around therapeutic uses and adverse effects of cannabinoids, including their efficacy for treatment of medical and possibly psychiatric problems, and issues related to THC’s addicability. But a few themes emerge. First, endogenous cannabinoid systems are found in many critical brain areas, and their biochemistry and receptor biology is quite different from more familiar neurotransmitters. Second, THC and its analogues also stimulate CB2 receptors, which could affect immune functions for better or worse, and clinicians may want to keep an eye on immune-related issues, including injury healing, response to infections, and autoimmune disorders, in patients who use marijuana. Finally, cannabis withdrawal, and possibly cannabis use disorder, might be treatable with cannabinoid analogues such as dronabinol or nabilone, but such use would be off-label and might fall under the federal prohibition against prescribing a “narcotic drug" to a “narcotic-dependent person” for detoxification or maintenance treatment without a special license.