Pubdate: Mon, 25 May 2015
Source: Time Magazine (US)
Copyright: 2015 Time Inc
Contact:  http://www.time.com/time/magazine
Details: http://www.mapinc.org/media/451
Authors: Bruce Barcott and Michael Scherer
Note: Barcott is a journalist who has contributed to the New York 
Times, National Geographic and other publications. Scherer is TIME's 
Washington bureau chief.

THE GREAT POT EXPERIMENT

Yasmin Hurd raises rats on the Upper East Side of Manhattan that will 
blow your mind.

Though they look normal, their lives are anything but, and not just 
because of the pricey real estate they call home on the 10th floor of 
a research building near Mount Sinai Hospital. For skeptics of the 
movement to legalize marijuana, the rodents are canaries in the 
drug-policy coal mine. For defenders of legalization, they are 
curiosities. But no one doubts that something is happening in the 
creatures' trippy little brains.

In one experiment, Hurd's rats spent their adolescence getting high, 
on regular doses of tetrahydrocannabinol (THC), the psychoactive 
compound in marijuana.

In the past, scientists have found that rats exposed to THC in their 
youth will show changes in their brain in adulthood. But Hurd asked a 
different question: Could parental marijuana exposure pass on changes 
to the next generation, even to offspring who had never been exposed 
to the drug?

So she mated her rats, but only after she had waited a month to make 
sure the drug was no longer in their system.

She raised the offspring, along with another group of rats that 
shared the same life experiences except for the THC. She then trained 
the children to play a game alone in a box. The prize: heroin.

Press one lever to get a shot of saline into the jugular vein. Press 
the other to get a rush of opiates.

Initially, the rats with THC-exposed parents performed about the same 
as the rats with sober parents. But when Hurd's team changed the 
rules, requiring the rats to work harder for the drug, differences emerged.

The rats with drug-using parents pushed the lever more than twice as 
much. They wanted the heroin more.

When she analyzed the brains of the rats, she also found differences 
in the neural circuitry of the ones with drug-using parents.

Even the grandkids have begun to show behavioral differences in how 
they seek out rewards. "This data tells us we are passing on more 
things that happen during our lifetimes to our kids and grandkids," 
Hurd explains, though it remains unclear how those changes manifest 
in humans. "I wasn't expecting these results, and it's fascinating."

Welcome to the encouraging, troubling and strangely divided frontier 
of marijuana science.

The most common illicit drug on the planet and one of the 
fastest-growing industries in America, pot remains surprisingly 
something of a medical mystery, thanks in part to decades of 
obstruction and misinformation by the federal government. Potentially 
groundbreaking studies on the drug's healing powers are being done to 
find treatments for conditions like epilepsy, posttraumatic stress 
disorder (PTSD), Alzheimer's disease, Parkinson's disease, 
sickle-cell disease and multiple sclerosis.

But there are also new discoveries about the drug's impact on 
recreational users.

The effects are generally less severe than those of tobacco and 
alcohol, which together cause more than 560,000 American deaths 
annually. Unlike booze, marijuana isn't a neurotoxin, and unlike 
cigarettes, it has an uncertain connection to lung cancer.

Unlike heroin, pot brings almost no risk of sudden death without a 
secondary factor like a car crash.

But science has also found clear indications that in addition to 
short-term effects on cognition, pot can change developing brains, 
possibly affecting mental abilities and dispositions, especially for 
certain populations. The same drug that seems relatively harmless in 
moderation for adults appears to be risky for people under age 21, 
whose brains are still developing. "It has a whole host of effects on 
learning and cognition that other drugs don't have," says Jodi 
Gilman, a Harvard Medical School researcher who has been studying the 
brains of human marijuana users. "It looks like the earlier you 
start, the bigger the effects."

Beyond Reefer Madness

That relatively measured tone is a far cry from the shrill warnings 
of Harry J. Anslinger, the first commissioner of the Federal Bureau 
of Narcotics, who in the 1930s set the standard for America's fraught 
debate over marijuana with wild exaggerations. "How many murders, 
suicides, robberies, criminal assaults, holdups, burglaries and deeds 
of maniacal insanity it causes each year, especially among the young, 
can only be conjectured," he wrote as part of a campaign to terrify 
the country.

