Now that you have a basic understanding of the endocannabinoid system, we can discuss how the medical use of cannabis can improve many conditions from which patients suffer. The administration of exogenous (from outside the body) cannabinoids derived from plants (referred to as phytocannabinoids) is really the manipulation of those “targets” identified so far in the endocannabinoid system. The phytocannabinoids in medical cannabis: effect the endocannabinoids and their activity at the cannabinoid receptors, have direct effects at cannabinoid receptors (CB1 and CB2 as well as other “G-protein coupled” receptors), modulate the degradative enzymes involved in removing endocannabinoids, and may interact and effect other receptors. The pervasiveness of the endocannabinoid system throughout the body and its role in maintaining homeostasis within and between the many systems involved explains to some degree why cannabis has historically been and can today be effective for such a wide variety of symptoms and diseases. Learning how each of the phytocannabinoids interacts individually on the endocannabinoid system and (in upcoming installments) how the combination and relative ratios of the individual cannabinoids and terpenes work together to achieve the desired response, will give you the tools needed to obtain the best possible response to medical cannabis treatment.

Phytocannabinoid: CBD

Cannabidiol (CBD) was first identified in 1940 at the University of Illinois by Dr. Roger Adams. It is one of the best studied phytocannabinoids to date. The effects of CBD on the endocannabinoid system are complex and only partially understood.

CBD binds weakly to the CB1 receptor without causing activation of the receptor as does the endocannabinoid anandamide (AEA). Its activity at CB1 has been shown to decrease the release of glutamate in brain tissue. Glutamate is an excitatory neurotransmitter- decreasing the amount of an excitatory neurotransmitter “slows down” neuron function along those pathways and may account for some of the relaxing and anti-seizure properties of CBD. It is well known that CBD can decrease some of the psychoactive effects of THC. This is thought to be by partially "blocking" the CB1 receptor so that THC can not fully activate it. CBD has very weak affinity for the CB2 receptor.

Many of the effects of CBD are attributed to its ability to increase the levels of the endocannabinoid anandamide (AEA). AEA is metabolized by the enzyme FAAH, making it inactive. CBD has been shown to decrease the activity of FAAH as well as decrease the reuptake of AEA, both changes resulting in increased levels of AEA. This may be the mechanism CBD exerts its anti-inflammatory and neuroprotective effects.

The binding of endocannabinoids to receptors is thought to be modified by CBD. By slightly changing the 3-D shape of the cannabinoid receptors, CBD can modify how well the endocannabinoids AEA and 2-AG attach to and activate the CB1 and CB2 receptors. It is the activation of the receptors which produce the effects.

In addition to working on the endocannabinoid system, CBD interacts on other receptors in the body. The Transient Receptor Potential Vanilloid Receptor 1 (TRPV-1), also known as the capsaicin receptor, is involved with thermoregulation and nerve pain perception. CBD activates this receptor to decrease the neuropathic ("nerve pain") pain sensations. CBD has also been shown to have activity on at least two other important receptors not directly involved with the endocannabinoid system. The 5-HT (serotonergic) receptor is activated by CBD. This is the same system targeted by the SSRI class of antidepressants, like Prozac, Zoloft, etc. This activity is believed to account for some of the antidepressant and anti-anxiety effects of CBD.

Gamma aminobutyric acid (GABA) is an inhibitory neurotransmitter in the nervous system. The GABA receptor is the site of action for the benzodiazepine class of drugs, like Valium, Xanax, etc. CBD activates the GABA receptor resulting in an increase of this inhibitory pathway activity. This is thought to be the way CBD may cause antiseizure effects, helps with anxiety and produces the overall calming effects experienced.

Although usually very safe and well tolerated, very high doses of CBD (much higher than anyone other than some severe seizure diagnoses may require) have shown laboratory evidence of liver toxicity. There have been no instances of liver failure from CBD use. Patients with severe glaucoma must be cautious as higher CBD doses can lead to an increase in intraocular (eye) pressures.

Back to the Big Picture

CBD is just one piece of the cannabinoid puzzle. For some patients, with diagnoses such as seizure disorders, administering only CBD can result in a marked improvement in symptoms. Most patients are not as simple as that. Getting the best results using phytocannabinoids as treatment usually requires a combination of them combined in certain proportions. Understanding how each cannabinoid functions individually is important in determining the combinations which best suit your medical issues and you as an individual.

Brian Nichol MD
Cannabis Expert