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Cannabis Station

Newfound brain pathway may let epilepsy patients steer around medical marijuana’s nasty side effects

With medical marijuana now legal in 23 states plus our nation's capital, a lot of people are experimenting with the plant. Plenty are using it to cop a buzz, but many are using it for entirely medical purposes.

Now, in a study published in Neuron, Stanford neuroscientist Ivan Soltesz, PhD, and his colleagues may have shown a way to enhance marijuana's medical virtues by countering some of its troubling side effects.

First, as background: What makes a drug get you high? As I wrote almost two years ago,  every psychoactive drug works by mimicking some naturally occurring, brain-produced substance.

Tetrahydrocannabinol and cannabidiol, two major active components in cannabis (marijuana, hashish, etc.) are stand-ins for a set of molecules in the brain called endocannabinoids. It turns out the the twisting mass of fat-encased, signal-carrying electrochemical cables that is your brain is loaded with manufacturing sites and receptors for endocannabinoids. These substances play a huge role in fine-tuning the rhythmic pulsations that serve as metronomes for the workings of numerous brain circuits. Marked changes in oscillatory patterns in one or another of these circuits typify conditions ranging from autism, schizophrenia and depression to Parkinson's and Alzheimer's and ringing in the ears.

Soltesz has a particular interest in endocannabinoids' involvement in epilepsy, in which out-of-control nerve-cell firing in an aberrant circuit in the brain (its location varies from one individual to the next) triggers a seizure. "Many patients with epilepsy have repeated spontaneous seizures that can't be controlled with existing drug therapies," he told me. "There's rapidly growing interest in the potential for controlling such difficult-to-treat seizures through medical marijuana."

Almost a third of patients with epilepsy have a treatment-resistant form, which is associated with severe medical consequences and a higher mortality rate. All too often, this recalcitrant variety begins in early childhood.

"So, people are giving kids marijuana extracts to control their medically intractable epilepsy," says Soltesz. Although there have been positive anecdotal reports and hints of success in clinical trials, "nobody has any clue as to what this actually does to the kids' brains, short- or long-term, because the mechanism of action of cannabis-like molecules is not understood," he says.

No placebo-controlled, double-blind studies concerning the safety and efficacy of cannabis-based experimental therapies for epilepsy have yet been published. A recently reported open-label trial reported a more than one-third reduction in seizure frequencies among 162 patients with severe intractable, childhood-onset epilepsy. But four of every five patients suffered adverse advents, with some 30 percent suffering "severe" adverse events.

One thing is sure: Cannabis is not purely benign. While its association with mental illness (for example, schizophrenia) is still debated, its component active substances are known to saturate endocannabinoid receptors in an all-important part of the brain called the hippocampus, obliterating both working memory (the ability to keep several things in mind at once - i.e., walk and chew gum) and spatial memory (the ability to recall where you are or to get where you're trying to go).

In the Neuron study, Soltesz and his colleagues painstakingly mapped out a hitherto unexplored molecular pathway via which endocannabinoids mediate cannabis-related effects on normal brain functions including memory. And they showed that blocking this pathway could prevent the spatial- and working-memory deficits cannabis causes.

The discovery raises the possibility that medical marijuana, or a cannabinoid derived from it, could be given alongside another drug that, by specifically blocking only the memory-shredding endocannabinoid receptor action in the hippocampus, would eliminate at least part of cannabis-based epilepsy treatments' dark downside.

Previously: The reefer connection: Brain's "internal marijuana" signaling system implicated in very early stages of Alzheimer's pathology, Possible trigger for childhood seizures identified and The brain makes its own valium: Built-in seizure brake?
Photo by Jeffrey Beall

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