Care and Feeding of the Endocannabinoid System: A Systematic Review of Potential Clinical Interventions that Upregulate the Endocannabinoid System

<div><p>Background</p><p>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.</p><p>Methodology/Principal Findings</p><p>We searched PubMed for clinical trials, observational studies, and preclinical research. Data synthesis was qualitative. Exclusion criteria limited the results to 184 <i>in vitro</i> studies, 102 <i>in vivo</i> 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.</p><p>Conclusions/Significance</p><p>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.</p></div

Anandamide (top figure) is metabolized into arachidonic acid and ethanolamine (bottom figures).

<p>Anandamide (top figure) is metabolized into arachidonic acid and ethanolamine (bottom figures).</p

Selection process for study inclusion.

<p>Selection process for study inclusion.</p

Effects of exercise upon the eCB system in rodent studies.

<p>Effects of exercise upon the eCB system in rodent studies.</p

Effects of chronic or subchronic ethanol upon eCB levels.

1<p>↑, increase; ↓, decrease; ≈, no change; assay; result compared to unsupplemented controls.</p

Effects of short- and long-term caloric restriction upon the brain eCB system in animal studies.

<p>Effects of short- and long-term caloric restriction upon the brain eCB system in animal studies.</p

Effects of PUFA supplementation upon eCB levels.

1<p>↑, increase; ↓, decrease; ≈, no change;</p

Antagonists of the primary catabolic enzyme for 2-AG, monoacylglycerol lipase (MAGL), prolong DSI.

<p>Diamonds indicate delivery of DSI-inducing voltage steps. Scale: 30 s/150 pA. (a) Bath application of MAGL inhibitors, JZL184 (1 µM) or OMDM-169 (2 µM), prolong DSI. (b) Group data showing recovery DSI in the presence of DMSO (Veh), JZL184, or OMDM-169. The DSI-inducing voltage step ended 1 s prior to time 0. The solid lines are best fitting single-exponential functions; the time constants of these functions were taken as the decay time constants (τ_decay) of DSI. (c) Group data showing increases in τ_decay of DSI in the indicated conditions. When applied for 40–120 min, JZL184 or OMDM-169, prolonged DSI; τ_decay was increased by ∼40% (DMSO: 13.9±1.1 s, n = 21; JZL184: 19.2±1.7 s, n = 15; OMDM-169: 20.4±1.6 s, n = 15; p<0.01, one way ANOVA).</p

Intracellular application of DAGL inhibitors reduces DSI to a greater extent than it reduces eCB_mGluR.

<p>(a) Intracellular infusion of OMDM-188 reduced DSI; each symbol represents averaged DSI values (3 trials) from one cell. Only data for 5 µM (n = 16) and 10 µM (n = 38) groups shown for clarity; both differ from Veh-In group, K-S test, p<0.01. (b) Group data. Includes results in (a), plus 2 µM (n = 6), 20 µM (n = 40) groups. ^* p<0.001, one-way ANOVA on ranks. (c) Sample continuous trace showing DSI trials and eIPSC suppression by eCB_mGluR. Scale: 2 min/200 pA. (d) Group data for experiments as in (c) with internal 5, 10 or 20 µM OMDM-188, or Veh only. DSI and eCB_mGluR were measured, and eCB_mGluR was plotted against DSI for each cell. For the cells (n = 28/35) within dotted oval, mean eIPSC reduction from baseline by DSI is 4.3±1.06%, mean eCB_mGluR eIPSC reduction is 49.0±2.32%. The straight line is a linear regression fit to the data for 10 and 20 µM DHPG (see text for discussion).</p

Use-dependent reduction of eCB_mGluR with internal DAGL inhibitor.

<p>(a) Sample eIPSCs (each trace is the mean of 3) from the same OMDM-188-loaded (20 µM in the pipette) cell in the indicated conditions. BL denotes the baseline response, and W, the response obtained after washing out DHPG. DHPG was applied 3 times at 20-min intervals starting ∼15–20 min after break-in. (c) As in (a) except that the 1^st DHPG application was given ∼40 min after break-in – i.e., at the same time as the 2^nd DHPG application in (a) – and the 2^nd one at 50–60 min after break-in. (e) As in (a), with vehicle only present in the internal solution. (b)(d)(f) Group data for experiments in (a), (c), and (e), respectively. ^*p<0.001, one way repeated ANOVA; Scale: 20 ms/200 pA.</p