Pubdate: Sun, 09 Apr 2017
Source: Toronto Star (CN ON)
Copyright: 2017 The Toronto Star
Author: Kate Allen
Page: A1


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

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

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 Legalization
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

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

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

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 prefrontal 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

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

"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

"It's the waiting game," Milloy said.
- ---
MAP posted-by: Matt