Vape Pens and Budder - Marijuana's Drift from Plant to Ultra-Potent Drug

Users of marijuana have long known and sometimes favored a marijuana extract called hashish (hash for short). It tends to be cleaner and more potent than the plant - the best marijuana buds are averaging 25-30% THC, while hash can be in the neighborhood of 45-55%. [1]

Apparently these already highly potent options are not enough (for reference, the best marijuana in the 1960s and 1970s averaged around 3-8% THC). New butane extraction methods are creating a drug that can be as high as 99% cannabinoids (of which 80-90% is THC), often known as budder.

"The top Budder sample was 99.6% pure," Dr Paul Hornby [a chemist and plant analyst] explained, "which means if you had an ounce of it, only a tiny fraction of a gram would be anything other than cannabinoids. We also tested Budder for toxins, solvents, molds, diseases, heavy metals and other contaminants. There were none. It's essentially just pure cannabinoids. I've tested a lot of cannabis materials, but this is the most impressive."

Hornby's tests also found Budder contains 80 to 90% of its cannabinoids as THC. It contains much smaller percentages of two other cannabinoids: cannabidiol and cannabinol. Of these two, cannabidiol (CBD) is most important because it has medicinal effects and moderates the stimulative effects of THC. [1]

This seems to create a drug with much higher chance of adverse effects. Cannabidiol (CBD), which has no psychotropic effects by itself [2], attenuates, or reduces [3] the higher anxiety levels caused by THC alone [4]. Consequently, the plant material used to create budder (or other extract forms, including the more mainstream use of "dab" with vape pens), will greatly impact the type of high the extract creates. Cannabis sativa has a much higher THC:CBD ration, and causes more of a "high, including the stimulation of hunger and a more energetic feeling. On the other hand, Cannabis indica has a higher CBD:THC ratio, producing more of a "stoned" or meditative feeling [5].

The mainstream media seems not to be aware of "budder" at this point, but the lower quality extracts (often produced at home by amateur chemists - two words which should never go together) are beginning to register with the media over the last year or two.

In December, 2013, The Daily Beast ran an article called "Hey Buddy, Wanna Dab? Inside The Mainstream Explosion of Cannabis Concentrates," which examined the rise of dab and the lack of purity in most street products (along with info on how to know if it's a clean product or not).

In March, 2014, Mother Jones ran a more in-depth article (produced below) on how these new extracts may impact legalization efforts around the country. Below that article is another from Slate, from February, 2014.

References

1. Brady, P. (5005, Jan 19). "Beautiful budder". Cannabis Culture Magazine.
2. Ahrens, J., Demir, R., Leuwer, M., et al. (2009). The nonpsychotropic cannabinoid cannabidiol modulates and directly activates alpha-1 and alpha-1-Beta glycine receptor function. Pharmacology 83 (4): 217–222. doi:10.1159/000201556. PMID 19204413.
3. Zuardi, A.W., Shirakawa, I., Finkelfarb, E., Karniol, I.G. (1982). Action of cannabidiol on the anxiety and other effects produced by ?9-THC in normal subjects. Psychopharmacology 76 (3): 245–50. doi:10.1007/BF00432554. PMID 6285406.
4. Fusar-Poli, P., Crippa, J.A., Bhattacharyya, S., Borgwardt, S,J., Allen, P., Martin-Santos, R., et al. (2009). Distinct Effects of Δ9-Tetrahydrocannabinol and Cannabidiol on Neural Activation During Emotional Processing. Archives of General Psychiatry 66 (1): 95–105. doi:10.1001/archgenpsychiatry.2008.519. PMID 19124693.
5. Holtzman, A.L. (2011, Mar 28). Cannabis Indica vs Sativa: A response to Continued cannabis use and risk of incidence and persistence of psychotic symptoms: 10 year follow-up cohort study. British Medical Journal, 342:d738. doi: http://dx.doi.org/10.1136/bmj.d738

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How Vape Pens Could Threaten the Pot Legalization Movement

Not everyone is going to welcome an innovation that facilitates getting high in public places—like high school hallways.

—By Josh Harkinson | Thu Mar. 20, 2014



One of many models of vape pens that can be used to discretely smoke marijuana concentrates. [SIK-photo]/Flickr

Last year, I joined some parents from my son's preschool for their semiregular "Dad's Night Out." We were at a crowded bar in Oakland, and somehow it emerged that I'd done some stories about marijuana. A dad immediately asked if I'd written about hash oil. Within a few minutes (for the sake of journalism, of course), I was trying a hit of nearly odorless vapor from what looked like a miniature flashlight. A single puff, and I was too high to order a second beer.

It might be an understatement to say that marijuana concentrates smoked from so-called vape pens—the pot version of e-cigarettes—accomplish for stoners what flasks full of moonshine do for lushes: Portable, discreet, and fantastically potent, they're revolutionizing the logistics of getting high, and minimizing the risk of discovery. Stories abound of people using vape pens to blaze away undetected at baseball games, city council meetings, kids' soccer matches, and, of most concern to parents and educators, high schools. Even if pot brownies have been around forever, this is probably not what your average Colorado or Washington voter had in mind when they cast a ballot to legalize recreational marijuana.

The concentrates typically used in vape pens are made by extracting THC from pot with water ("bubble hash"), transferring it into butter ("budder"), or refining it into what's known as butane hash oil (BHO, or "errrl," since stoners need a slang term for everything pot-related). From there, it can be refined further into a wax or an amber-like solid ("shatter"). These products are up to three times stronger than the most mind-bending buds. In short, it ain't your father's schwag, and its snowballing popularity among young people is reshaping the culture of the pot scene: One customarily smokes (or "dabs") BHO from specially designed bongs known as "oil rigs," and not at the designated hour of 4:20, but rather at 7:10—which, in case you're wondering, is "OIL" upside down and backwards.

"Baking Bad," the headline of a recent Slate piece on the concentrates scene, aptly sums up how the trend could become a PR nightmare for the legalization movement. As the name implies, making butane hash oil involves extracting THC from cannabis using butane—you know, lighter fluid. The growing rash of butane lab fires and explosions could suggest that potheads are going the way of meth tweakers. And when BHO is improperly made, it can be tainted with toxins.

