Cannabis Mimicking Molecule Helps with THC Withdrawal and Stomach Bleeding

Researchers are continuously searching for novel molecules that mimic the benefits of cannabis but lack its psychoactive effects. A new study published in The Journal Pharmacology, Biochemistry, and Behavior shows that one such molecule can both dampen the effects of THC withdrawal and help protect again NSAID-induced stomach bleeding.

Cannabis: Therapeutic Benefits Come With Side Effects

Humans have valued the cannabis plant for thousands of years. That’s because cannabis is well-known for its powerful ability to fight against inflammation, nausea, and pain–among other ailments. But in the past century, many governments have placed legal restrictions on its cultivation and use, even for the purposes of research. Researchers and health care providers also have ethical concerns about the potential substance abuse among cannabis users. As a result, researchers have turned their focus away from cannabis itself and towards the endocannabinoid system.

What is the Endocannabinoid System?

The endocannabinoid system is a biological system present throughout our bodies, including our brains and immune system. It’s made up of different neurotransmitters, called endocannabinoids, and receptors. The endocannabinoid system regulates a wide variety of processes, including mood, memory, appetite, pain, and immune response. By learning more about the endocannabinoid system, researchers hope to harness the therapeutic benefits of cannabis without worrying about legal restrictions or unwanted side effects, like intoxication and dependence. The primary cannabinoid receptors are CB1 and CB2. When a person ingests cannabis, tetrahydrocannabinol (THC), the primary psychoactive cannabinoid in cannabis, enters the bloodstream. Once it reaches the brain and the rest of the body, THC binds to CB1 and CB2 receptors. This unique interaction between THC and cannabinoid receptors creates many of the side effects, including the “high,” that people associate with cannabis. Our bodies also produce our own cannabinoids. Here are two examples:


Often referred to as the “bliss molecule,” researchers believe anandamide contributes to runner’s high.

2-arachidonoyl glycerol (2-AG)

Present in high levels in the nervous system, 2-AG helps to modulate the wide-reaching endocannabinoid system throughout the body.

Harnessing the Power of the Endocannabinoid System in the Lab

Researchers are currently working to create custom, synthetic cannabinoids in the lab. The idea is that these synthetic molecules will share some of the desirable effects, like anti-inflammation and pain reduction, without the psychoactive and sedative properties of cannabis. One class of synthetic molecules is called CB1 positive allosteric modulators (PAMs). These molecules have special properties—they can bind to secondary site on the CB1 receptor and increase the effects of the primary CB1-binding cannabinoids like THC or 2-AG. Researchers have identified a synthetic CB1 PAM that looks promising. It’s called ZCZ011. This impressive little molecule can reduce pain in mice without the psychoactive effects of cannabis.

The New Study

Naturally, researchers wanted to learn more about ZCZ011. In a recently published study, researchers from West Virginia University explored the effects of ZCZ011 on THC withdrawal and stomach protection from nonsteroidal anti-inflammatory drugs (NSAIDs, similar to Aspirin or Tylenol).

THC Withdrawal

Repeated exposure of the cannabinoid receptors to THC can lead to withdrawal symptoms. In mice, these symptoms include tremors in the paws and twitching of the head. To test the effects of ZCZ011 on THC withdrawal, researchers administered high doses of THC to mice for six days. To induce withdrawal, the researchers stopped administering THC after the sixth day and evaluated behavioral changes in the mice.


The mice showed typical withdrawal symptoms, including paw tremors and head twitches. But when researchers gave the mice ZCZ011, the mice experienced fewer symptoms. They were worried that ZCZ011 was simply sedating the mice and making them move less. But when they tested ZCZ011 by itself, it had no effect on the ability of the mice to move around their cages.

Cannabis and Stomach Protection

Cannabis has an impressive ability to protect against stomach ulcers and bleeding. To test whether ZCZ011 also has gastroprotective effects of, the researchers gave mice high doses of an NSAID.


The high dose of the NSAID induced stomach bleeding in the mice. The researchers found that, by itself, ZCZ011 didn’t have an effect on the stomach bleeding. But ZCZ011 did prevent stomach bleeding when combined with another molecule, JZL184. Researchers previously showed that JZL184 increases the levels of the cannabinoid 2-AG and blocks NSAID-induced stomach bleeding. The researchers gave the mice a very small dose of JZL184—so small that it has no effect on its own. But when combined with ZCZ011, the combination reduced stomach bleeding in the mice.

Implications of the New Research

Previous studies showed that ZCZ011 can reduce inflammation and pain in mice. This new study showed that ZCZ011 has more to offer—it can reduce symptoms of THC withdrawal and NSAID-induced stomach bleeding. More people seek treatment for cannabis use disorder (CUD) than any other illicit drug. CUD can be especially damaging to teens. Unlike many other drugs, there are no approved pharmaceuticals to help treat CUD. ZCZ011 offers a possible treatment option that lacks psychoactive and sedative effects for those suffering from CUD. While ZCZ011 doesn’t provide protection from stomach bleeding on its own, the combined protective effects of ZCZ011and JZL184 could help researchers better understand the mechanisms that control ulcer formation and stomach bleeding.

Closing Thoughts

CB1 positive allosteric modulators (PAMs) like ZCZ011 offer a new approach for harnessing the therapeutic power of the endocannabinoid system. Without the psychoactive and sedative effects of cannabis, ZCZ011 represents a promosing new therapy for the treatment of cannabis use disorder and stomach inflammation.

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