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In recent years, cannabis has been at the center of one of the most important developments in modern science – significantly advancing our understanding of health and disease.

Research on the effects of cannabis led directly to the discovery of a major biochemical signaling system in the human body – the endocannabinoid system – which plays a pivotal role in regulating a wide range of physiological processes that affect our mood, our blood pressure, our bone density, our metabolism, our intestinal fortitude, our energy level, how we experience pain, stress, hunger, and much more.

“By using a plant that has been around for thousands of years, we discovered a new physiological system of immense importance,” says Israeli scientist Raphael Mechoulam. “We wouldn’t have been able to get there if we had not looked at the plant.”

Described by Mechoulam as “a medicinal treasure trove,” cannabis contains more than 100 unique biologically active compounds known as “cannabinoids,” including tetrahydrocannabinol (THC) and cannabidiol (CBD).

THC causes the high that cannabis is famous for, CBD does not; both have important therapeutic attributes.

In addition to phytocannabinoids produced by the plant, there are endogenous cannabinoids – marijuana-like molecules – that occur naturally in the human brain and body. And there are also synthetic cannabinoids created by pharmaceutical researchers, who are developing new compounds that target the endocannabinoid system for therapeutic benefit.

Some of these novel synthetic compounds activate the same cannabinoid receptors – CB1 and CB2 – in the brain and body that respond pharmacologically to THC and other cannabis components.1

Medical scientists are also experimenting with synthetic drugs designed to improve “endocannabinoid tone” without binding directly to cannabinoid receptors.

Here are ten strategies that scientists are currently pursuing in an effort to harness the healing potential of the endocannabinoid system.

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10 Strategies to Target the Endocannabinoid System:

1. Single-molecule plant cannabinoids

Dronabinol, marketed in pill form as Marinol, is a synthetic THC isolate combined with sesame oil. It got fast-tracked for approval by the Food and Drug Administration in 1985 in response to rising patient demand for medical marijuana.

Other THC preparations are also FDA-approved, including Syndros, a Schedule 2 liquid THC drug produced by Insys. But patented single-molecule THC is a poor substitute for whole plant cannabis.

Even though it is highly psychoactive and potentially dysphoric, pharmaceutical THC is legally accessible in all 50 states as a prescription medication.

Cannabidiol is also a FDA-approved pharmaceutical marketed as Epidiolex for children with two kinds of referactory seizure disorders. Produced by GW Pharmaceuticals, Epidiolex is a botanically-derived CBD isolate combined with a tiny amount of cannabidivarin (CBDV), a “minor” cannabinoid that also has potent anti-epileptic properties.

Several biotechnology companies are seeking to harvest single-molecule cannabinoids, such as CBDV, from a yeast substrate. As this methodology improves, drug developers may have access to numerous single-molecule cannabis compounds for R & D purposes.

2. Synthetic cannabinoid analogs

Scientists have created synthetic analogs of plant cannabinoids for research purposes and for commercial sale and distribution. Nabilone, a synthetic THC analog, was developed by Eli Lilly and Co. as a treatment for chemotherapy-induced nausea and vomiting.

Marketed under the trade name Cesamet, this synthetic cannabinoid is used as an adjunct therapy for chronic pain management in Canada and other countries. Clinical trials of Nabilone have indicated some effectiveness for fibromyalgia, irritable bowel disease, Parkinson’s, PTSD-related nightmares, and multiple sclerosis.

Researchers are using various synthetic analogs to investigate the biochemical pathways and molecular mechanisms of the endocannabinoid system. Some of these compounds, such as WIN55,212-2 and CP55,940, bind to both cannabinoid receptors – CB1 and CB2. (So does THC.) Other experimental drugs target only one type of cannabinoid receptor and not the other.2

A cannabinoid agonist binds to a cell receptor and causes it to initiate a signaling cascade that modulates various physiological processes and protects neurons against toxic insults. A cannabinoid antagonist binds to a cell receptor and prevents it from signaling.