But perhaps the biggest emerging concern with concentrates is how they may enable minors to abuse pot. Though many high schoolers use vape pens to inhale candy-flavored oils that don't contain psychoactive substances, a study by the Centers for Disease Control and Prevention found that 10 percent had used the devices in 2012 to consume nicotine concentrates (i.e., they'd tried "e-cigarettes"), double the number from the previous year—and that number is likely an underestimate. Emily Anne McDonald, an anthropologist at the University of California-San Francisco, told me her interviews with teens and young adults in New York suggest that the use of vape pens for pot is gaining steam—"especially for getting around the rules and smoking marijuana in places that are more public." She's currently applying for a grant to study the use of pot-concentrate vape pens by young people in Colorado.

Not surprisingly, some cities and states that allow medical marijuana don't look kindly on concentrates. In July, an appeals court in Michigan, where pot is legal for medical use and decriminalized for recreational use in many cities, ruled that concentrates aren't allowed under the state's medical marijuana law. In 2012, the Department of Public Health in pot-friendly San Francisco asked the city's dispensaries to stop carrying concentrates. (It later reversed itself in the face of a backlash.) A recently introduced California bill supported by law enforcement interests would revise its medical pot rules to ban pot concentrates statewide.

The rising popularity of BHO "certainly is a safety issue," acknowledges Bill Panzer, a member of the board of directors of the California chapter of the National Organization for the Reform of Marijuana Laws (NORML). Yet Panzer doesn't see prohibition as the solution. "You can either tell people to stop using concentrates, which they won't," he says, "or you can say, 'Let's regulate it and make sure it's done safely."

After some fierce debates, lawmakers in Colorado and Washington have ultimately decided to permit and regulate concentrates. Colorado requires anyone who makes BHO to operate out of a facility that is separate from a grow operation and that has been certified by an industrial hygienist or professional engineer. Washington state's Legislature last week passed a bill allowing state-licensed pot shops to sell concentrates, as long as the amount sold to any one customer doesn't exceed seven grams. But there are plenty of do-it-yourself recipes online.

Although more states may decide to regulate the production and sale of concentrates (see our maps of the pot regulation landscape), they'll have a much harder time preventing people from toking from vape pens on the sly. NORML's Panzer isn't worried. He brings up the example of an obnoxiously drunk baseball fan who sat next to his son at a recent Oakland A's game. "I have never seen anybody on weed doing that," he says. "Anytime you are replacing alcohol with cannabis, that's positive."

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Here is another article, this one from Slate:

Baking Bad

How dabbing—smoking potent, highly processed hash oil—could blow up Colorado’s legalization experiment.

By Sam Kamin and Joel Warner
February 5, 2014


Darkside shatter dab, made by TC Labs for Natural Remedies in Denver. Courtesy of Ry Prichard/CannabisEncyclopedia.com
Brad Melshenker, owner of the Boulder, Colo.-based 710 Labs, knows his operation, with its extensive ventilation systems, industrial hygienist–approved extraction machine, vacuum ovens, and workers wearing respirator masks looks like something out of a marijuana version of Breaking Bad. It’s why he calls his lab manager, Wade Sanders, “Walter,” after the show’s protagonist, Walter White.

And like the famously pure and powerful blue meth White cooked up on Breaking Bad, the product produced by 710 Labs’ fancy equipment is extremely concentrated, powerful, and coveted: butane-extracted hash oil (BHO). The lab’s finished BHO might not look like much—a thin, hard, and shiny brown slab, like peanut brittle without the peanuts—but when a piece of this “shatter,” as it’s called, is placed on the nail of a specially designed pipe that’s been superheated by a blowtorch, it vaporizes and delivers a direct hit of 70 to 90 percent THC, three times the potency of the strongest marijuana strains. As Melshenker puts it, if smoking regular pot is like drinking a beer, “dabbing,” as this process is known, is a shot of hard liquor. Vice calls the result, “The smoothest slow-motion smack in the face of clean, serene stonedness that you’ve ever experienced.” Rolling Stone reports, “Your head spins, your eyes get fluttery, a few beads of sweat surface on your forehead and, suddenly, you're cosmically baked.” Some pot aficionados vow to never smoke the old way again.


Gucci Earwax, a butane extraction, made by Mahatma Extreme Concentrates for Karmaceuticals in Denver. It won the first-place medical concentrate trophy at the High Times 2013 Denver U.S. Cannabis Cup. Courtesy of Ry Prichard / CannabisEncyclopedia.com
Hash, in other words, is no longer just a way to make use of leftover marijuana trim. It’s now becoming the main attraction. (Butane isn’t the only way to extract hash oil from marijuana, either; some concentrate-makers use carbon dioxide– or water-based extraction methods.) At Greenest Green, Melshenker’s Boulder dispensary, the inventory used to be 60 percent marijuana flower, 30 percent BHO, and 10 percent edibles. Now it’s the opposite: 60 percent BHO, 30 percent flower, and 10 percent edibles. And roughly 40 dispensaries statewide contract with 710 Labs to turn their marijuana into shatter or “budder,” a gloopier version. (Because of delays in Boulder’s regulation process, 710 Labs won’t be able to produce recreational BHO until Feb. 17.)

Hash oil is even fueling its own subculture. Forget 4:20; “dab heads” or “oil kids” light up at 7:10. (Turn the digits upside down and you have “OIL.”) Connoisseurs sport specially designed blowtorches and incredibly pricey “oil rig” pipes; a top-of-the-line rig from Melshenker’s Faulty Pelican glass company sets you back $14,000. There’s even dab gear, made by companies like Grassroots.

“There’s a whole industry here,” says Melshenker, whose business card doubles as a stainless-steel dabber, the tool used to apply BHO to an oil rig’s superheated nail.

