Science is still hazy as legal pot looms
As Ottawa readies legislation, researchers say there are gaps in understanding its effect on brain
After punching a string of numbers into a bolted-down, fireproof, alarm-protected safe — the location of which can’t be divulged for security reasons — Steven Laviolette pulls out a tiny vial. Inside that vial is an even tinier dab of dark tar. The tar is purified THC, the mind-altering compound in marijuana.
The street price for a gram of weed is about $10. A gram of this stuff costs about $2,000, not counting the cost of the researcher’s time acquiring it. Laviolette, a professor in the departments of anatomy and cell biology and psychiatry at Western University’s Schulich School of Medicine and Dentistry, studies the effects of marijuana on the brain. His lab is investigating the troubling brain changes associated with THC, and also — a rapidly growing avenue of research — the very different and perhaps protective brain changes associated with cannabidiol, or CBD, another compound found in the plant.
This week the government of Canada is expected to unveil legislation legalizing marijuana. As the country hurtles toward the end of nearly a century of prohibition on recreational pot, researchers say there are major gaps in our understanding of the drug.
Both the scientists who study its potential therapeutic effects and those who research its risks have been frustrated by the barriers they must leap to generate knowledge that fills those gaps — evidence that should be informing policy.
Researchers who want to access marijuana for experiments must apply for an exemption from Health Canada for each individual compound from the plant they hope to study, of which there are hundreds — including those that have no known intoxicating effects, like CBD.
If approved, they must navigate the opaque and expensive world of acquiring these compounds. And even though legalization seems certain to boost what is already one of the world’s highest national marijuana usage rates, scientists say there is not enough funding to study how the drug impacts health, behaviour and the brain — especially teenage brains.
“Now is when we need to be doing this research, and the money is just not there,” Laviolette said. “If we’re going to be the only North American country that has full legalization, there’s no reason that we shouldn’t become global leaders.”
The members of Canada’s small cannabis research community, many of whom have been collaborating in recent months to set a national research agenda, will be scrutinizing the new legislation.
“Really, science has been stuck for the past 80 or 90 years or so, unable to do many of these tests,” said M-J Milloy, a professor in the Department of Medicine at the University of British Columbia and a research scientist at the B.C. Centre on Substance Use, who studies the effects of cannabis use among people living with HIV/AIDS.
“Hopefully when it is legalized many of those barriers will fall away.”
Cannabis is a complex plant. It contains more than 100 chemical compounds, known as cannabinoids. The most well-studied of these is THC, the “psychoactive” one: it gives users the feeling of being high. CBD is another actively investigated cannabinoid, though less well understood. Cannabis also contains hundreds of other compounds belonging to several other chemical families, like terpenes, the oils that give various varieties of weed — and other plants — different aromas. Both THC and CBD have therapeutic effects. But the list of symptoms for which there is solid evidence that marijuana helps is very short.
In an exhaustive report published in January by the U.S. National Academies of Sciences, Engineering, and Medicine, cannabis and compounds derived from it were deemed an effective therapy backed by “conclusive or substantial evidence” for only three problems: chronic pain in adults, chemotherapy-induced nausea and spasticity in multiple sclerosis.
The list of therapies for which there was limited, insufficient or no evidence is much longer and includes Tourette’s syndrome, traumatic brain injury, epilepsy and ALS.
“I think at the end of the day everyone agrees that the best medical care is based in evidence. And unfortunately we just don’t have enough for many conditions to guide us,” Milloy said.
As a researcher working with patients who have HIV, Milloy has good reason to sympathize with those who turn to cannabis for relief regardless of what the research says. The medical marijuana movement was spurred in the 1990s by AIDS patients who had little else in the way of effective, tolerable treatments.
Patients in similar positions today are frustrated. Doctors are frustrated, too.
Lack of evidence “was the dominant theme of our discussions with the medical community,” reported the Task Force on Cannabis Legal- ization and Regulation, the group mandated to consult widely and offer advice to the Canadian government. Physicians object to being the access point for medical marijuana when they have scant information on its risks, benefits, proper dosages or possible interactions with other drugs, information they would have for any other prescription drug. The Canadian Medical Association (CMA), because of the lack of scientific evidence, does not support the use of marijuana in clinical settings.
