We know less about marijuana than we think — here are the biggest mysteries researchers are trying to solve

Kevin Loria

• Marijuana is easier to access than ever, with more than 20% of Americans living in a state that has voted to legalize recreational use — and a majority living in states that have legalized medical use.
• But when you talk to researchers who study cannabis, they say there's still a lot we don't know about marijuana.
• There are a few big studies happening right now that should for the first time offer some answers to essential questions.

In many ways, it's the age of access to pot.

As of last November, more than 20% of Americans live in states that have voted to legalize recreational marijuana use. A majority live in states that allow access to medical marijuana.

In Colorado, cannabis aficionados can attend $125 per person dinners, where multiple varieties of weed are paired with chef-prepared gourmet meals. In New York — a state with a relatively strict medical marijuana law — 98-year-olds like Ruth Brunn rely on cannabis oil to soothe the debilitating pains of neuropathy. Weed's more legally accessible now than it has been since the "Reefer Madness" era of the 1930s; the varieties available now, created with the aid of modern botany and chemistry, are unparalleled in history.

With that in mind you might think that scientific researchers would have a pretty good handle on exactly how regular or casual marijuana use affects humans, how medical marijuana should be best used, and what potential risks there may be to cannabis use.

But if you thought that the recent warming towards marijuana is fully backed by scientific understanding, you might be surprised.

"There are so many basic questions that need to be addressed," says Ryan Vandrey, an associate professor of psychiatry who researches marijuana at Johns Hopkins Medicine. "The practical use and legalization of these things is happening faster than the science can keep up."

Vandrey and a number of other experts interviewed by Business Insider say that even though we know far more about marijuana than we did just a few decades ago, there are important topics — ranging from questions about how marijuana affects the brains of different users to questions about how to make use of medical cannabis — where the legal policy has far outpaced the science. It's not about being anti- or pro-marijuana, it's simply that scientists want to know more — especially now, when it's such an important topic because of the wave of legalization.

The Drug Enforcement Agency (DEA) considers marijuana a drug with no medical value, so it's hard to get approval to research it and impossible to study the cannabis products most people use, since researchers can only give study participants cannabis grown at DEA-approved facilities. "It's pretty amazing" that we have so many unanswered questions, says Staci Gruber, an associate professor of psychiatry at Harvard Medical School and director of the Marijuana Investigations for Neuroscientific Discovery program at McLean Hospital. "It ain't new, it's been around for thousands and thousands of years, it's not like we just made this in a lab." 

Many of the most common inquiries fit into three categories: questions about how recreational marijuana will affect users both young and old; questions about how medical marijuana affects patients; and questions about the marijuana plant itself.

And while marijuana is still distressingly hard to research, there are a number of ongoing studies that should help answer some of the most pressing questions.

Here's what we're learning from that research and what we still need to know.

A sacred plant, a casual vice, a risky drug, or a powerful medicine — what's in the plant?

The cannabis plant itself is a fascinating organism, one that humanity has used for thousands of years for reasons ranging from religious rituals to performance enhancement to just plain partying.

But within that plant there are somewhere around 400 chemical compounds, more than 60 of which are special compounds known as cannabinoids. These bond with a relatively recently discovered system in our brain that interacts with naturally-produced cannabinoids. In every animal, these natural (endogenous) cannabinoids play multiple roles, affecting mood, appetite, memory, consciousness, pain response, blood pressure, and more. The cannabinoids from marijuana tap into that same system, which is why the plant has such wide-ranging effects.

We're pretty far from fully understanding how that system works and even further from understanding all the compounds in marijuana.

 
Theo Stroomer/Getty
Common and uncommon cannabinoids
The most famous cannabinoid, THC, is largely responsible for marijuana's ability to get users high.

Cannabidiol, CBD, is the next best known — it seems to be important for many medical uses of marijuana. In one of the studies that Gruber's team is working on at the Marijuana Investigations for Neuroscientific Discovery (MIND) center at McLean Hospital in Massachusetts, researchers are testing to see if CBD can help reduce anxiety. It also plays a role in pain relief and several of the other known medical uses of marijuana.