Colorado’s thriving dabbing scene could just be one more bit of proof that the state is becoming a global mecca for marijuana. After all, the state’s legalized marijuana experiment has so far been an unqualified success. Despite the surprisingly limited number of recreational pot shops that opened their doors on Jan. 1—and the hefty crowds waiting in line to patronize them—the state hasn’t experienced widespread product shortages or weed prices high enough to trigger an Uber-style backlash. Yes, there was that story about 37 deadly marijuana overdoses on the first day of sales, but it turned out to be an obvious hoax. The few pundits who’ve complained about Colorado’s legalized pot, like David Brooks and Nancy Grace, have found their arguments blasted full of holes, not to mention lambasted on Saturday Night Live. The Justice Department is looking into ways to help banks play nice with marijuana businesses—a very serious problem—and even President Obama in a recent New Yorker profile conceded it’s important for the experiment to go forward.

Soon enough, then, Colorado’s small-scale experiment should spread far and wide, with controversial drug laws getting the boot, millions of clandestine tokers coming out of the closet, and governments reaping the benefits in taxes and fees. That is unless something goes terribly wrong, derailing the whole legalization movement.

Such a gloomy outcome isn’t out of the question. The only reason that Colorado is enjoying fame as the first place to legalize pot is thanks to a combination of fortunate timing, plucky advocates, forward-thinking lawmakers, and a remarkable lack of snafus. Colorado’s 2012 legalization attempt very well could have floundered if the effort hadn’t enjoyed remarkably positive media coverage. Considering the precipitous rise of the state’s medical marijuana industry and lawmakers’ keen efforts to moderate it, all it could have taken was the right bad headline—a high-profile crime or a boneheaded political move—to set the endeavor back considerably. Recall that alcohol prohibition was built on the temperance movement’s carefully crafted tales of woe and violence. As Salvation Army Commander Evangeline Booth once put it:

Drink has drained more blood …
Dishonored more womanhood,
Broken more hearts,
Blasted more lives,
Driven more to suicide, and
Dug more graves than any other poisoned scourge that ever swept its death-dealing waves across the world.

Mixed shatter slab by TC Labs. The product is broken prior to packaging to fit into the 1 gram or less packaging requirements. Courtesy of Ry Prichard / CannabisEncyclopedia.com
In Colorado, however, there have been very few sordid marijuana tales that could be used to demonize the drug—so far. Weed-fueled horror stories could still emerge in the state—and with the world watching, such calamities could have an international impact. So what are the biggest potential risks? A major concern is diversion, taking Colorado’s legal pot and offloading it to the black market or selling it out of state. While Colorado has established an extensive tracking system to prevent this from happening, there will always be tourists trying to take home a pot-infused souvenir. Beyond diversion, there’s the menace of crime—not just the threat of burglaries and organized crime in a largely cash-based industry, but also the distant possibility of banks or other financial institutions getting slapped with federal money laundering charges if they accept any of that free-flowing marijuana cash. Finally, there’s the prospective collateral damage, such as kids accidentally eating pot brownies—something that’s already in the news—or a violent pot-related car crash.

If any of these calamities do occur, Colorado’s red-hot dabbing scene could in fact be the source of the problem. Dabbing certainly appears on the surface to be dangerous: Kids are freebasing marijuana! It looks like they’re smoking crack! But it’s important to remember that there’s no evidence that it’s possible to overdose on pot. (Compared to say, acetaminophen, overdoses of which killed more than 1,500 Americans during the past decade.) So you can smoke the strongest dab imaginable—or even, if you’re a showboat, smoke 50 dabs in a row—and science says it won’t kill you. It will just get you really, really high.


Mars OG ISO dab, an isopropyl alcohol extraction made by Pink House Labs in Denver. Courtesy of Ry Prichard/CannabisEncyclopedia.com
But just because something won’t poison you the way alcohol can doesn’t mean it can’t lead you to do something stupid enough that will kill you. And there seem to be enough disconcerting variables associated with dabbing culture—a production process laden with volatile chemicals; a highly concentrated, easily transportable final product; and incredibly stoned kids with blowtorches—it seems only a matter of time until somebody in the scene does something very stupid and possibly fatal.

Yes, dabbing might not be as inherently dangerous as, say, a bar full of binge-drinkers. But it’s important to remember that recreational marijuana isn’t necessarily replacing alcohol use—it’s just adding a new legal vice to the options people already have. While some researchers predict legalized marijuana will decrease alcohol use, others predict it could lead to “heavy drinking” and “carnage on our highways.” So will folks really reach for a dabbing pipe instead of a shot glass—or will they reach for both?

Questions like this have led California and Washington to outlaw the production of smokeable marijuana concentrates. Colorado, however, has gone the opposite route: In November it released a draft of proposed concentrate production rules, positioning itself to become the only place in the world where marijuana concentrate production is both legal and regulated. The idea is to police the blooming subculture, to stay on top of it, so it ends up more akin to tattooing than meth. “If we outlaw concentrates, people will make them in their basements and blow themselves up,” says Norton Arbelaez, co-owner of the Denver dispensary RiverRock Wellness, which operates a concentrate production facility. But just because a concentrate extraction system is certified by a third-party industrial hygienist, as will likely be required by Colorado’s concentrate rules, doesn’t mean that system can’t still accidentally blow up.

It makes sense that Colorado is at the vanguard of legalized dabbing. It’s made a habit of taking risks when it comes to marijuana. Colorado can’t regulate away the chance that dabbing or some other marijuana-related endeavor will lead to a spectacular accident, either industrial or personal. But so far its legalization effort has taken pains to thoughtfully minimize such risks—and so far, it’s working.

~ Sam Kamin is professor and director of the Constitutional Rights and Remedies program at the University of Denver Sturm College of Law.

~ Joel Warner is a former Westword staff writer.

Jerome Groopman - Marijuana: The High and the Low

From The New York Review of Books, Jerome Groopman reviews A New Leaf: The End of Cannabis Prohibition, and he also adds a pretty solid background on the use of cannabis in history. This is an excellent overview and review of the book and the issues around making medical marijuana more accessible.