3. Synthetic cannabinoid antagonists

Cannabinoid CB1 receptors, which mediate the psychoactive effects of THC, are concentrated in the brain and central nervous system. When THC binds to CB1, it can make a person feel stoned – and hungry. The “munchies,” scientists confirmed, are linked to stimulation of CB1 receptors in areas of the brain that regulate hunger and satiety. If activated, CB1 receptors induce appetite; if blocked, they reduce it.

“SR141716,” a synthetic CB1 antagonist developed by the French pharmaceutical giant Sanofi-Aventis, was initially utilized as a research tool: By blocking CB1 and monitoring which functions were altered, scientists advanced their understanding of the endocannabinoid system.

Sanofi strategists believed they had invented the perfect diet pill, and they promoted SR141716 as an appetite suppressant in Europe. But the diet drug, sold as “Rimonabant,” proved to be too blunt an instrument. Before long, the synthetic CB1 antagonist was pulled from circulation because of dangerous side effects – high blood pressure, nausea, vomiting, anxiety, mood swings, depression, headaches, seizures, sleep disorders, and a heightened risk of suicide.

If nothing else, the CB1 antagonist debacle provided vivid evidence that a well-functioning endocannabinoid system is essential for good health.

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4. Peripherally restricted CB1 agonists

Cannabinoid CB1 receptors, the most prevalent protein receptors in the human brain, influence many neurological functions, including marijuana’s mood-altering effects. CB1 receptors are also expressed in the enteric nervous system (the gut), the liver, kidneys, heart and other peripheral organs.

Stimulating CB1 receptors can deliver significant therapeutic benefits, but THC’s psychoactivity limits its medical utility, according to Big Pharma catechism, which defines the CB1-mediated marijuana “high” as an adverse side effect that drug designers should avoid if they hope to win regulatory approval of their patented synthetic novelties.

So pharmaceutical researchers have created peripherally-restricted CB1 agonists (such as AZ11713908) that only activate CB1 receptors outside the central nervous system, but don’t cross the blood-brain barrier.

A peripherally restricted CB1 agonist won’t cause side effects such as disconcerting dysphoria or useless euphoria. But such a compound has never been approved for therapeutic use by the FDA.

5. Peripherally restricted CB1 antagonists

More than a dozen years after the Rimonabant debacle, medical scientists are taking another look at CB1 receptor antagonists – from a different perspective.

Instead of blocking CB1 receptors in the brain, the current emphasis is on selectively blocking only CB1 receptors outside the central nervous system. Drug developers have created a new generation of experimental CB1 antagonists that don’t cross the blood-brain barrier.

Whereas blocking CB1 receptor signaling in the brain produces detrimental neurological effects, CB1 antagonism in peripheral organs has shown intriguing therapeutic potential in preclinical studies. A team of scientists at National Institutes of Health (NIH) in Bethesda, Maryland, reported that CB1 receptor antagonism enhances insulin sensitivity in pancreas and liver cells and delays age-related muscle loss.

Another NIH-backed study found that a peripheral CB1 blockade may have therapeutic possibilities for treating alcoholism. And according to researchers at RTI International in North Carolina, CB1 receptor antagonists, which lack central nervous system penetration, should be considered worthy drug development candidates for liver disorders. 

6. Selective CB2 agonists

Scientists have been hot on the trail of another type of synthetic cannabinoid – a “selective CB2 agonist” – that will bypass the brain while acting on the peripheral nervous system, where CB2 receptors are concentrated. CB2 receptors regulate immune activity, pain perception, inflammation, and metabolic function.

Tinkering with synthetic compounds (such as HU 308 and JWH 133) that selectively stimulate CB2 receptors raises the prospect of healing without the high because CB2 receptors are localized primarily outside the brain and are not responsible for the intoxicating effects induced by THC.

Cannabinoid researchers have their eyes on the ultimate prize, the pharmaceutical Holy Grail – a non-addictive painkiller bereft of adverse side effects. Animal experiments focusing on the CB2 receptor initially showed promise.

But problems inevitably arise when selectively targeting a cannabinoid receptor subtype and treating it as an on/off switch.