But those are still just two components of the plant.

"We know a lot about THC and we're starting to learn about CBD," says Vandrey. "Out of about 400 [compounds] we know a decent amount about two."

That means there's a lot to learn about which compounds might contribute to psychoactive effects and which might potentially have medical uses.

Special strains and changing potency
Further complicating this question is the fact that growers create numerous strains of cannabis with different characteristics. We see this most frequently now with high THC strains of marijuana.

The data on this isn't perfect, but it is true you can get stronger pot now than ever before, largely because of innovations in growing practices. About 20 years ago, a high THC concentration might have been 10 or 12%. In legal shops in Colorado and Washington now, it's not hard to find concentrations of 18, 24, or even 30% THC.

Every tweak is going to change the health effects of the plant. High THC plants tend to have low CBD, for example, according to Krista Lisdahl, an associate professor of psychology and director of the Brain Imaging and Neuropsychology Lab at the University of Wisconsin at Milwaukee.

In general, THC potency keeps going up. Lisdahl says this could be worrisome, since there is some research indicating that some of the brain changes seen in heavy marijuana smokers are not present in smokers who smoke higher CBD, lower THC strains. This could make the trend away from CBD a negative for some medical users.

Gruber wonders what will happen when THC concentration "goes up to 40,50, 60%." People consume THC at those levels in some concentrated forms of cannabis, but we don't know if that sort of consumption carries additional health risks or not. On the one hand, high potency stuff may be worse for cognition, but on the other, Gruber says she's had people tell her they smoke less when they use more concentrated products.

"We should probably be doing a better job of understanding what the effects are," she says.

Common knowledge isn't backed up by science
Even much of what we think we know isn't really backed up with scientific evidence. It's commonly understood that cannabis can be broadly divided into indica and sativa strains, with indica providing more of the mellowing, body-high (theoretically better for relaxation) and sativa providing a more energizing, creative high — and then there are hybrids of the two.

But there are no scientific studies that prove this, making it hard for recreational smokers to know exactly what they're getting and what effect it'll have. Experienced users might find nothing to worry about here, but as weed becomes more accessible, these are some of the sorts of questions it's hard not to have an answer to. When we buy booze, the differences between a session beer, high ABV double IPA, and bottle of Scotch are all clearly defined.

This complicates using cannabis in a medical context.

 
Ayrn Taylor, a United Food and Commercial Workers union (UFCW) member and employee at the Venice Beach Care Center, displays medical marijuana during a media visit at the medical marijuana dispensary in Los Angeles. REUTERS/Jonathan Alcorn
 
When it comes to marijuana, "millions of people are using different types of cannabis products for supposedly therapeutic purposes," says Vandrey. Different, strains, different concentrations, all consumed in different ways. At Johns Hopkins, Vandrey is studying the how different ways of consuming marijuana — orally, smoking, vaping — all affect the body. And while he says that not all of his work can be talked about yet, we do know that the mode of ingestion makes a big difference for how people feel the effects and how they manifest themselves.

Who sets the standards?
Many substances might fall under the medical cannabis umbrella, but depending on their specific cannabinoid content and the means through which they are ingested, they're going to have different effects. All those people using products for therapeutic purposes are "lacking information about which types of products to choose, what doses to use, and how cannabis compares to other medications," according to Vandrey.

We do know that marijuana has legitimate medical uses — a recent report by the National Academies of Science, Engineering, and Medicine (NASEM) found a number of ways in which marijuana seems to be medically effective. But the report also noted that a lot more information about how marijuana and its various components affect users is needed.

At present, that's hard to study. The marijuana that researchers can give people for experiments has to come from approved facilities and tends to be far weaker than what people actually use. A researcher in Colorado can walk into a store and buy marijuana but they can't get approval to give that product to participants in a study.