Marijuana: The High and the Low

Jerome Groopman
February 20, 2014 Issue

A New Leaf: The End of Cannabis Prohibition
by Alyson Martin and Nushin Rashidian
New Press, 264 pp., $17.95 (paper)

Jeff Chiu/AP Images Medical marijuana patient Kevin Brown at the Apothecarium, a medical cannabis dispensary in San Francisco, December 2011
In the summer of 2006, a young scientist from Israel joined my laboratory. He came to learn how viruses attack cells, a major focus of my research program. And I looked forward to drawing on his expertise in an emerging area of science that intrigued me: the biological effects of cannabinoids, the active chemical compounds in the marijuana plant. The Israeli researcher had trained at Jerusalem’s Hebrew University with Professor Raphael Mechoulam, a chemist credited with the discovery in 1964 of delta-9-tetrahydrocannabinol (THC), the primary psychoactive compound in marijuana. Mechoulam later characterized cannabidiol (CBD), a related substance plentiful in the plant, as distinct from THC in that it had no discernible effects on mood, perception, wakefulness, or appetite.1

The work of the young scientist proved productive. In short order, he tested the effects of several cannabinoids on a herpes virus that promotes the development of Kaposi’s sarcoma, a disfiguring and sometimes fatal tumor among people with impaired immunity, like those with AIDS. It turned out that CBD, the plentiful, nonpsychoactive compound, could switch off the malignant effects of the virus.2 Scientists in my department also found that cannabinoids could alter how white blood cells migrated in response to physiological stimuli, a key aspect of immune defense; other research teams found that THC inhibited the growth and spread of lung cancer and CBD of breast cancer in laboratory models.3 Clearly, chemicals in the plant could have diverse and potent effects on normal and malignant cells.

But what I found most fascinating was that we have a natural or “endogenous” cannabinoid system. In 1988, researchers identified a specific docking site, or receptor, on the surface of cells in the brain that bound THC. This first receptor was termed cannabinoid receptor 1, or CB1.4 Five years later, a second receptor for cannabinoids, CB2, was found.5 This latter docking protein was less plentiful in the central nervous system but richly present on white blood cells. Again, it was Raphael Mechoulam who discovered the first endogenous cannabinoid, a fatty acid in the brain, which he termed “anandamide.” (The name is derived from the Sanskrit word ananda, which means “bliss.”) When anandamide attached to CB1 it triggered a cascade of biochemical changes within our neurons.6

Other endogenous cannabinoids were later identified. This makes evolutionary sense, since the CB1 and CB2 receptors would not be present on our cells if we did not normally make molecules to dock on them. The physiological ramifications of endogenous cannabinoids appeared quite broad; their most impressive effects were related to perception of and response to pain.

CANNABIS is one of the oldest psychotropic drugs in continuous use. Archaeologists have discovered it in digs in Asia that date to the Neolithic period, around 4000 BCE. The most common species of the plant is Cannabis sativa, found in both tropical and temperate climates. Marijuana is a Mexican term that first referred to cheap tobacco and now denotes the dried leaves and flowers of the hemp plant. Hashish is Arabic for Indian hemp and refers to its viscous resin. An emperor of China, Shen Nung, also the discoverer of tea and ephedrine, is held to be among the first to report on therapeutic uses of cannabis in a medicinal compendium that dates to 2737 BCE. In 1839, William O’Shaughnessy, a British doctor working in India, published a paper on cannabis as an analgesic and appetite stimulant that also tempered nausea, relaxed muscles, and might ameliorate epileptic seizures. His observations led to widespread medical use of cannabis in the United Kingdom; it was prescribed to Queen Victoria for relief of menstrual discomfort.7

The cannabis plant contains some 460 compounds, including more than 60 cannabinoids. THC, the key psychoactive substance in marijuana, has increased from about 1–5 percent to as much as 10–15 percent in cultivated plants since the 1960s. When herbal cannabis is smoked, some 20 to 50 percent of the THC is absorbed via the lungs. When herbal cannabis is eaten, less THC reaches the brain because it is metabolized as it passes from the gut through the liver. THC accumulates in fatty tissues, from which it is slowly released, and acts primarily on CB1 receptors in the brain’s mesolimbic dopamine system, which is believed to contribute to the positive reinforcing and rewarding effects of the drug.8

While smoking or eating cannabis typically results in the user’s feeling “high,” with a relaxed, euphoric sense as anxiety and alertness decrease, some first-time users, as well as individuals who have psychological problems, can experience dysphoria, fear, and panic. Typically, when high on marijuana, there is an increased sense of sociability, although among those who have a dysphoric reaction, there can be sharp social withdrawal. Perception of time is altered, generally with perceived time faster than clock time; spatial perception also may change, and colors may seem brighter and music more resonant. High doses of cannabis can result in hallucinations, which may account for its religious use in some cultures. Yet unlike opioids, there are no reported cases of death due to a THC overdose, probably because cannabinoids do not inhibit our respiratory drive, which would result in asphyxiation. Among regular users, abstinence from marijuana can cause an uncomfortable or distressing withdrawal syndrome.

In 2008 the World Health Organization published a Mental Health Survey of 54,068 persons age sixteen and older in seventeen nations. On the basis of this survey, cannabis was found to have been used at least once by some 160 million people between the ages of fifteen and sixty-five; reported use was lowest in the People’s Republic of China, 0.3 percent, and highest in the United States, 42.4 percent, with New Zealand close behind.9

Despite such widespread use, cannabis is illegal in most countries. Harry J. Anslinger, a prominent prohibitionist, successfully lobbied Congress to pass the Marihuana Tax Act in 1937, making access to the plant costly. Anslinger was the head of the Federal Bureau of Narcotics and presented cannabis use to the public as an unalloyed danger, resulting in “reefer madness.” The American Medical Association opposed the Marihuana Tax Act, fearing that it would limit medicinal study and potential prescription of the plant. Long a part of the United States Pharmacopeia, a compendium that set standards for medicines and foods, cannabis was removed in 1942.

In 1970, Congress enacted the Controlled Substances Act, classifying marijuana along with heroin as a Schedule I drug. Drugs in this category have a proven potential for abuse and no medical value. (Opium, the source of morphine, and amphetamines are Schedule II drugs, classified as less dangerous despite their potent addictive properties.) Soon thereafter, President Nixon launched the “war on drugs,” and in 1986, President Reagan signed the Anti-Drug Abuse Act, which mandated prison sentences without parole for offenders convicted of possession and sale of all illegal drugs, including marijuana.

