BOSTON—Stacy Gruber of Harvard Medical School laid out the numbers: 28 states and the District of Columbia have medical marijuana laws, 17 others allow some cannabis-based products, and eight states now allow recreational use. The US has turned into a grand experiment on the medicinal use of pot, even as the federal government's classification of the drug makes it extremely difficult to do good research on it.

But that doesn't mean research isn't getting done. Gruber and two other researchers described what they're learning about medicinal marijuana at the meeting of the American Association for the Advancement of Science. “This is the direction we’re headed," Gruber said, "and it’s good to be prepared.”

Canadian vigilance

Mark Ware of McGill University had a term for one way of tracking the effect of pot use: pharmacovigilance. Harmful side effects of drugs like acetaminophen and Vioxx weren't caught during clinical trials. Instead, they were identified by tracking the use of these drugs once they became available to the general population. This regular monitoring of drug users is what he called pharmacovigilance. It's the same process that has made us aware of the widespread abuse of prescription opioids.

So far, indications are positive. Cannabis users are reporting lower use of other drugs, such as selective serotonin reuptake inhibitors (SSRIs) and other antidepressants. There's also a drop in pain prescriptions in states allowing medical use. That in turn has led to a 25 percent drop in opioid mortality in these states compared to those where medical use remains prohibited. While the data is correlative, it's certainly suggestive of significant changes following the legalization of medical use.

Canada, Ware suggested, is also a great place to do pharmacovigilance for marijuana. It has a federally regulated medical use program, handled by 38 licensed producers. These producers offer 160 distinct strains in various forms, making it possible (if difficult) to identify the major components of what patients are taking. So he's involved in two Canadian studies that plan to do careful pharmacovigilance.

Ware also described a couple of in-progress studies that plan to build on this sort of approach. In one, chronic pain clinics enrolled patients, both pot users and controls, for a one-year follow-up study that tracks adverse events. Ware's team has also been training doctors in the Quebec area to enroll patients in a long-term tracking study; they're currently at 1,000 of their planned 3,000.

South of the border

Ryan Vandrey of Johns Hopkins was doing something similar here in the US thanks to cooperation with the Realm of Caring (RoC) registry. The research cohort that Hopkins and RoC have set up includes people in all 50 states, ranging in age from one to 86. People using cannabis products for cancers, autoimmune problems, behavioral issues, neural and psychological problems, pain, and autoimmune disorders are all represented.

One thing that's clear: cannabis is not the first drug of choice for many of these people. That idea shows up in both raw numbers—35 percent say it's a drug of last resort—and in many other statistics. Patients in the cohort are using an average of three other prescriptions and two over-the-counter medications. And only a quarter of the people in the registry had a history of prior cannabis use, which is about half the national average.

As for the products they're using, well... Vandrey said that only 17 percent of the products they've tested are accurately labeled. A quarter had more drug than promised, and a few didn't appear to have any active ingredients. The median dose was 55mg—which Vandrey called "a hefty dose"—but it ranged up to over 1,200mg.

Given the chaos in the products on the market, the Johns Hopkins group has turned to the federal government, obtaining a supply of marijuana in order to test its behavior once ingested. The pot was ingested through a single method (passive exposure, vaporized, ingested, or smoked), and the participants then provided blood and urine samples over the following hours and provided self-assessments of their mental and physical states. Vandrey showed a hilarious image of a dozen people in sterile gowns and caps in a room filled with the smoke emanating from the six who were allowed to smoke as much pot as they wanted.

The work showed that passive ingestion does show up in the blood (enough to fail a blood test), but the effects are minor. 10mg doses are also relatively weak; dosages didn't start showing effects that were consistently stronger than placebo until 25mg. Both smoking and vaporizing showed a similar effect, with a quick spike in drug levels in the blood followed by a fairly rapid decline; the spike was larger when a vaporizer was used. Ingesting cannabis didn't show any sort of spike, but ingesting helps maintain a long-lasting presence of the drug in the bloodstream. This finding is important, because it can allow us to tailor the route of intake to whether the event is sudden-onset or a chronic problem.

Side effects were about what you'd expect: some vomiting and a few panic and anxiety issues.

Your brain on drugs

Ultimately, however, researchers want evidence that marijuana is actually treating something, which is where Stacy Gruber's talk came in. A recent review of medical uses suggested that there was substantial evidence that marijuana is effective against chronic pain, chemotherapy side effects, and some symptoms of multiple sclerosis. There's limited evidence for it helping lots of other issues, but these studies need a lot more work. Gruber is leading efforts to try to close the evidence gap through the MIND program: marijuana investigations for neuroscientific discovery.

She described an observational study of people who are already using medical marijuana. Samples of their drug are sent to labs for analysis, and her group follows their neurological state, using a baseline performed prior to treatment. At this point, 33 participants have completed their first three-month follow-up, which consists of surveys, a battery of tests, and some MRI scans.

Most of the results aren't significant at three months of use, but some stand out. To begin with, opioid use is down by 43 percent, consistent with some of the population-level measures. Users also report improvements in pain management, social function, and fatigue, though self-reported measures always have to be viewed with caution.

The big results, however, come in tests of executive function—the ability of our more detailed thought processes to override our gut reactions. Things like the ability to quickly pick out the word "green" even when it's displayed in red lettering. Here, many tests show significant improvements; the remainder are all statistically insignificant. There are no drops. This is about the exact opposite of what you'd expect from marijuana use, but Gruber reminded the audience that many of these patients are in chronic pain, which we know detracts from executive function. Successfully treating the pain has the potential to restore more careful thought.

Strikingly, the effects were backed up by a functional MRI study that looked at brain activity in areas known to be involved with executive control. Healthy controls showed a strong response in those brain regions while taking executive function tests, a response that was absent in the patients during the baseline study. Three months later, activity in those areas looked indistinguishable from those of controls.

It's important to note that this doesn't mean that cannabis is improving people's mental acuity. But it does hint that the drug may be effectively treating a condition that would otherwise rob us of it. And in these early days of the US' grand cannabis experiment, that sort of detailed information is hard to come by.