The debate over medical marijuana seems to have gotten louder since the drug’s use was approved in 20 states and the District of Columbia. Still, marijuana has been used medicinally for more than 3,000 years…and today, many people recognize it as a legitimate therapy for pain, nausea, appetite loss, glaucoma, multiple sclerosis and seizure disorders.
But: Marijuana also can cause memory problems and impair cognitive function. For instance, research shows that marijuana diminishes the ability to discriminate time intervals and space distances and interferes with the performance of mental tasks. Effects are not only short-term (immediately after using the marijuana), but also may persist long-term—reducing marijuana’s medicinal usefulness and hindering its acceptance.
Now, a surprising discovery in a laboratory may point to an antidote—a way to preserve marijuana’s medicinal benefits while reducing its unwanted cognitive side effects. The solution suggested by the new research, while not perfect, is simple and inexpensive, involving something you probably already have in your medicine cabinet—the common pain reliever ibuprofen (Motrin, Advil).
MARIJUANA MECHANISM REVEALED
Marijuana’s most potent psychoactive ingredient is delta-9-tetrahydrocannabinol (commonly known as THC). Drugs based on THC are FDA-approved to treat nausea and pain for cancer patients, but the cognitive and memory impairments that come along with them can be so difficult to bear that the treatment isn’t used as much as it otherwise would be. There has been no effective FDA-approved treatment for these side effects because scientists haven’t understood the molecular pathways responsible for the impaired learning and memory deficits.
Researchers think they have now figured it out. Using mice injected with THC, researchers learned that THC increases the levels of an enzyme called cyclooxygenase-2 (COX-2) in the hippocampus, a brain region involved in learning and memory. The more THC the mice received, the more their COX-2 levels rose. They also found evidence that repeated exposure to THC led to persistently elevated levels of COX-2.
Water test: The researchers wondered whether they could prevent THC-induced cognitive impairment by inhibiting COX-2 production—so they put mice’s memories to the test. First, mice were placed in a water maze and trained to quickly find a hidden platform that allowed them to escape the water (mice do not like water). After the training, some of the mice were given just THC…others were given THC and a COX-2 inhibitor drug…and still others were not given any medications at all. Then these mice were again placed in the water maze to test their learning and memory.
Results: The mice that received just THC spent a long time looking for the hidden platform, indicating memory impairment—because they couldn’t remember the escape route they had learned previously. (And it wasn’t just that the mice were temporarily too intoxicated to perform the task, because the test was repeated numerous times, including after a long enough interval that the drug’s intoxicating effects would have faded.) In contrast, the mice that received THC plus the COX-2 inhibitor did remember the location of the platform and were able to escape the maze quickly…as quickly, in fact, as the mice who weren’t given any THC at all! In other words, with COX-2 inhibited, memory was no longer negatively affected by THC.
DENDRITIC SPINE DAMAGE
In another test, the researchers examined the dendritic spines in the brains of the mice. Dendritic spines are the parts of the neurons (nerve cells) where the synapses responsible for receiving and transmitting messages are located. Synapses and dendritic spines are plastic (capable of continuous alteration) and highly susceptible to the environment, and they can lose length and density when under stress—as they do after repeated THC exposure. Until now, though, scientists didn’t know that it was elevated COX-2 levels that were responsible for that damage.
How did they figure this out? They looked at the dendritic spines of two groups of mice receiving THC. One group included normal mice, and the other included mice that had been specially bred without COX-2 receptors. The specially bred mice did not lose dendritic spine density despite receiving THC.
Next, the researchers gave all of the normal mice THC, and some of them also received the COX-2 inhibitor. In the mice that received both medications, synaptic plasticity and dendritic spine density were virtually unchanged. The mice that received only THC, though, showed significant reductions in synaptic plasticity and spine density.
Questions remain: This study did not investigate whether inhibiting COX-2 would also inhibit marijuana’s beneficial effects, so the researchers can’t say if it does or not. But they did confirm that another important benefit of THC—its ability to reduce the beta amyloid protein deposits and neuronal degeneration associated with Alzheimer’s disease—persists even when COX-2 is inhibited.
COX-2 may sound familiar to you, and that’s because it’s also known for being responsible for pain and inflammation in humans. Many drugs are currently available to inhibit the action of COX-2, including over-the-counter ibuprofen and the prescription drug celecoxib (Celebrex). However, COX-2 inhibitors can have side effects, including abdominal pain, headache, internal bleeding, blurred vision, ringing in the ears, increased blood pressure and a risk for kidney failure—so they certainly are not risk-free.
Bottom line: Of course, it’s too early to say whether inhibiting COX-2 would have the same beneficial effects on human THC users as it does on mice. However, if you are using or considering trying medical marijuana or a pharmaceutical THC drug, it can’t hurt to show this article to your doctor. Even if he/she doesn’t know much about this research, your doctor should be able to help you weigh the potential benefits and risks of trying a COX-2 inhibitor as a means of reducing the cognitive downsides of THC therapy.