Partially because of that, it's even hard to measure what's in these products. There's no one approved system for testing cannabis products, so people running two different tests on marijuana samples might get different results. Those results might vary even more if they use a test meant for conventional marijuana (flower) on an edible. For those who really want to better understand the plant and to see how to use it most effectively to help people in a medical context, that's a real problem.

"[One] thing that's absolutely critical is the development of standards around product manufacturing and labeling," says Vandrey.

Some states have started to require that marijuana products be tested for potency and to make sure they are free of contaminants — Colorado has rules that recreational and medical products be tested and Washington started to require testing after approving recreational marijuana, for example.

However, it's not clear that a fully accurate means of testing cannabis products exists yet. One analysis of 75 medical marijuana products purchased in Los Angeles, San Francisco, and Seattle found that only 17% were accurately labeled. Some sort of national standard might require devising more accurate tests.

 
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How is using medical marijuana going to affect patients?

The unknowns about what various cannabinoids do and how they interact with each other create plenty of questions about the best ways to use medical marijuana.

But that doesn't mean we know nothing. The aforementioned NASEM report did find that cannabis (both regular marijuana and various products derived from it) can effectively treat chronic pain along with other conditions, with pain being the reason most people seek it out. Researchers have good reasons to think that in states where people switch from opioids to marijuana to manage pain, overdose and addiction rates are dropping. Even though there's much to be learned about what sort of cannabis best treats what condition, there are reasons to think it's effective.

"You have to kind of respect the fact that there seem to be people who have very serious health problems and have found positive effects from the use of cannabis," says Vandrey. "It's up to us to try to figure out how and why and to develop very specific targeted therapeutics based on what we can find out."

But how is using medical marijuana regularly — especially to treat something like chronic pain, which may have no known cause and therefore no known end — going to affect the people using it?

The effects of a daily medical toke
We don't have definitive answers yet, but Gruber's MIND program in Massachusetts is doing a lot to figure that out. The early data is both surprising and encouraging.

In one of their studies at McLean Hospital, Gruber and colleagues are following a group of medical marijuana users over time (longer than a year) to see how their health changes. By checking in on those users every couple months, they'll see if the product is helping them, and they'll also see how using marijuana is affecting the patients' sleep, cognitive ability, and quality of life. Additionally, they're tracking brain activity to see if any changes occur over time.

"I think this large scale observational study is the first of its kind and will really serve the public," Gruber says.

It's only with studies like this that track people over time that we really see what sort of effects the drug is having on patients' lives. And since this particular study is so thorough and focused on patients that are older than the participants in many other studies, it tells us more about how marijuana affects adults, especially adults using for a medical reason — we have lots of data on young users but little data on users like this, with an average age of about 48 or 49.

She stresses that it's really early to draw conclusions from this ongoing work. But one of the first studies to come out of this particular project had an encouraging finding. Their preliminary results showed that three months into their medical marijuana treatment, a group of users (24 people, still relatively small) showed significant improvement in tests of cognitive function. Tests of heavy recreational smokers in the past have shown worse cognitive function. This was the opposite.

The imaging data they've seen so far also showed some interesting changes in brain activity. For patients like this, many of whom struggle with pain, previous brain scans showed abnormal blood flow when doing cognitive tasks. After a few months of medical marijuana, that mental activity started to look like the activity in a healthy control population.

In a way, this isn't surprising. If your mind is no longer struggling with constant pain or anxiety, cognitive tests might become easier. But that had never been demonstrated before, which just shows how much we have to learn about the effects of medical cannabis use.

 
Diners smoke marijuana as they eat dishes prepared by chefs during an evening of pairings of fine food and craft marijuana strains served to invited guests dining at Planet Bluegrass, an outdoor venue in Lyons, Colo. Chefs and pot growers trying to explore fine dining with weed face a legal gauntlet to make pot dinners a reality, even where the drug is legal. Brennan Linsley/AP

What about recreational users?

Recreational pot is still harder to come by than medical marijuana — the current political administration has implied that laws legalizing it may be at risk.