Patients, doctors and advocacy groups disagree on key issues related to medical marijuana. But “there is consensus on the need for more research,” the task force found. The CMA agrees, saying it will “continue to urge that Health Canada support development of rigorous research on the effects, both positive and adverse.”
“Unfortunately, cannabis has developed a bit of a reputation as a panacea in some groups,” Milloy said. “We need to really test cannabis, develop good medical evidence, so people know whether or not this hope and optimism is warranted.”
Medical marijuana may help individuals. But recreational use of the drug could have population-wide health benefits, too, if users replace other more dangerous drugs with cannabis.
A curious theme emerges when interviewing scientists who study marijuana. At a certain point, some of them want to know when the media will finally address the overwhelming public-health burden of alcohol.
The World Health Organization ranks alcohol use as the third leading risk factor globally in lost healthy years, ahead of tobacco. According to the Centre for Addiction and Mental Health (CAMH), alcohol-related problems, from health care to law enforcement, cost Ontario $5 billion a year.
As alcohol supplies a steady current of sickness and mayhem, prescription opioids have been a skyrocketing source of overdoses and deaths.
How many binge drinkers might replace alcohol with safe amounts of recreational weed if it was legal? How many sufferers of chronic pain might choose marijuana instead of highly addictive opioids?
In Colorado and Washington, the two U.S. states that voted to legalize marijuana in 2012, researchers have been tracking these types of questions. The Canadian Centre on Substance Abuse (CCSA), an agency that was created by Parliament to synthesize evidence and inform policy, led delegations to both states in 2015.
There are some hints from states where medical marijuana is legal that suggest patients are choosing cannabis over opioids. The full picture is not clear. But in general, in Colorado and Washington, the CCSA delegation found that those trying to answer basic questions about the impacts of legalization were frustrated because they lacked data from before the changes were made for comparison. Both states devoted a portion of marijuana sales to research — money that didn’t start flowing until after sales began.
“The major take-home message there, for Canada: make sure that you not only invest in research on an ongoing basis, but invest proactively in collecting baseline data,” said Rebecca Jesseman, Senior Policy Advisor for the CCSA.
Positive health outcomes like opioid replacement aren’t the only changes researchers will be tracking.
“The obvious thing in Canada would be to monitor for things like hospital admissions for psychosis and schizophrenia,” said Robin Murray, a professor of psychiatric research at King’s College London.
Cannabis is very safe in the patterns most adults use it. But there is a broad, mistaken perception that the drug is harmless. Marijuana affects cognitive skills including memory. It increases the risk of psychosis. Eight or 9 per cent of all users will develop a dependence in their lifetime.
But most troubling of all is the large body of evidence linking adolescent THC exposure to the risk of developing schizophrenia — a risk that increases the earlier in life the drug is tried, the more heavily it is used and the more potent the pot. The nature of that link, however, is deeply convoluted. From before the teenage years until the mid to late 20s, the human brain undergoes major remodelling: synapses are pruned, other neuronal connections are formed. This is especially true of the prefron- tal cortex, which contains a high density of cannabinoid receptors, and which is particularly implicated in schizophrenia.
In his laboratory at Western, Laviolette is trying to figure out whether and how cannabis might hijack adolescent brain development.
In one experiment, he studied a group of rats that were either 30 or 60 days old when they arrived at the lab. Thirty days, Laviolette explains, “is roughly the rat equivalent of when all those big changes are happening in the brain that correspond to what’s happening in the teenage brain,” while 60 days marks full maturity. Half of the rats from both age groups were treated with escalating doses of THC. The other half received a sham treatment.
People with schizophrenia suffer from disturbances in social functioning and heightened anxiety, among other symptoms. A month after treatment, Laviolette’s lab ran the animals through tests validated for rat-equivalent functions: hanging out with familiar and unfamiliar rats, exploring open areas or travelling from relaxing dark boxes to stressful light-filled ones.
