By David N. Leff

Along with embryonic stem cell research, smoking marijuana to relieve pain is a hot political topic. Some states have sought to legalize medicinal marijuana, but U.S. law forbids it.

¿What with all the toxins in the smoke, and the other chemicals,¿ observed behavioral pharmacologist Aron Lichtman, ¿I don¿t think marijuana would ever be approved by the FDA. There are a lot of carcinogens in the smoke, and other compounds that would have to be tested. Oral THC [tetrahydrocannabinol, marijuana¿s active ingredient] is legally available,¿ Lichtman pointed out. ¿It¿s approved by the FDA as an anti-emetic to relieve the nausea and vomiting of cancer chemotherapy; also for AIDS patients with the wasting syndrome that increases their appetite.

¿But patients don¿t like it in that oral form,¿ he continued. ¿They have to take pretty high doses, which are hard to titrate. Most patients don¿t want to be that intoxicated. And all of a sudden feeling nauseous again, and having to take another pill.

¿Also, oral THC has a very long onset of action,¿ Lichtman pointed out. ¿It takes from one to two hours for peak effects. With smoking, patients can get the central nervous system effects within five or 10 minutes.¿ Lichtman is an associate professor of pharmacology and toxicology at Virginia Commonwealth University in Richmond.

¿We¿re working on some other rational approaches to this medicine,¿ he continued. ¿Just as patients don¿t smoke opium for pain relief, people have taken the active opiates ¿ morphine or codeine ¿ out of them. You can take these extracts in pill form or by injection, the same as with THC. The challenge really is finding an appropriate route of administration for oral THC. Another possibility we¿re working on is inhalation ¿ through a nebulizer or a metered-dose inhaler. The pure aerosol would go to the same brain pathway as smoking. So if we already know what the active chemical is, we could use that same amount of administration but without the smoke.¿

Lichtman is senior author of a paper electronically released today in the Proceedings of the National Academy of Sciences (PNAS), dated July 31, 2001. Its title: ¿Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase.¿ The article¿s co-senior author is biochemist and molecular biologist Benjamin Cravatt, at the Scripps Research Institute in La Jolla, Calif.

Whole New Class Of Pain-Killing Drugs¿

¿First, as a very general implication for this work,¿ Lichtman told BioWorld Today, ¿since we were able to knock out the enzyme that breaks down anandamide, and thereby increased anandamide levels, we were able to show ¿ in mice ¿ that there¿s a function to this endocannabinoid system that appears to modulate different pain sensitivities. This offers a possibility, instead of targeting cannabinoid receptors, that this enzyme could be targeted instead. So it opens up a whole new class of drugs that would be useful in pain control, among other potential applications ¿ instead of general cannabinoid-based therapies.¿

Anandamide, he explained, is a short-lived substance synthesized in the mammalian brain. It can mimic the behavioral effects produced by marijuana¿s active ingredient. The enzyme that cuts off anandamide¿s short life of five minutes or less is fatty acid amide hydrolase ¿ FAAH for short.

¿What these mice allowed us to do,¿ Lichtman went on, ¿was to see whether this FAAH enzyme is indeed primarily responsible for the degradation of anandamide. Sure enough, our in vivo experiments really showed that FAAH is the major enzyme responsible. So mice with their FAAH genes knocked out, while looking pretty much normal, gave full-blown cannabinoid responses to anandamide, whereas the wild type, the ones that still synthesize the enzyme, were unaffected by anandamide.¿

The co-authors compared how both the FAAH-minus and wild-type FAAH-plus mouse strains tolerated pain of moderate, graduated intensity. They did so first by dipping the tips of the animals¿ tails into hot water, and counting the time it took the mice to pull them free. Second, they placed the animals onto an electric hot plate and measured how long before they licked or shook a limb. Third, they injected formalin, an irritant liquid, under the paw pads of one leg and gauged their tolerance of that painful insult.

In addition, the team tested catalepsy and rectal temperature ¿ two other physiological factors that correlate with cannabis behavior. For catalepsy, a form of mindless, catatonic rigidity, they scored how long a mouse could keep its front paws on a narrow rod. And body temperature duly dropped 8 degrees, as expected.

¿Then we also looked at the cannabinoid antagonist, SR141716A, in relation to the hot-plate test,¿ Lichtman recounted, ¿and found that the elevated latencies [time to withdraw] showed that analgesia ¿ pain relief ¿ was blocked by the antagonist.¿

From Brief Ouch To Chronic Sciatica

As for eventual application to human patients, he observed, ¿At this point, anandamide by itself would be rapidly broken down, so would be therapeutically useful for a very short time. One more practical way to go,¿ he added, ¿could be giving individuals a very specific enzyme inhibitor for FAAH. The other way would be administering these FAAH enzyme inhibitors in conjunction with anandamide.¿

So far, their mouse model has measured only acute, brief pain. ¿One of the things that Dr. Cravatt and I want to look at next,¿ Lichtman said, ¿is long-term chronic pain, for which cannabinoids seem pretty effective as well. One such model,¿ he went on, ¿is chronic, constrictive ligation of the sciatic nerve around one afflicted hind limb. It could show some sciatica, and more hypersensitivity to pain than in the acute mechanical or heat tests. We¿ll be doing this in the next six months or so.¿

¿This model system,¿ Cravatt told BioWorld Today, ¿does suggest that FAAH might be clinically a more selective way of upregulating cannabinoid activity in models for pain than just injecting THC or smoking marijuana. You might get pain relief without the cognitive or locomotor side effects that come with more global activation of the cannabinoid system. That requires a lot of work yet,¿ he concluded, ¿but I think it is one of the more provocative results coming out of this work.¿

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