Marijuana-like Drugs without the Side Effects

Pain Management, November 2010, Volume 3, Issue 7

Researchers are studying a compound that can treat and prevent neuropathic pain, potentially addressing a significant unmet pain management need for several patient populations without the adverse effects of marijuana.

Researchers are studying a compound that can treat and prevent neuropathic pain, potentially addressing a significant unmet pain management need for several patient populations without the adverse effects of marijuana.

Marijuana’s anti-inflammatory properties have been touted as a possible cure for everything from Crohn’s disease to Tourette syndrome. But the negative side effects, including impaired perception, diminished short-term memory, loss of concentration and coordination, and hallucinations, suggest that it’s far from being a perfect drug. Based on recent findings on CB2 receptors—one of two cannabinoid receptors in the body—new drugs capable of delivering the anti-inflammatory properties of marijuana without the negative side effects may one day become a real option.

For six years, Mohamed Attala Naguib, MD, and colleagues have been researching potential targets for CB2 receptors in treating neuropathic pain. MDNG: Pain Management spoke with Naguib, a faculty member in the general anesthesiology department at the Cleveland Clinic in Ohio, about his research efforts.

What sparked your interest in this area of research?

I have a working hypothesis regarding neuropathic pain and neuroinflammation. For years, there were many conflicting views about the origin of neuropathic pain and how to treat it. Putting the pieces together from the last decade, I was able to create a working hypothesis, which helped me better understand the role of cannabinoid receptors in modulating neuropathic pain and other neuroinflammatory conditions.

What is your hypothesis regarding CB2 agonists and the inflammatory process?

As you know, there are at least two cannabinoid receptors in the body: Cannabinoid 1 (CB1) and Cannabinoid 2 (CB2). CB1 was discovered and cloned first from the central nervous system (CNS) in 1990, and it mediates the effect of marijuana. CB2 was discovered and cloned in 1993 from the peripheral immune cells; normally, you don’t see CB2 expressed in the CNS unless there’s some form of insult or neuroinflammatory condition in the CNS. CB2 expression helps to modulate the neuroinflammatory processes and prevent it. My working hypothesis is that stimulating CB2 receptors with an endogenous CB2-agonist will shut down the inflammatory process and facilitate recovery.

What are some of the key findings of the study (Pharmacological Characterization of a Novel Cannabinoid Ligand, MDA19, for Treatment of Neuropathic Pain; that focused

on MDA19? Is that compound one of your chief targets?

MDA19 is one compound among over 100 compounds that we discovered and patented at the University of Texas MD Anderson Cancer Center. MDA19 is not really our lead compound; our lead compound is called MDA7, which is highly selective for the CB2-receptor. This is important because CB2 agonists are not known to have any psychoactive effects. We have conducted animal studies with MDA7 showing that we can both treat and prevent neuropathy. MDA19 has some CB1 activity in vitro, but not for in vivo testing.

What are the clinical implications of this research?

It can be useful because millions of diabetic, shingles, and cancer patients suffer from neuropathy. If we are right, CB2 agonists could prevent neuropathy without the addictive psychoactivity side effects of marijuana or other CB1 active compounds.

Were there any surprising results or unexpected difficulties during the studies?

With the MDA19 studies there was no problem, but it was intriguing to find, initially, different responses of MDA19 in different in vitro assays. We had to confirm the data many times until we were sure that it wasn’t technical error, and to reveal that MDA19 was a protean agonist. Depending on the cell context, a protean agonist ligand can be an agonist, neutral antagonist, or inverse agonist at the same receptor type. In different in vitro assays, it can behave as an agonist, or antagonist, or without any activity.

Were there any goals that weren’t met?

No. Actually, the whole process was interesting and challenging, especially trying to confirm the data we were getting from different assays. We were happy with the results.

What else did you find about MDA7?

MDA7 is our lead compound. We have some data published in the literature about this molecule. It’s a highly selective CB2 agonist that exhibits no CB1 agonistic activity. We have done some toxicity work, and so far, the drug does not appear to have any major toxicity. So, the goal is to proceed with this compound to applicable studies required by the FDA to move the drug toward clinical studies. We have shown that MDA7 can be used to do more than treat neuropathic pain; we went beyond that and we asked the question, “Can we actually prevent the development of neuropathic pain by using MDA7?” Prevention of peripheral neuropathy is a huge unmet need for patients, especially for those receiving chemotherapy, where neuropathy is a key dose-limiting toxicity. It’s been shown in different studies that in patients with cancer, increasing the dosage of paclitaxel can result in a better outcome. But some patients develop severe neuropathies even within the classic drug schedule, and they cannot continue with the treatment. What we have shown is that we can prevent the development of paclitaxel-induced neuropathy in the animal model. We looked at the molecular mechanism and the data is going to be submitted to a major journal for publication.

And part of the reason why you focused on CB2 receptors is because with these receptors you don’t have the motor effects that are associated with CB1?

Not only this, CB2 has no CNS psychoactivity, catalepsy, or decreased motor coordination, which are good points. Actually, CB2 receptors are involved in the modulation of central neuroinflammation, and this was the reason.

What is the likelihood that a drug based on these CB2 agonists may hit the market within the next five years?

With proper funding, an approval in 5-6 years is possible. For me, it’s a matter of securing funds for further development: pre-clinical, Phase I and Phase II, etc. But, I’m very optimistic that CB2 agonists will have a major effect on central neuroinflammatory conditions, such as peripheral neuropathy, Alzheimer’s, and multiple sclerosis.

Have you seen any complications so far with CB2 agonists?

We have given the drug to animals repeatedly, daily, for weeks, and we have not seen any negative effects. That said, like any other chemical entity, when we conduct FDA required toxicological studies, we may find something.