THE STUDY of cannabinoids, both those derived from plant sources as well as the endocannabinoids that exist naturally within our body, is now an extensive enterprise that spans the globe and links numerous scientists in both academic centers and pharmaceutical companies.

Mitch Earleywine, a prominent researcher on drugs and addiction at SUNY Albany, observed how results from current studies on marijuana are akin to Rorschach blots. “People purportedly see these ambiguous pictures in a way that reveals more about them than the ink.” Many who make public policy or are associated with interest groups, he contends, may respond to marijuana research according to the views of these groups: their interpretations say more about their own biases than about the actual data. For example, prohibitionists contend that THC often appears in the blood of people involved in auto accidents; yet they omit the fact that most of these people also had been drinking alcohol. Antiprohibitionists cite research that showed no sign of memory problems in chronic marijuana smokers; but they do not mention that the cognitive tests were so easy that even an impaired person could perform them.

Two recent reviews avoid such biases and critically examine data from more than a hundred randomized placebo-controlled clinical trials involving some 6,100 patients with a variety of medical conditions.10 Marijuana appears useful in treating anorexia, nausea and vomiting, glaucoma, irritable bowel disease, muscle spasticity, multiple sclerosis, symptoms of amyotropic lateral sclerosis (Lou Gehrig’s disease), epilepsy, and Tourette’s syndrome. (Recent clinical trials confirm many of the claims of Emperor Shen Nung and Dr. O’Shaughnessy.) Despite findings from experiments in my laboratory and others, its anticancer effects in patients are more uncertain and neither THC nor CBD is a proven antineoplastic agent, i.e., effective in treating abnormal growth of tissue.

Judy Foreman, an accomplished medical journalist, devotes a chapter to marijuana in her recent book A Nation in Pain: Healing Our Biggest Health Problem.11 She judiciously reviews the data on the risks and benefits of marijuana as a therapy for medical conditions marked by pain, highlighting where it appears ameliorative, where it falls short, and where there is lack of clarity about its value. Foreman writes:

To put it bluntly, marijuana works. Not dazzlingly, but about as well as opioids. That is, it can reduce chronic pain by more than 30 percent. And with fewer serious side effects. To be sure, some researchers think it’s too soon to declare marijuana and synthetic cannabinoids a first-line treatment for pain, arguing that other drugs should be tried first. But that may be too cautious a view.

Ultimately, marijuana may be used in conjunction with opioids like morphine to allow for lower doses and fewer of the side effects of the opioid family of analgesics. While chronic pain seems amenable to amelioration by marijuana, its impact on reducing acute pain, such as after surgery, is minimal.

How do cannabinoids reduce pain? Some of the benefit appears to result from cognitive dissociation: you realize that pain is present, but don’t respond to it emotionally. If you are able to detach yourself from pain in that way, there is less suffering.

EVERY therapy, whether a drug or a procedure, involves a tradeoff of benefits versus risks. Perhaps the most controversial and important concern around cannabinoids is whether they increase the risk of psychoses like schizophrenia. This question is most germane for adolescents and young adults. A number of studies reviewed the health records of young people in Sweden, New Zealand, and Holland who reported cannabis use, as compared to the records of those who did not. A combined or metaanalysis of results from nearly three dozen such studies linked cannabis use to later development of schizophrenia and other psychosis.12

The limitation of such observational studies is that they may suggest an association but in no way prove a causal link. Indeed, the medical literature is littered with observational studies that were taken as meaningful but later overturned when randomized placebo-controlled trials were conducted. Here the Women’s Health Initiative comes to mind. This was a randomized study, using placebos as controls, that reversed some four decades of thinking about the alleged benefits of hormonal replacement therapy among postmenopausal women in preventing dementia and heart disease. No one is likely to conduct a randomized controlled trial of thousands of teenagers, assigning one group to smoke or ingest cannabis and the other group to receive placebos. The issue of marijuana as a cofactor in the development of schizophrenia and other psychosis will therefore remain unresolved.

What is clear is that cannabis impairs cognition and psychomotor responses. Numerous studies show that it lengthens a person’s reaction time and impairs his or her attention, concentration, short-term memory, and assessment of risks. These changes in psychomotor performance can last longer than the feeling of being high. Trials with licensed pilots found that marijuana impaired performance on a flight simulator for up to twenty-four hours.13 Further, most of the pilots were unaware that their performance was still impaired a day later. Several studies demonstrate associations between cannabis and collisions: drivers who use it are estimated to be some two to seven times more likely to be responsible for accidents compared to drivers not using drugs or alcohol.14

The American Psychiatric Association, in the new DSM-5, has defined a diagnosis of “cannabis use disorder.” These people had a repeated pattern of use with harmful consequences, such as inability to fulfill major responsibilities at work and persistent social problems at home. Both the DSM-5 and the World Health Organization’s International Classification of Diseases 10th edition (ICD-10) also include a list of possible symptoms of withdrawal from using cannabis: significant fatigue, sleepiness, psychomotor retardation, anxiety, and depression.15 Yet there is fierce argument about whether marijuana is addictive. Proponents of cannabis doubt that it can cause true addiction, a physiological condition with compulsive craving and use despite harm; they argue that any dependence is less significant than that seen with alcohol. Opponents of cannabis use, particularly those from the National Institutes of Health, affirm both dependence and addiction as real risks, although at a much lower percentage than that seen with cocaine or heroin.16

A New Leaf is a detailed account of the history of the regulation of cannabis, presenting in a blow-by-blow manner the legal and political battles around its prohibition. It opens on a celebratory note, with the legalization of marijuana for recreational use in two states:

Another prohibition is ending. On November 6, 2012, voters in Colorado and Washington were the first in the world to successfully challenge nearly a century of bad policy and misconceptions about cannabis.

In downtown Seattle, the Hotel Ändra was dressed white and blue, the team colors of Washington State’s…campaign….

Around 7 p.m., the owner of one of the largest and most successful medical cannabis dispensaries in the country arrived. Steve DeAngelo was unmistakable even in a crowd, with his signature long, tight pigtail braids and dark fedora…. Earlier that year, he was the star of his own Discovery Channel show, Weed Wars. His two Harborside Health Centers are in the Bay Area, but he had a soft spot for Seattle. Just a few months before, he had spoken at Seattle’s well-known Hempfest, attended by tens of thousands each year. “I’ve been working on this issue for my entire life…. And I know tonight…that there’s going to be a whole lot of angels dancing in heaven,” DeAngelo said, his eyes flooding.