So how much do we know about the recreational use of marijuana and what are the big questions?
"We have no shortage of data from chronic, heavy users," says Gruber. But we know far less about occasional smokers, she says.

When we look at the "effects" of recreational marijuana, it's important to consider the context. It's one thing to compare marijuana to hard drugs like opioids or to substances like alcohol. Some research so far indicates that marijuana is "safer" in many ways than these substances (people don't overdose and even though marijuana can be habit forming it doesn't seem to be as habit-forming as alcohol).
That doesn't mean it's harmless.

In studies of those chronic, heavy users, "we see marijuana users have slower processing speed, worse memory and learning scores on certain tests, poorer sustained attention," says Lisdahl. There are also links to depression and sleep problems in some of those users, and some heavy users show brain changes linked to poorer emotional control or memory. These changes have been particularly observed in people who began using marijuana before ages 16 or 17.

That's not something unique to cannabis; many substances may harm the developing brain. When it comes to adolescent use, Lisdahl says that alcohol seems to be particularly bad, but that there are still some unique brain changes associated with marijuana use.

We still don't know, however, whether marijuana causes those changes or whether certain people (with certain brains) are more likely to use marijuana in the first place.

What it looks like when kids first start trying pot
One research effort that Lisdahl is involved in right now could help change uncover some of these mysteries. The ABCD Study is "extremely exciting, not just for marijuana — there are hundreds of things we can look at," she says.

ABCD is a research effort that will follow 10,000 kids around the country — starting when they are 9 or 10 years old— for 10 years. It's coordinated out of UCSD and there are 21 different sites around the country.

 
AP
For this study, researchers will analyze the schools kids are enrolled in, look at where they live, track images of their brains, see how much they exercise and sleep, and more. They'll track everything from stress to puberty hormones to substance use. They'll also see them before and after they begin experimenting with any substances, including marijuana, alcohol, nicotine, and other drugs.

"It's the first of its kind worldwide of this scope and depth," says Lisdahl. Following kids over a long period of time is probably the best way to understand when and why they start using a substance, according to Gruber.

When it comes to recreational substance use, we know a lot about alcohol — that it affects sleep, cognition, domestic violence likelihood, and other things. Researchers want to know answers to those questions about marijuana, too. From what we can tell, adult use seems to be less associated with brain changes, though that doesn't mean there are no cognitive effects.
 
Even if it turns out that marijuana causes the negative effects on young brains that researchers think it may, that doesn't mean prohibiting it completely was the most effective policy in the US (it certainly didn't stop it from being available).

Legalization doesn't necessarily increase usage rates for kids based on what we've seen so far. Kids in Colorado and Washington aren't using more after legalization, though Lisdahl says that since those states already had the highest rates of youth usage, they don't tell us whether or not, say,  kids in Indiana will start smoking more pot if it's legalized there. Education may help keep those youth usage rates down.

No matter what, these next few years of observing states with legal marijuana — and of researchers following thousands of kids — will tell us a lot.

Scratching the surface

These ongoing studies will help answer some of the most pressing questions, but it's going to take some time. It'll be 10 years (or longer) before the ABCD study really starts to reveal how participants' lives have changed over time. And even then, many of the questions asked in the study are only scratching the surface.

For instance, a lot of baby boomers have started smoking pot regularly since it was legalized — or started smoking again — and we don't know much about the effects that might have. It's important to learn how safe marijuana is for pregnant women. There are connections between marijuana use, low birth weight, and time spent in the NICU for infants, so we certainly can't say it's safe, even if some women are already using it to control nausea.

Several of the researchers I spoke with say we need to know more about how marijuana affects what's probably the most common user — the "casual" user who doesn't smoke every day or even every week, but just every so often.

None of this is meant to demonize cannabis or to call it a miracle plant — it's just another substance out there, one that humans have used for a long time, one that can be used in ways with negative, positive, and neutral effects.

As Gruber explains it, "We're not really after the good or the bad — we're after the truth."