In 2014, a scientific literature review called “Care and Feeding of the Endocannabinoid System: A Systematic Review of Potential Clinical Interventions that Upregulate the Endocannabinoid System” was published by McPartland, Guy & Di Mazo. It was sponsored by GW Pharmaceuticals, maker of the first prescription CBD product Epidiolex.
This is the best-written summary of the endocannabinoid system I’ve read. It’s worth reading in its entirety but in case you want to skim it, here are the highlights:
The human endocannabinoid system helps us “relax, eat, sleep, forget, and protect.”
The main endocannabinoids (eCB) are: N-arachidonylethanolamide (anandamide, AEA) and sn-2-arachidonoylglycerol (2-AG). An enzyme called FAAH breaks down AEA. MAGL breaks down 2-AG.
A number of diseases and conditions are associated with poor eCB function: migraine, fibromyalgia, irritable bowel syndrome, schizophrenia, multiple sclerosis, Huntington‘s, Parkinson’s, anorexia.
Dr. Ethan Russo proposed that Clinical Endocananbinoid Deficency Syndrome (CEDS) may cause depression & failure to thrive.
Correcting CEDS may be accomplished by:
- augmenting eCB biosynthesis;
- decreasing eCB degradation;
- augmenting or decreasing receptor density or function.
But there are extremely few humans studies of how to correct CEDS. So we are guessing & trying to figure it out.
Non-steroidal anti-inflammatory drugs: NSAIDs inhibit two cyclooxygenase (COX) enzymes, COX1 and COX2, and thereby block the conversion of arachidonic acid (AA) into inflammatory prostaglandins. Ibuprofen, ketorolac, and flurbiprofen also block the hydrolysis of AEA into arachidonic acid and ethanolamine.
Combining NSAIDs with cannabinoids (either eCBs or exogenous cannabinoids) produces additive or synergistic effects.
Some NSAIDs inhibit FAAH and enhance the activity of eCBs, phytocannabinoids, and synthetic cannabinoids.
Acetaminophen metabolite NAP blocks the breakdown of AEA by FAAH, inhibits COX1 and COX2, and acts as a TRPV1 agonist – similar to CBD.
Stress: Chronic exposure to stress hormones downregulates the eCB system.
Opiates: Acute opiate administration enhances the activity of eCBs, phytocannabinoids, and synthetic cannabinoids. Chronic opiate administration, however, may have a deleterious effect on the eCB system.
Antidepressants: The effects of antidepressant drugs or treatments upon the eCB system… likely result in CB1 upregulation, at least in some brain regions. Preclinical studies suggest agonist trafficking may be responsible for variable responses.
Antipsychotics: CB1 upregulation during antipsychotic drug treatment may explain appetite enhancement, weight gain, and CB1 supersensitivity. Antipsychotic drugs likely upregulate CB1 expression in parts of the rodent brain.
Valium: Administration of diazepam to mice is accompanied by strong elevation of brain eCB levels.
Omega-3 Fatty Acids: Adequate levels of dietary omega-3s are required for proper eCB signaling.
Omega-3 PUFAs may impact the eCB system via a second mechanism: eCB biosynthetic enzymes readily accept ω-3s as substrates. An omega-3-rich diet markedly elevated the N-acyl-ethanolamide metabolite of DHA, called DHEA, the N-acyl-ethanolamide metabolite of EPA, called EPEA, and the sn-2-glycerol-ester metabolite of EPA, called 2-EPG. FAAH catabolized DHEA.
DHEA and EPEA showed high binding affinity for CB1 and acted as partial agonists.
Probiotics & Breast Milk: Probiotics and prebiotics also modulate CB1 expression. Human breast milk contains small amounts of AEA and high levels of 2-AG – but the biological significance of this is not known.
Plastics: Phthalates are plasticizers added to water bottles, tin cans, food packaging, and even the enteric coating of pharmaceutical pills. Phthalates may act as endocrine disruptors and carcinogens. They also block CB1 as allosteric antagonists.