The authors describe a similar scene in Denver:

Brian Vincente, a lawyer who advocated for medical cannabis in Colorado for nearly a decade,… took the stage. “Tonight we made history. This is something you’re going to tell your kids about,” Vincente said. “Marijuana prohibition started in 1937. The first person arrested was in Colorado.” The crowd booed. “Colorado fucking turned this thing around tonight.” And with the f-word came gaiety.

These successes resulted from a unique effort joining groups from the ends of the political spectrum:

The support of conservative Republicans and Libertarians was as important to the Colorado…campaign as that of Democrats and liberals…. The swing state of Colorado, birthplace of the Libertarian party, is decidedly purple. The Libertarian Party of Colorado emphatically endorsed Amendment 64 in May, for example, while the Colorado Democratic Party offered support but stopped short of an endorsement. The Republican Liberty Caucus of Colorado also endorsed the amendment because prohibition is “inconsistent with Republican values,” which call for more “personal responsibility” and less “federal overreach.”

RECENT articles in The New Yorker17 and The Nation18 describe in a succinct and focused way the political terrain around cannabis legalization for medicinal or recreational use in the United States. The New Yorker article features Professor Mark Kleiman, a drug policy expert at the University of California, Los Angeles, who sees legalization through the perspective of a scientist, who regards it as a kind of ongoing experiment. Legalization will test a group of hypotheses about public policy, and he suspends conclusions until more data are available.

As with every social initiative, there could be negative effects and Kleiman advocates close monitoring of excessive use among adolescents and of driving under the influence when cannabis is legal for recreational use. He “appears,” according to the New Yorker article, “to derive grim pleasure from informing politicians that they have underestimated the complexity of a problem.” One major concern is that when legal marijuana goes on sale in Washington State this spring, the current black market will not disappear; rather, legal over-the-counter marijuana will be competing with illicit sources. Kleiman argues that to support the legal market, there should be even greater law enforcement pressure on those who do not respect the rules. In Washington, few in government wanted to hear such a proposal.

Similarly, Kleiman is not confident that alcohol will become less appealing as marijuana is made available. While he acknowledges that alcohol is the greater danger of the two, he raises the possibility that cannabis will be used to complement drinking. Finally, he says that in the “Manichaean world of politics,” the pendulum may swing from marijuana as illegal—with sale or use of it causing imprisonment—to “going all the way to ‘We should sell it like cornflakes.’”

Unlike the cautious New Yorker piece, the articles in The Nation offer a robust endorsement of legalization. The cover of the magazine displays a photograph of a young Barack Obama flashing the V for victory sign with friends in high school clustered around the logo of the “Choom Gang.” An accompanying editorial by Katrina vanden Heuvel notes that recent presidents, including Bill Clinton, George W. Bush, and Barack Obama, all “have more or less owned up to breaking America’s drug laws” through possession or use of cannabis; if they had been observed by the police, they might well have been incarcerated, with no hope of a career leading to the White House. A New Leaf emphasizes the risks of arrest for possession. Racial discrimination, with disproportionate numbers of African-Americans arrested, is one ugly reality of prohibition:

While cannabis users who are arrested are not often sent to prison, there are still more than twenty thousand people incarcerated for mere possession. According to a comprehensive 2013 report released by the ACLU, between 2001 and 2010 more than 8 million cannabis arrests were made in the United States (88 percent for possession), and the possession enforcement alone cost more than $3.6 million in 2010.  

Across the country, blacks are nearly four times more likely than whites to be arrested for cannabis possession, despite comparable rates of use; in some counties that number increases from four to thirty. Finally, 62 percent of those arrested are twenty-four or younger, which means their arrest records will follow them throughout adulthood.

All of these wasted hours, dollars, and arrests are a distraction from hard drug use and trafficking:

Again, when cannabis—which accounts for 80 percent of all illegal substance use in the United States—is removed from the drug war picture, the country can more effectively discuss and implement a new and more fitting public health approach for the remaining hard drugs.

SEVERAL years ago, I consulted on the case of a young woman with anemia. Her internist had made an exhaustive evaluation of her condition but had found no cause for it. The patient had been under a great deal of stress at work, and when I asked how she dealt with this, she said she had been smoking marijuana every night. A bone marrow examination showed reduced numbers of cells, not severe enough to be classified as aplastic anemia, but certainly abnormal in a woman in her twenties. The numerous components of cannabis are not known to be toxic to blood cells; marijuana smoking has not been reported as a cause of anemia. But I recalled that some of the illicit crops had been sprayed with toxins that might have deleterious effects on blood cell development.

So together we decided that she would suspend smoking, and over a period of months her anemia was resolved. A subsequent bone marrow examination showed full restoration of normal blood cell numbers. This was not definitive proof, but it certainly suggested that something in the grass she got from a dealer was the potential culprit. If there is not adequate oversight of the marijuana on sale, those seeking street cannabis could be exposed to dangerous contaminants.

In a forthcoming book, Weed Land, Peter Hecht, a journalist at The Sacramento Bee, charts the evolution of California’s medical marijuana law, the first in the nation.19 Much of the momentum behind its passage came from a joining of forces between AIDS activists and academic physicians like Donald Abrams at San Francisco General Hospital, who demonstrated the clinical benefits of augmented appetite and relief of pain in patients with cachexia from HIV. Medical marijuana, now legal in twenty states and the District of Columbia, is regulated like a supplement rather than a drug. There is no standardization of optimal amounts of psychoactive THC and nonpsychoactive CBD, although they must be free of toxins. (A British company, GW Pharmaceuticals, makes Sativex, an oral spray containing extracts of two standardized cannabis strains that are mixed to give exact doses of THC and CBD. Sativex was approved in several countries, but not in the United States.)

