The “classic” endocannabinoid (eCB) system includes the cannabinoid receptors CB1 and CB2, the eCB ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their metabolic enzymes. An emerging literature documents the “eCB deficiency syndrome” as an etiology in migraine, fibromyalgia, irritable bowel syndrome, psychological disorders, and other conditions. We performed a systematic review of clinical interventions that enhance the eCB system—ways to upregulate cannabinoid receptors, increase ligand synthesis, or inhibit ligand degradation.
We searched PubMed for clinical trials, observational studies, and preclinical research. Data synthesis was qualitative. Exclusion criteria limited the results to 184 in vitro studies, 102 in vivo animal studies, and 36 human studies. Evidence indicates that several classes of pharmaceuticals upregulate the eCB system, including analgesics (acetaminophen, non-steroidal anti-inflammatory drugs, opioids, glucocorticoids), antidepressants, antipsychotics, anxiolytics, and anticonvulsants. Clinical interventions characterized as “complementary and alternative medicine” also upregulate the eCB system: massage and manipulation, acupuncture, dietary supplements, and herbal medicines. Lifestyle modification (diet, weight control, exercise, and the use of psychoactive substances—alcohol, tobacco, coffee, cannabis) also modulate the eCB system.
Few clinical trials have assessed interventions that upregulate the eCB system. Many preclinical studies point to other potential approaches; human trials are needed to explore these promising interventions.
The endocannabinoid (eCB) system consists of receptors, endogenous ligands, and ligand metabolic enzymes. Metaphorically the eCB system represents a microcosm of psychoneuroimmunology or mind-body medicine. Cannabinoid receptor 1 (CB1) is the most abundant G protein-coupled receptor expressed in the brain, with particularly dense expression in (rank order): the substantia nigra, globus pallidus, hippocampus, cerebral cortex, putamen, caudate, cerebellum, and amygdala . CB1 is also expressed in non-neuronal cells, such as adipocytes and hepatocytes, and in musculoskeletal tissues. Cannabinoid receptor 2 (CB2) is principally associated with cells governing immune function, although it may also be expressed in the central nervous , .
The quintessential eCB ligands are N-arachidonylethanolamide (anandamide, AEA) and sn-2-arachidonoylglycerol (2-AG). AEA and 2-AG are released upon demand from cell membrane-embedded phospholipid precursors. The primary biosynthetic enzyme of AEA is N-acyl-phosphatidylethanolamine phospholipase D (NAPE-PLD). 2-AG is biosynthesized by two isoforms of diacylglycerol lipase, DAGLα and DAGLβ. AEA and 2-AG work in a homeostatic fashion, thus they are broken down after they activate CB1 or CB2. AEA is catabolized primarily by fatty acid amide hydrolase 1 (FAAH1), and 2-AG is catabolized by monoacylglycerol lipase (MAGL), and, to a lesser extent, α,β-hydrolase-6 (ABHD-6), cyclooxygenase 2 (COX2), and FAAH1.
This “classic eCB system” has expanded with the discovery of secondary receptors, ligands, and ligand metabolic enzymes . For example, AEA, 2-AG, N-arachidonoyl glycine (NAGly) and the phytocannabinoids Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) may also serve, to different extents, as ligands at GPR55, GPR18, GPR119, and several transient receptor potential ion channels (e.g., TRPV1, TRPV2, TRPA1, TRPM8). The effects of AEA and 2-AG can be enhanced by “entourage compounds” that inhibit their hydrolysis via substrate competition, and thereby prolong their action. Entourage compounds include N-palmitylethanolamide (PEA), N-oleoylethanolamide (SEA), and cis-9-octadecenoamide (OEA, oleamide).
The eCB system's salient homeostatic roles have been summarized as, “relax, eat, sleep, forget, and protect” . It modulates embryological development, neural plasticity, neuroprotection, immunity and inflammation, apoptosis and carcinogenesis, pain and emotional memory, and most importantly from the viewpoint of recent drug development: hunger, feeding, and metabolism. Obese individuals seem to display an increased eCB tone, driving CB1 activation in a chronic, feed-forward dysfunction (reviewed by ). An antagonist or inverse agonist of CB1 called rimonabant (aka, SR141716 in preclinical studies) was approved for the treatment of obesity. It was subsequently withdrawn from the market due to adverse effects .
Other diseases are associated with suboptimal functioning of the eCB system. Russo  proposed that migraine, fibromyalgia, irritable bowel syndrome, and related conditions represent CEDS, “clinical endocannabinoid deficiency syndromes.” Fride  speculated that a dysfunctional eCB system in infants contributes to “failure to thrive” syndrome. Hill and Gorzalka  hypothesized that deficient eCB signaling could be involved in the pathogenesis of depressive illnesses. In human studies, eCB system deficiencies have been implicated in uncompensated schizophrenia , migraine , multiple sclerosis , Huntington's , , uncompensated Parkinson's , irritable bowel syndrome , uncompensated anorexia , and chronic motion sickness .
Correcting CEDS may be accomplished via at least three molecular mechanisms: 1. augmenting eCB ligand biosynthesis; 2. decreasing eCB ligand degradation; 3. augmenting or decreasing receptor density or function. Clinical interventions for CEDS are largely unknown; this provided a rationale for reviewing potential clinical approaches. The paucity of human clinical trials led us to include preclinical studies in a systematic review. A systematic review uses an objective, transparent approach for research synthesis, with the aim of minimizing bias. Systematic reviews usually analyze human clinical trials, but the methodology can be applied to preclinical studies , . We previously conducted a systematic review of in vitro CB1 ligand binding affinity and receptor distribution . The review has alerted others to inter-species differences in preclinical studies, and other methodological issues (e.g., ).
Potential clinical interventions (intervention groups) include pharmaceutical drugs, such as analgesics (acetaminophen, nonsteroidal anti-inflammatory drugs, opiates, glucocorticoids), antidepressants, antipsychotics, anxiolytic agents, and anticonvulsants. We also investigated therapeutic approaches classified as “complementary and alternative medicine” (CAM). The National Center for Complementary and Alternative Medicine (NCCAM) defines CAM as “a group of diverse medical and healthcare systems, practices, and products, that are not currently part of conventional medicine” (http://nccam.nih.gov/health/whatiscam/). The NCCAM categorizes CAM practices into three broad groups: “natural products” (dietary supplements and herbal remedies), “mind and body medicine” (meditation, yoga, and acupuncture), and “body-based practices” (massage, spinal manipulation). For the purposes of this review, we add “lifestyle modifications,” including diet, weight control, exercise, and commonly-used psychoactive substances—alcohol, tobacco, coffee, and cannabis.
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