Early clinical trials for synthetic CB2 agonists didn’t pan out, though not for lack of trying. “If drug discovery is a sea, then CB2 is a rock that is surrounded by shipwrecked-projects,” remarked Italian scientist Giovanni Appendino.

But there’s been progress. Selective CB2 agonists are currently in phase 3 clinical trials for treating autoimmune dysfunction.

7. Water-soluble cannabinoids

In their natural form, plant cannabinoids and endocannabinoids are oily, hydrophobic substances that don’t dissolve in water. But these lipid molecules can be structurally altered so that they become water soluble without diminishing their bioactivity.

Scientists have developed several ways of synthesizing water-compatible derivatives of THC and other cannabinoids that are more bioavailable than their oily, naturally-occurring counterparts.

The first water-soluble version of THC was created in 1972. Subsequent research found that water-friendly cannabinoid derivatives can lower intraocular pressure in rabbits. A water-soluble cannabinoid ester, “O-1057,” exhibited stronger analgesic properties than THC in preclinical experimentation.

These days, internet retailers and CBD storefronts are claiming to sell water-soluble cannabidiol formulated as a nanoemulsion. Pure CBD delivered via nanotechnology is supposed to provide exceptionally high bioavailability and remedial effect compared to a hydrophobic CBD oil extract. But there are major trade-offs that may cancel out the alleged advantages of nanoemulsified single-molecule CBD.

Nanofied CBD may be easier to absorb systemically, but it also metabolizes much quicker, thereby reducing duration of affect.

And a CBD isolate typically requires a much higher dose for therapeutic efficacy than a whole plant CBD-rich concentrate.

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8. Allosteric cannabinoid receptor modulators

Because direct, full-on stimulation of cannabinoid receptors in the brain may trigger undesirable psychoactive effects, scientists have developed synthetic compounds that change the shape of the CB1 receptor and influence how it signals without causing a THC-like high. These compounds, known as allosteric modulators, can either amplify or decrease a receptor’s ability to transmit a signal.

A “positive allosteric modulator” increases the potency and/or efficacy of CB1 receptor activation by anandamide and 2AG (the two main endogenous cannabinoids), thereby boosting the protective effects of the endocannabinoid system.

Scientists at the University of Aberdeen in Scotland have synthesized a positive allosteric modulator of CB1 to treat pain and neurological disorders. When researchers at Virginia Commonwealth University tested this experimental drug (“ZCZ011”) on mice, it reduced inflammatory pain by magnifying the CB1 receptor’s response to anandamide.

But allosteric effects are rarely consistent across species, which significantly impedes drug development in this area.4

9. Inhibitors of endocannabinoid metabolizing enzymes

Medical scientists are experimenting with synthetic designer drugs to enhance endocannabinoid tone without binding directly (or allosterically) to cannabinoid receptors.

Pharmacological augmentation of endocannabinoid signaling can be achieved by inhibiting fatty acid amide hydrolase (FAAH) and/or monoglycerol lipase (MAGL), the catabolic enzymes that break down the brain’s own marijuana-like molecules, anandamide and 2AG, respectively.

Simply put, less FAAH and MAGL means more anandamide and 2AG, resulting in greater cannabinoid receptor activity throughout the body. Drugs that suppress endocannabinoid-metabolizing enzymes indirectly boost cannabinoid receptor signaling without causing the vivid psychoactive effects associated with synthetic and plant-based CB1 agonists.

Indirect modulation of endocannabinoid signaling via FAAH or MAGL inhibition has been shown to ease pain, anxiety, colitis, hypertension, opiate withdrawal, diarrhea, and arthritis in various animal models. But FAAH and MAGL also regulate a raft of other endogenous molecules that profoundly influence human mood and behavior, and this global effect poses significant challenges when trying to develop targeted therapeutic options for inflammatory conditions and stress-related disorders. 

While drug developers investigate synthetic FAAH-inhibitors (such as URB597) and MAGL-inhibitors (such as JZL 184), one need look no further than the kitchen spice rack for phytonutrients that regulate endocannabinoid tone by inhibiting the same catabolic enzymes. Nutmeg, one of many culinary spices that interact with the endocannabinoid system, inhibits the breakdown of both anandamide and 2AG, the brain’s own marijuana.

