The scientists who study marijuana’s potential risks and therapeutic benefits have been frustrated by the barriers they must leap to do work that’s needed now more than ever.
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 department of Anatomy and Cell
Biology and Psychiatry at Western University’s Schulich School of
Medicine & Dentistry, studies the effects of marijuana on the brain.
His lab is investigating both some of 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 of all stripes,
from neurobiologists to clinicians to epidemiologists, 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 a special 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,” says Laviolette. “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 past 80 or 90 years or so, unable to do many
of these tests,” says 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 over 100 different 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 different
varieties of weed — and conifers and citrus 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, anxiety
disorders, ALS and addictions.
“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,” says Milloy.
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 Legalization and
Regulation, the nine-member 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 their respective advocacy groups disagree on key issues
related to medical marijuana. But “there is consensus on the need for
more research aimed at understanding, validating and approving
cannabis-based medicine,” 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,” says Milloy. “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. One in four Canadian drinkers
engages in risky alcohol use, according to Statistics Canada, and the
rates are rising. According to the Centre for Addiction and Mental
Health (CAMH), alcohol-related problems, from health care to law
enforcement to lost productivity, 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, if the plant
was easier to obtain?
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,
in fact, choosing cannabis over opioids. The full picture is not yet
clear. But in general, in both states, the CCSA delegation found that
those trying to answer fundamental 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 legal
marijuana sales to research — money that didn’t start flowing until
after sales began, when it was too late.
“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,” says Rebecca Jesseman, Senior Policy Advisor
for the CCSA.
In Canada, “there are a lot
of potential data sources right now, but what we need is better
communication and co-ordination . . . to really pull together all the
diverse pieces into a comprehensive picture.”
Positive health outcomes like opioid replacement aren’t the only changes researchers will be tracking after legalization.
“The
obvious thing in Canada would be to monitor for things like hospital
admissions for psychosis and schizophrenia,” says Robin Murray, a
professor of psychiatric research at King’s College London.
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 prefrontal cortex, which contains a high
density of cannabinoid receptors, and which is particularly implicated
in schizophrenia.
In his laboratory at
Western University, with the little vials of purified THC, Laviolette is
trying to figure out whether and how cannabis might hijack adolescent
brain development.
In one experiment,
Laviolette 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 intriguingly, 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 most 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 says, for how closely they mimicked schizophrenia.
He adds 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. That was sort of our motivation, to really
get a grip on these pathways.”
Understanding
the basic neurobiology of cannabis has real policy implications. It
could help lawmakers set a safe age limit for legal marijuana
consumption or identify biomarkers for those most at risk.
It
could also help establish maximum THC and minimum CBD content. Other
research has found that CBD may modulate the effects of THC on the
brain, 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 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. We do know, however, 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?” says Ross. “People are constantly asking me
questions, and they want a definitive answer. We just can’t give a
definitive answer, even on age. We talk about cannabis in adolescents as
potentially dangerous, but how do we make that cut-off? Why do we say
18 or 25? Those are really important questions.”
Ross, like Laviolette and many others, 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 cannabis 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 researchers. Their complaints are shared widely
in the health sciences, however: CIHR grant application success rates
have been a huge 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 approximately 115 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 also 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,” says Milloy.
The departments tasked with drafting the new cannabis legislation can’t be oblivious to the calls for more research.
The
government’s legalization task force referenced the “shortcomings in
our current knowledge base around cannabis” and “appeals for ongoing
research and surveillance” on page one of its report.
The
CCSA gathered nearly 50 experts to set a national research agenda for
non-medical cannabis use, a document that concludes with the statement
that “Canada deserves rigorous and excellent research to inform the many
health and public policy decisions before us.”
The cannabis research community is watching to see if the government acts on those calls.
“It’s the waiting game,” says Milloy.
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