For a physician like myself prescribing a therapy, this is an uncomfortable situation, because a prescription should be exact in specifying how much drug is delivered. Further, side effects may occur in patients taking multiple other medications, due to so-called “drug-drug interactions.” Such interactions have not been well studied with THC and CBD, in part because of the restriction of access to the plant for the clinical research community. Scientists in my laboratory studied pure chemicals, THC and CBD, under strict federal oversight; we purchased the cannabinoids from chemical companies that used quality control. As Martin and Rashidian note, clinical study of the plant itself, with its scores of active chemicals, is another matter:

The federal government has imposed additional and unique restrictions on cannabis research, with little rationale—beyond politics. The federal government has enabled only one institution, the University of Mississippi, to legally grow cannabis for research on its behalf, although it is free to award additional and alternative contracts. And cannabis is the only research substance for which the government is the sole supplier. For a scientist to receive cannabis from the federal farm at the University of Mississippi, a trifecta of approvals…must be obtained from the FDA, DEA, and a Public Health Service panel.

Perhaps as states legalize marijuana, this barrier to research will be lowered, as it was for stem cell research, once restricted by federal law. And as more studies are conducted on marijuana for medical or recreational uses, opponents and enthusiasts may both discover that they were neither entirely right nor entirely wrong.

Notes

1. Mohamed Ben Amar, “Cannabinoids in Medicine: A Review of Their Therapeutic Potential,” Journal of Ethno-pharmacology, Vol. 105 (2006); Arno Hazekamp and Franjo Grotenhermen, “Review on Clinical Studies with Cannabis and Cannabinoids 2005–2009,” Cannabinoids, Vol. 5 (2010). ↩

2. Y. Maor, J. Yu, P.M. Kuzontkoski, B.J. Dezube, X. Zhang, and J.E. Groopman, “Cannabidiol Inhibits Growth and Induces Programmed Cell Death in Kaposi Sarcoma–Associated Herpesvirus-Infected Endothelium,” Genes & Cancer, Vol. 3, No. 7–8 (2012); X. Zhang, J.F. Wang, G. Kunos, and J.E. Groopman, “Cannabinoid Modulation of Kaposi’s Sarcoma–Associated Herpesvirus Infection and Transformation,” Cancer Research, Vol. 67, No. 15 (August 1, 2007). ↩

3. S. Ghosh, A. Preet, J.E. Groopman, and R.K. Gaju, “Cannabinoid Receptor CB 2 Modulates the CXCL 12/ CXCR 4-Mediated Chemotaxis of T Lymphocytes,” Molecular Immunology, Vol. 43 (2006); A. Preet, R.K. Ganju, and J.E. Groopman, “∆ 9 -Tetrahydrocannabinol Inhibits Epithelial Growth Factor–Induced Lung Cancer Cell Migration in Vitro as Well as Its Growth and Metastasis in Vivo,” Oncogene, Vol. 27 (2008); X. Zhang, Y. Maor, J.F. Wang, G. Kunos, and J.E. Groopman, “Endocannabinoid-like N-arachidonoyl Serine Is a Novel Pro-angiogenic Mediator,” British Journal of Pharmacology, Vol. 160 (2010); A. Preet, Z. Qamri, M. Nasser, A. Prasad, K. Shilo, X. Zou, J.E. Groopman, and R. Ganju, “Cannabinoid Receptors, CB 1 and CB 2, as Novel Targets for Inhibition of Non-Small Cell Lung Cancer Growth and Metastasis,” Cancer Prevention Research, Vol. 4 (2011); A. Shrivastava, P.M. Kuzontkoski, J.E. Groopman, and A. Prasad, “Cannabidiol Induces Programmed Cell Death in Breast Cancer Cells by Coordinating the Cross-Talk Between Apoptosis and Autophagy,” Molecular Cancer Therapeutics, Vol. 10 (2011). ↩

4. W.A. Devane, F.A. Dysarz III, M.R. Johnson, L.S. Melvin, and A.C. Howlett, “Determination and Characterization of a Cannabinoid Receptor in Rat Brain,” Molecular Pharmacology, Vol. 34 (November 1, 1988). ↩

5. S. Munro, K.L. Thomas, and M. Abu-Shaar, “Molecular Characterization of a Peripheral Receptor for Cannabinoids,” Nature, Vol. 365 (1993). ↩

6. W.A. Devane, L. Hanus, A. Breuer, R.G. Pertwee, L.A. Stevenson, and G. Griffin, “Isolation and Structure of a Brain Constituent That Binds to the Cannabinoid Receptor,” Science, Vol. 258 (December 18, 1992). ↩

7. D. Baker, G. Pryce, G. Giovannoni, and A.J. Thompson, “The Therapeutic Potential of Cannabis,” Lancet Neurology, Vol. 2 (May 2003). ↩

8. Mitch Earleywine, Understanding Marijuana: A New Look at the Scientific Evidence (Oxford University Press, 2002). ↩

9. L. Degenhardt, W.T. Chiu, N. Sampson, et al., “Toward a Global View of Alcohol, Tobacco, Cannabis, and Cocaine Use: Findings from the WHO World Mental Health Surveys,” PLoS Medicine, Vol. 5 (July 2008). ↩

10. See Amar, “Cannabinoids in Medicine: A Review of Their Therapeutic Potential,” and Hazekamp and Grotenhermen, “Review on Clinical Studies with Cannabis and Cannabinoids 2005–2009.” ↩

11. Oxford University Press, 2014 ↩

12. M. Large, S. Sharma, M.T. Compton, T. Slade, O. Nielssen, “Cannabis Use and Earlier Onset of Psychosis,” Archives of General Psychiatry, Vol. 68, No. 6 (2011). ↩

13. V.O. Leirer, J.A. Yesavage, and D.G. Morrow, “Marijuana Carry-Over Effects on Aircraft Pilot Performance,” Aviation, Space, and Environmental Medicine, Vol. 62, No. 3 (1991); D.G. Newman (Australian Government, Australian Transport Safety Bureau), “Cannabis and Its Effects on Pilot Performance and Flight Safety: A Review” (2004). ↩

14. M. Asbridge, J.A. Hayden, and J.L. Cartwright, “Acute Cannabis Consumption and Motor Vehicle Collision Risk: Systematic Review of Observational Studies,” BMJ, Vol. 344, No. 14 (2012). ↩