10. Endocannabinoid reuptake inhibitors

Another way to augment endocannabinoid tone entails delaying the reuptake of anandamide and 2AG. Scientists have synthesized reuptake inhibitors (such as AM404) that target transport molecules known as fatty acid binding proteins. These membrane-penetrating fatty acid binding proteins facilitate the intracellular transport and reuptake of endogenous cannabinoids.

By blocking access to these critical transport molecules, synthetic reuptake inhibitors increase endocannabinoid levels in the brain’s synapses. This results in heightened cannabinoid receptor signaling and endocannabinoid-induced protective effects.

THC and CBD also inhibit endocannabinoid reuptake. Enhancing endocannabinoid tone via reuptake inhibition may be a key mechanism whereby plant cannabinoids confer protective effects against seizures and neurodegeneration, as well as many other health benefits.

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Fool’s Gold?

Despite repeated setbacks, the possibility of healing without the high persists as an idée fixe among cannabinoid scientists and pharmaceutical researchers.

The lack of success thus far with CB1 antagonists, peripherally restricted CB1 agonists, allosteric modulators, selective CB2 agonists, and other non-euphoric cannabinoids underscores the challenges and limitations of synthetic, monomolecular medicine that targets a single protein receptor and treats it like an on/off switch, while forsaking whole plant synergies.

Synthetic CBD analogs are also in development. By tweaking the mother molecule and removing, adding or editing a molecular side chain, pharmaceutical researchers hope to create a marketable compound that is more potent and more selective than botanical CBD.

But a CBD isolate is not inherently superior to a whole plant CBD-rich extract. Preclinical studies that compare the efficacy of single-molecule CBD and full spectrum CBD-rich oil concentrates indicate that CBD solo is effective only at precise, high doses – whereas whole plant CBD-rich extracts have a much wider and safer therapeutic window and are effective at significantly lower doses. Problematic drug interactions are also much likelier with high dose single-molecule CBD.

Regulatory policy should not privilege single-molecule meds over full spectrum cannabis remedies. Patients are best served by having access to a wide range of cannabinoid-based therapeutic options, including artisanal whole plant preparations and synthetic isolates, if and when they become available.

Martin A. Lee is the director of Project CBD. He’s authored and edited several books, including Smoke Signals, Acid Dreams, and The Essential Guide to CBD. © Copyright, Project CBD. May not be reprinted without permission.

Footnotes

  1. Only four cannabis compounds bind directly to either one or both cannabinoid receptors. THC activates CB1 and CB2. Cannabinol (CBN), a THC breakdown component, activates the CB1 receptor, though with less potency than THC. Tetrahydracannabivarin (THCV), the propyl variant of THC, binds to both cannabinoid receptors, activating CB2 while blocking CB1. And beta caryophyllene, an aromatic terpene found in many cannabis strains, green leafy vegetables, and common kitchen spices, activates CB2. Other cannabinoids, including CBD, interact with the endocannabinoid system indirectly without binding like lock and key to a cannabinoid receptor.
  2. Developed as a research tool to study that endocannabinoid system, JWH-018 is a synthetic cannabinoid compound that activates the CB1 receptor but not CB2. After the formula for this potent CB1 agonist was published in the scientific literature, JWH-018 surfaced as a street drug known as “Spice” or “K2.” Media accounts typically mischaracterize Spice as “synthetic marijuana.”
  3. U.S. government scientists have not given up entirely on Rimonabant. The fact that this compound blocks the euphoric effects of cannabis is a big plus to the National Institute on Drug Abuse, which has sponsored research on utilizing CB1 blockers to treat various addictions, including “cannabis dependence.”
  4. Canadian scientists have identified CBD as a “negative allosteric modulator” of the CB1 receptor based on in vitro research. This means that CBD, when administered in combination with THC, will alter the shape of the CB1 receptor in a way that weakens its binding affinity for THC. As a negative allosteric modulator of CB1, CBD lowers the ceiling on THC’s psychoactivity, which might be why people don’t feel as high when using CBD-rich cannabis as compared to a THC-infused product.

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