As recently as the 1970s, President Richard Nixon talked about the 
drug as a weapon of the nation's enemies. "That's why the communists 
and the left-wingers are pushing the stuff," he was recorded saying 
in private. "They're trying to destroy us."

The official line today is better grounded in data and research.

And the new focus is squarely on brain development. "I am most 
concerned about possibly harming the potential of our young people," 
says Dr. Nora Volkow, the head of the National Institute for Drug 
Abuse (NIDA), which funds Hurd's and Gilman's work. "That could be 
disastrous for our country."

But decades of prohibition and official misinformation continue to 
shape public views. "The government did not spend as much effort in 
finding out the facts about marijuana," says Hurd. "That strategy of 
scaring people rather than provide knowledge has made people 
skeptical now when they hear anything negative."

As states now rush to legalize pot and unwind a massive 
criminalization effort, the federal government is trying to play 
catch-up on the science, with mixed success.

The only federal marijuana farm, at the University of Mississippi, 
has recently expanded production with a $69 million grant in March, 
and Volkow has expressed a new openness to studies of marijuana's 
healing potential. In the coming months, Uncle Sam will begin a 
10-year, $300 million study with thousands of adolescents to track 
the harm that marijuana, alcohol and other drugs do to the developing brain.

High-tech imaging will allow researchers for the first time to map 
the effects of marijuana on the brain as humans age.

But scientists and others point out that a shift to fund the real 
science of pot still has a long way to go. The legacy of the war on 
drugs haunts the medical establishment, and federal rules still put 
onerous restrictions on the labs around the country that seek to work 
with marijuana, which remains classified among the most dangerous and 
least valuable drugs. "We can do studies on cocaine and morphine 
without a problem, because they are Schedule II," explains Fair 
Vassoler, a researcher at Tufts University who has replicated Hurd's 
rat experiment with synthetic pot. "But marijuana is Schedule I."

That means that under the law, marijuana has "no medical benefit," 
even though 23 states have legalized pot as medicine and NIDA 
acknowledges that "recent animal studies have shown that marijuana 
can kill certain cancer cells and reduce the size of others." And 
marijuana researchers face barriers even higher than those faced by 
scientists studying other Schedule I drugs, like heroin and LSD. Pot 
studies must pass intensive review by the U.S. Public Health Service, 
a process that has delayed and thwarted much research for more than 15 years.

The result is sometimes a catch-22 for scientists seeking to 
understand the drug. "The government's research restrictions are so 
severe that it's difficult to find and show the medical benefit," 
says neurobiologist R. Douglas Fields, the chief of the 
nervous-system-development section at the National Institutes of Health (NIH).

That all may change soon. On Capitol Hill, a left-right coalition of 
Senators Kirsten Gillibrand of New York, Rand Paul of Kentucky and 
Cory Booker of New Jersey introduced a bill in March to federally 
legalize medical marijuana in states that have already approved it. 
"For far too long," said Paul, a Republican candidate for President, 
"the government has enforced unnecessary laws that have restricted 
the ability of the medical community to determine the medicinal value 
of marijuana."

The Cannabinoid System

Harm researchers and neuroscientists aren't completely deadlocked. 
They agree on at least one thing.

Marijuana's positive and negative effects both spring from the same 
source: the body's endocannabinoid system. First discovered in the 
late 1990s, it's a complex neural system that researchers are only 
beginning to fully comprehend.

A little Brain Science 101: Human gray matter contains around 86 
billion neurons, a type of cell that essentially talks to other cells 
in the brain through electrochemical processes.

Neurons talk to each other through chemical messengers known as 
neurotransmitters including dopamine, serotonin, glutamate and 
compounds called endocannabinoids which in turn send instructions to 
your body about what to do.

Researchers now know the body produces endocannabinoids, which 
activate cannabinoid receptors in the brain.

Interestingly, one plant on earth produces a similar compound that 
hits those same receptors: marijuana. Just as poppy-derived morphine 
mimics endorphins, marijuana-derived cannabinoids like THC and 
cannabidiol (CBD) mimic endocannabinoids, which impact feelings of 
hunger and pleasure. Cannabinoid receptors are especially widespread 
in the brain, where they play a key role in regulating the actions of 
other neurotransmitters.