The rats that had been exposed to THC as adolescents were significantly less socially motivated than their sober peers, spent much more time in the dark and explored their surroundings less. But the rats that had been treated with THC as adults didn’t exhibit the same disturbed behaviour. In most tasks, the adult rats who had been exposed to THC acted the same as those who hadn’t been.
Laviolette was shocked when he examined the adolescent rats’ brains, looking for a particular molecule called GSK-3. In humans with schizophrenia, this molecule is significantly “down-regulated:” it appears less, linked to a hyperactive dopamine system. In the THC-treated rats, GSK-3 was almost absent, their dopamine systems in overdrive.
“These results made our jaws drop,” Laviolette said, for how closely they mimicked schizophrenia.
He added that animal testing can only take us so far. “We would never say a rat has schizophrenia — it’s a human disease.”
But “we’re in a weird situation where we’re about to legalize a drug and we have no idea what the downstream molecular signalling pathways are: what it’s doing in the brain.”
Understanding the basic neurobiology of cannabis has policy implications. It could help lawmakers set a safe age limit for legal marijuana or identify biomarkers for those most at risk. It could help establish maximum THC and minimum CBD content. Other research has found that CBD may modulate the effects of THC, and that it may function as an antipsychotic treatment. Laviolette is also studying the mechanisms behind this: his research has shown that CBD produces the opposite molecular changes to THC, increasing GSK-3 and decreasing dopamine hyperactivity.
Ruth Ross, a professor at the University of Toronto’s pharmacology and toxicology department, studies the mechanisms of CBD too. While we know what receptors in the brain THC acts on, we don’t understand all of CBD’s targets. But we do know that THC content has been rising in recreational weed, while CBD drops.
“If you make the statement that cannabis is safe, you’re then asking, well, what’s safe? Is it a 50/50 combination of THC and CBD? Or high THC? And who is it safe for?” Ross said. “People are constantly asking me questions, and they want a definitive answer. We just can’t give a definitive answer, even on age.”
Ross says more support is needed for this research. “Targeted funding would be incredibly helpful, but of course research takes time. We’re not going to have these answers instantly.”
The Canadian Institutes of Health Research (CIHR) recently announced a one-year, $1-million “catalyst grant” to help researchers develop studies on the impact of legalization, noting many “evidence gaps” about the health effects of the drug and its behavioural, social and economic implications. The federal budget also directed $9.6 million of existing funds over five years for public education and public health surveillance.
Experts in the field described this as a positive step, though it doesn’t help neuroscientists or other lab researchers. Their complaints are shared widely in the health sciences, however: CIHR grant application success rates have been a source of consternation for researchers of all stripes in recent years. In 2016, just 13 per cent of all applications for the two major open grant types were successful.
A CIHR spokesperson said the $1 million in funding was called a catalyst grant because it is “an initial first step toward contributing to a future funding program to answer key questions about the health and social impact of the legalization.”
Aside from the financial constraints, there are practical barriers. In January, Laviolette spent two days reapplying for his research exemptions; Health Canada says there are about115 active exemptions related to cannabis. Milloy, who works with human subjects using what is still an illegal substance as a therapy, described the “substantial efforts to get the permissions required, both at the university and national levels, to do this kind of research.”
Other cannabis researchers lamented the time they spend sourcing cannabis from private suppliers. A Health Canada-supported portal could remove that difficulty and encourage consistency in the types of plants used in research, a problem plaguing the field that hampers the ability to draw conclusions from the research that does exist.
“The time people or their staff are taking to do these sorts of things is time they’re not doing science,” Milloy said. The departments tasked with drafting the new cannabis legislation can’t be oblivious to the calls for more research.
The government’s task force referenced the “shortcomings in our current knowledge base” and “appeals for ongoing research” on page 1 of its report.
The CCSA gathered nearly 50 experts to set a national research agenda for non-medical cannabis use, a document that concludes “Canada deserves rigorous and excellent research to inform the many health and public policy decisions before us.”
Cannabis researchers are watching to see if the government acts.
“It’s the waiting game,” Milloy said.
“We need to really test cannabis . . . so people know whether or not this hope and optimism is warranted.”
M-J MILLOY UNIVERSITY PROFESSOR AND RESEARCH SCIENTIST