Cannabinoids for stress and pain management
The endocannabinoid system has a significant role to play in regulating stress and pain, said Cecilia Hillard, PhD, at the 2019 Institute for Functional Medicine Annual International Conference in San Antonio, Texas.
Cannabis is an annual herb. The botanical family includes hemp, cannabis indica, and cannabis sativa. There are over 100 unique chemicals and a family of terpenephenols found in cannabis. Strains have differing amounts of tetrahydrocannabinol (THC) and cannabidiol (CBD), thus aggregated data regarding effects of cannabis on humans are difficult to interpret, Hillard said.
THC activates G protein coupled receptors, Hillard said. The CB1 cannabinoid receptor is highly expressed throughout the central nervous system. Found on the presynaptic side, it couples to inhibition of neurotransmitter release. It is also present in the liver, adipose tissue, pancreas, and skeletal muscle. The CB2 cannabinoid receptor is expressed by immune cells and in the spleen. It is found in the highest amounts in B cells, followed by T cells, macrophages, and microglia. It suppresses inflammation in the periphery.
Endocannabinoids are endogenous ligands of cannabinoid receptors. Anandamide is an ethanolamide of arachidonic acid, synthesized from a low abundance lipid. It is enzymatic, though specifics are not understood, Hillard said. It Is degraded by several hydrolases, including fatty acid amide hydrolase. 2-Arachidonoylglycerol (2-AG) is a glycerol ester of arachidonic acid, synthesized from PIP2. It is degraded by lipases, hydrolases, and esterases.
Endocannabinoid signaling is on-demand, Hillard said. Receptor density, desensitization, genetics, epigenetics, and accessory proteins regulate signaling. Further, endocannabinoid signaling regulates synaptic activity.
For stress, glucocorticoids regulate 2-AG and cannabinoid receptors regulate anandamide, Hillard said. Endocannabinoid signaling is a stress-effector. Challenges to homeostasis—from trauma and injury, psychological stress, pain, exercise, or starvation—can lead to endocannabinoid signaling and changes in synaptic activity, which can either contribute to stress responses (stress-enhanced memory formation or stress-evoked eating) or oppose or dampen stress responses (reduced anxiety and fear responses or reduced endocrine and neuronal responses).
Glucocorticoids increase 2-AG synthesis. It occurs in all brain regions with glucocorticoid receptors, including the hypothalamus, hippocampus, prefrontal cortex, and the amygdala. Membrane glucocorticoid receptor mechanism is not clear. Loss of CB1 receptor signaling prolongs HPA axis activation by stress, according to a 2011 article in the Journal of Neuroscience.
Stress is a critical determinant of relapse to substance use, Hillard said. There are reports by drug users that stress contributes to relapse and drug use. High incidence of anxiety and mood disorders and post-traumatic stress disorders in substance use disorder populations. Personalized stress imagery precipitates drug craving in individuals with substance use disorder.
CB1 receptors are involved in reward, Hillard said. They are present in the brain reward circuit, and signaling increases consumption of highly palatable foods and promotes self-administration of rewarding drugs, including cocaine, alcohol, and heroin.
Since stress increases CB1 receptor signaling, and CB1 receptor signaling increases drug seeking, does CB1R activation contribute to stress-induces relapse? Stress-potentiated reinstatement is blocked by CB1 receptor antagonist, Hillard said. Further, inhibition of 2-AG synthesis blocks corticosterone-potentiated reinstatement. Corticotropin-releasing factor increases fatty acid amide hydrolase activity and reduces anandamide.
Brain anandamide inversely correlates with anxiety, Hillard said. Stress suppresses brain anandamide and increases anxiety. A 2013 study published in the journal Molecular Psychiatry found the effects of chronic stress are absent in fatty acid amide hydrolase null mice.
Regarding endocannabinoid signaling and pain, CB1 receptors are present at the peripheral, spinal, and supraspinal levels of the pain circuit. Enzymes involved in the inactivation of the endocannabinoids are present at the same sites. Nerve injury, inflammation, and significant acute pain all increase endocannabinoid concentrations. CB1 receptor activation along the pathway reduces pain, Hillard said.
There is therapeutic potential for elevation of CB1 receptor activity, Hillard said. Possible approaches include direct agonist of CB1 receptors or indirect agonists, inhibiting endocannabinoid metabolism. CB1 receptor agonists are limited but existing options can orally administered, mucosally administered, or derived from cannabis. However, chronic cannabis use can lead to tolerance, cannabis hyperemesis syndrome, and psychosis. CB1 receptors do have some benefits, Hillard said. To treat pain, modest efficacy is best, she said.
The endocannabinoid system is a critical component of the stress response. Preclinical studies support beneficial effects in treatment of pain and stress-related disorders, particularly of fatty acid amide hydrolase activity inhibitors. Human studies have lagged, but experience with cannabis indicates that direct agonists have high potential for adverse effects.
Editor’s note: This article is part of Integrative Practitioner’s live coverage of the 2019 Institute for Functional Medicine Annual International Conference. For a full list of coverage, click here.