"The more we investigate the hidden recesses of the brain, the more 
it seems like practically every neuron either releases 
endocannabinoids or can sense them using cannabinoid receptors," 
explains Gregory Gerdeman, a neuroscientist and endocannabinoid 
researcher at Florida's Eckerd College. Neurotransmitters carry out 
brain communication through synapses. "But too much synaptic 
excitation is poisonous it damages cells," says Gerdeman. 
"Endocannabinoids are a mechanism for putting on the brakes when that 
toxic level of excitation is approached."

Cannabinoids like CBD may be thought of as neuroprotectants that is, 
brain protectors. In fact, the NIH actually owns a patent (No. 
6630507) on cannabinoids as neuroprotectants, based on the work of 
researcher Aiden Hampson and his mentor, Nobel Prize winning 
neuroscientist Julius Axelrod. They found that CBD showed particular 
promise in limiting neurological damage in patients with Alzheimer's 
disease and Parkinson's disease and in those who have suffered a 
stroke or head trauma.

Endocannabinoids also play a role in the regulation of pain, mood, 
appetite, memory and even the life and death of individual cells. 
Curiously, cannabinoid receptors aren't densely packed in the medulla 
(within the brain stem), which controls breathing and the 
cardiovascular system.

That's why a heroin overdose can be fatal the drug shuts down the 
respiratory control center but a marijuana overdose generally can't. 
PTSD researchers are keen to crack the cannabinoid code because the 
compounds appear to play a role in extinguishing unpleasant memories. 
"Part of what happens with PTSD is that the brain's stress buffers 
have been blown out by trauma," says Gerdeman. "Endocannabinoids 
within the amygdala" the brain region important for emotional 
learning and memory "act as a key mechanism for what we call memory 
extinction."

But what accounts for the potentially healing effects of pot in some 
can cause harm in others.

That's because endocannabinoids appear to play a critical role in the 
development of the adolescent brain.

If the brain were a house, the childhood years would be spent pouring 
the foundation and framing up the walls.

Adolescence is when the wiring and plumbing get finished.

Neural networks are refined and strengthened through pruning.

The strong synapses, axons and dendrites are preserved, the weak culled.

Researchers now believe the cannabinoid system plays a critical role 
in this neural fine-tuning. This is where the worries about teenage 
pot use come to the fore. At the precise moment when the brain relies 
on a finely calibrated dose of endocannabinoids, the adolescent weed 
smoker floods the system. "If you actively and repeatedly overload 
the endogenous cannabinoid system," says Volkow, "you are going to 
disrupt that very well-orchestrated system."

That disruption may lie at the heart of still inconclusive science 
about marijuana's impact on human behavior, especially among younger 
users. Early studies suggest that there may be long-lasting impacts 
on mental acuity, higher brain function and impulse control for younger users.

There is also a well-documented connection between pot smoking and 
schizophrenia, a condition that affects about 1% of the U.S. 
population. Scientists have been aware of the link since the 1970s. 
Among those with a family history of mental illness, marijuana can 
hasten the emergence of schizophrenia.

Researchers are trying to identify the mechanisms in play. "Many 
genes are undoubtedly involved in risk for schizophrenia," says Dr. 
Michael Compton, a professor at Hofstra North Shore LIJ School of 
Medicine and the head of psychiatry at New York City's Lenox Hill 
Hospital. "But there are also a host of social or environmental 
influences at work." For a subset of the population, the earlier the 
initiation of marijuana use, the earlier the onset of psychosis.

Here's why that matters: The later schizophrenia emerges, the greater 
the likelihood of recovery.

Schizophrenia onset in a 15-year-old is often permanently 
life-altering. In a 24-year-old, it can be less damaging, because the 
person has had the chance to accomplish more psychological and 
social-developmental milestones. But that doesn't mean all teenage 
pot users are smoking themselves into mental illness. Darold 
Treffert, the Wisconsin psychiatrist who first documented the 
marijuana-schizophrenia link in the 1970s, puts it this way: "Perhaps 
some persons can safely use marijuana, but schizophrenics cannot." A 
test or a clear genetic marker to identify kids who are vulnerable to 
schizophrenia is likely years away.

The Healing Possibilities

While American research on the potential harms from marijuana is 
booming, the U.S. continues to lag in funding investigations into the 
possible benefits.

In the late 1990s, the U.S. and British governments commissioned 
separate studies of medical marijuana.

The U.K. study was spurred by multiple-sclerosis patients' using pot 
to calm spasticity. The U.S. study, done by the Institute of 
Medicine, was in response to California's 1996 legalization of 
medical marijuana.