Herbs & Spices: Yangonin, a kavalactone extracted from kava, Piper methysticum, exhibits affinity for CB1.
Curcumin, extracted from curry powders, elevates eCB levels and brain nerve growth factor (NGF) in a brain region-specific fashion.
Alkamides from Echinacea species bind to CB2… and act as CB2 agonists with immunomodulatory effects.
The principal terpenoid in black pepper, (E)-β-caryophyllene (BCP), binds to CB2 and acts as an agonist.
Social Isolation & Chronic Stress: Social isolation stress decreased CB1 density in the supraoptic nucleus of rats.
Chronic stress impairs the eCB system, via decreased levels of AEA and 2-AG.
Mice given access to a running wheel recovered their chronic stress-induced synaptic defects. Accordingly, social play in rats increased CB1 phosphorylation (a marker of CB1 activation) in the amygdala and enhanced AEA levels in the amygdala and nucleus accumbens.
Acupuncture & Massage: Acupuncture reduced stress-related behavior (from maternal separation in rats) and normalized HPA-induced corticosterone release.
Massage and osteopathic manipulation of asymptomatic participants increased serum AEA 168% over pretreatment level.
Eating: Increased food intake, adiposity, and elevated levels of AEA and 2-AG apparently spiral in a feed-forward mechanism. Weight loss from caloric restriction breaks the cycle, possibly by reducing CB1 expression and reducing eCB levels.
Exercise: In humans, serum AEA levels doubled over baseline in male subjects after ≥30 min running, and increased significantly in male subjects after biking. Serum 2-AG levels did not significantly increase.
Strenuous hiking at high altitudes (up to 3196 m) significantly increased serum AEA levels over baseline.
Serum AEA levels in male and female runners significantly increased after 30 minutes of moderately intense treadmill running.
In summary, medium- to high-intensity voluntary exercise in mammals, including humans, increases eCB signaling, via increased serum AEA levels (but not 2-AG), and possibly increased CB1 expression. “Runner’s high” may be an eCB-induced reward for exercise.
Alcohol: Within 10 minutes, the consumption of a moderate amount of alcohol reduces plasma AEA and 2-AG concentrations.
Acute ethanol may enhance endogenous eCB release and eCB signaling, although it varies by brain area and synapse, and this complexity requires further testing. Two studies suggest ethanol dampens the effects of the eCB system. Chronic ethanol consumption and binge drinking likely desensitize or downregulate CB1 and impair eCB signaling.
Cannabis: THC mimics AEA and 2-AG by acting as an agonist at CB1 and CB2. But rather than simply substituting for AEA and 2-AG, McPartland and Guy proposed that Cannabis and its many constituents work, in part, by “kick-starting” the eCB system.
Chronic, high dosing of THC causes a predictable desensitization and downregulation of CB1 and CB2, accompanied by drug tolerance.
The degree of CB1 downregulation correlated with years of chronic cannabis smoking. CB1 densities returned to normal after four weeks of abstinence. Variable downregulation in different brain regions may explain why frequent users of cannabis develop tolerance to some effects of THC, such as anxiogenesis and cognitive impairment, but not to its euphoric effect.
2-AG acts as a full agonist at rodent and human CB1 and CB2.
AEA is a partial agonist like THC, with an efficacy somewhat greater than THC in mouse brain.
The effects of THC upon the eCB system oscillate between potentiation and suppression, depending on acute versus chronic dosage. The dividing line between “acute” and “chronic” is a gray zone, and likely differs amongst individuals.
The potential synergy between THC and the eCB system is analogous to the potential synergy between AEA and 2-AG: Rodent studies that combined FAAH and MAGL inhibitors indicated that AEA and 2-AG may activate CB1 receptors in different parts of the central nervous system. Each causes unique behavioral effects, and when both are enhanced, new effects emerge.
image credit: Paul Hamilton