Both studies reached a similar conclusion: medical pot wasn't a 
hippie's delusion.

The research showed that the stuff held real therapeutic potential 
for specific conditions, including epilepsy, chronic pain and glaucoma.

The British responded by treating marijuana as a plant with biotech prospects.

U.K. officials licensed GW Pharmaceuticals, a startup lab in 
Salisbury, England, to grow weed and develop cannabinoid drugs, some 
of which U.S. scientists like Hurd use in their research.

The Americans, meanwhile, doubled down on the war on drugs.

Barry McCaffrey, Bill Clinton's drug czar, was outraged at the 
Institute of Medicine's results. "I think what the IOM report said is 
that smoked marijuana is harmful, particularly for those with chronic 
conditions," he said pretty much the opposite of the report's 
conclusions. Nonetheless, he and then Attorney General Janet Reno 
vowed to prosecute medical-marijuana patients and doctors who 
prescribed the drug. Shortly thereafter, the U.S. Department of 
Health and Human Services adopted even tougher strictures against the 
study of marijuana as a medicine.

The federal antipot policies resulted in a strange kind of scientific 
trade deficit.

The U.S. leads the world in studies of marijuana's harm, but we're 
net importers of data dealing with its healing potential. THC 
discoverer Raphael Mechoulam runs the world's leading cannabinoid lab 
at the Hebrew University of Jerusalem. Spanish biologist Manuel 
Guzman is doing cutting-edge work on the potential of cannabinoids to 
retard the growth of glioblastoma, one of the deadliest forms of brain cancer.

Canada's health agency may soon approve the world's first clinical 
trial to test medical marijuana on military and police veterans with PTSD.

There are signs of change at home, though.

This year, the Colorado department of public health awarded $9 
million in grants for medical-marijuana research, funded with tax 
revenue from state-licensed pot stores.

They will be among the first U.S. clinical trials to look into the 
effectiveness of marijuana for childhood epilepsy, irritable-bowel 
disease, cancer pain, PTSD and Parkinson's disease. Dr. Kelly Knupp, 
a pediatric-epilepsy specialist at Children's Hospital in Denver, 
will track children using high-CBD marijuana strains to calm 
seizures. "Some of these children can have 100 to 200 seizures a 
day," Knupp says. "We're hoping we can measure seizure frequency to 
see if there's any improvement" among kids trying the cannabinoid medicine.

This Is a Rat on Drugs

Back at Hurd's Upper East Side lab, the rats have begun to show the 
way. In a separate experiment, she gave heroin-addicted rats doses of 
CBD and found that it decreased their willingness to work hard for 
more heroin, suggesting that parts of marijuana could help human drug 
addicts stay clean.

She is now testing that hypothesis by giving CBD tablets, made in 
England, to recovering human addicts in New York City.

She is also continuing to study the behavior of rats whose only 
exposure to marijuana's active ingredients came through the DNA 
passed on to them from their parents or grandparents. That research 
suggests that THC may have epigenetic effects, which have been found 
in other drugs like cocaine and heroin, changing the way genes 
express themselves in the brains of offspring.

This doesn't necessarily mean that parents who smoked weed in high 
school have damaged their kids, because those changes may be overrun 
by other behaviors. The science is too new to know for sure. "It's 
not a given that this is going to happen," Hurd explains of her rats. 
"They tell us the potential."

That word potential still qualifies much of what is known about pot, 
but it won't be that way for long. The science of pot is likely to 
expand in the coming years, and it could boom if federal restrictions 
are lifted.

What the government once dismissed as a communist plot that prompted 
murderous rages has turned out to be a window into the very workings 
of the human mind. In the years to come, researchers may yet find 
genetic markers that predispose people to pot-induced psychotic 
reactions, map out the specific ways in which THC changes the brain 
and find new medicines for some of the most intractable illnesses. 
Until then, the great marijuana experiment will continue in a country 
where 1 in 10 adults and 35% of high school seniors admit to 
conducting their own, mostly recreational, research.

Portions of this article were adapted from Barcott's new book "Weed 
the People, the Future of Legal Marijuana in America," from TIME 
Books, is now available wherever books are sold, including 
Amazon.com, Barnes & Noble and Indiebound.
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MAP posted-by: Jay Bergstrom