15. D.S. Hasin, K.M. Keyes, D. Alderson et al., “Cannabis Withdrawal in the United States: Results from NESARC,” Journal of Clinical Psychiatry, Vol. 69, No. 9 (2008). ↩

16. See Baker et al., “The Therapeutic Potential of Cannabis,” and Foreman, A Nation in Pain. ↩

17. Patrick Radden Keefe, “Buzzkill,” The New Yorker, November 18, 2013. ↩

18. Katrina vanden Heuvel, “Why It’s Always Been Time to Legalize Pot,” and other articles in The Nation ’s “Special Issue: Marijuana Wars,” November 18, 2013. ↩

19. Peter Hecht, Weed Land: Inside America’s Marijuana Epicenter and How Pot Went Legit (University of California Press, May 2014). ↩

The Future of Medicinal Marijuana - Less High (THC), More Healing (CBD)

Hashish Smokers by Gaetano Previati, 1877. Private collection. Photo by Getty Images

I'm sure this will harsh the high of some dedicated marijuana users, but the future of good weed lies in reducing the THC content through breeding while increasing the CBD content.

• THC: tetrahydrocannabinol, the primary psychoactive compound in cannabis and is what causes the subjective "high"
• CBD: cannabidiol, produces the calming, anti-anxiety effects of the drug

The illicit marijuana market has systematically increased the THC content by 10-15% over the last decade or so. At the same time, there has been a significant reduction of CBD, sometimes to levels as low as 0.1%. A recent article in The Guardian (UK) suggests that this high-THC/low-CBD marijuana, "skunk weed," is something new, but it was the goal 30 years ago when I was still smoking weed.

From Wikipedia:

Decades ago, growers in the US bred CBD almost entirely out of cannabis plants because their customers preferred varietals that were more mind-altering due to a higher THC, lower CBD content.[50] To meet the demands of medical cannabis patients, growers are developing more CBD-rich strains.[52]

In November 2012, an Israeli medical cannabis facility announced a new strain of the plant which has only cannabidiol as an active ingredient, and virtually no THC, providing some of the medicinal benefits of cannabis without the euphoria.[53][54] The researchers said the cannabis plant, enriched with CBD, "can be used for treating diseases like rheumatoid arthritis, colitis, liver inflammation, heart disease and diabetes". Research on CBD enhanced cannabis began in 2009, resulting in Avidekel, a cannabis strain that contains 15.8% CBD and less than 1% THC. Raphael Mechoulam, leading cannabinoid researcher, noted "It is possible that (Avidekel's) CBD to THC ratio is the highest among medical marijuana companies in the world, but the industry is not very organized, so one cannot keep exact track of what each company is doing".[55]

One wonders if all of the people on the internet arguing so vociferously for marijuana legalization based on its medicinal qualities would still support legalization if only the high-CBD strains were allowed.

From Project CBD:

Cannabidiol (CBD) is a compound in cannabis that has medical effects but does not make people feel “stoned” and can actually counter the psychoactive effects of THC. After decades in which only high-THC Cannabis was available, CBD-rich strains are now being grown by and for medical users.  

The reduced psychoactivity of CBD-rich cannabis makes it an appealing treatment option for patients seeking anti-inflammatory, anti-pain, anti-anxiety, and anti-psychotic effects without disconcerting lethargy or dysphoria.

Scientific studies underscore CBD’s potential as a treatment for many conditions, including chronic pain, diabetes, cancer, cardiovascular disease, alcoholism, PTSD, schizophrenia, antibiotic-resistant infections, rheumatoid arthritis, MS, epilepsy, and other neurological disorders. 

There is significant scientific evidence that THC has some seriously negative effects on the human brain. The results from a 2008 study in the British Journal of Psychiatry compared THC only, THC+CBD, and no cannabis found clear differences in levels of delusions and anhedonia:

Our results show higher levels of unusual experiences – an analogue of hallucinations and delusions – in individuals who had evidence of only Δ9-THC in their hair compared with those with both Δ9-THC and CBD, and those with no cannabinoid. There were also greater levels of delusions in this THC only group compared with individuals who showed no evidence of cannabinoids in their hair, with a similar trend in the THC+CBD group. The THC+CBD group reported less anhedonia than the other two groups.

A 2012 study in Psychological Medicine reached similar conclusions:

CBD attenuates the psychotic-like effects of cannabis over time in recreational users. Higher THC negatively impacts on memory and psychological well-being. These findings raise concerns for the harms stemming from use of varieties such as ‘skunk’ (sensimillia), which lack any CBD but currently dominate the supply of cannabis in many countries.

A 2012 study published in the Proceedings of the National Academy of Sciences found that ongoing marijuana use compromised cognitive functions across a the whole spectrum, including memory and intelligence. They also found that subjects who showed marijuana dependence by age 18 suffered greater IQ losses than those who did not. Here is the abstract:

Recent reports show that fewer adolescents believe that regular cannabis use is harmful to health. Concomitantly, adolescents are initiating cannabis use at younger ages, and more adolescents are using cannabis on a daily basis. The purpose of the present study was to test the association between persistent cannabis use and neuropsychological decline and determine whether decline is concentrated among adolescent-onset cannabis users. Participants were members of the Dunedin Study, a prospective study of a birth cohort of 1,037 individuals followed from birth (1972/1973) to age 38 y. Cannabis use was ascertained in interviews at ages 18, 21, 26, 32, and 38 y. Neuropsychological testing was conducted at age 13 y, before initiation of cannabis use, and again at age 38 y, after a pattern of persistent cannabis use had developed. Persistent cannabis use was associated with neuropsychological decline broadly across domains of functioning, even after controlling for years of education. Informants also reported noticing more cognitive problems for persistent cannabis users. Impairment was concentrated among adolescent-onset cannabis users, with more persistent use associated with greater decline. Further, cessation of cannabis use did not fully restore neuropsychological functioning among adolescent-onset cannabis users. Findings are suggestive of a neurotoxic effect of cannabis on the adolescent brain and highlight the importance of prevention and policy efforts targeting adolescents.

The negative impact of cannabis use on young people is not unexpected. The adolescent and teen years are the second most important period of brain development in a person's life (after infancy). It is also not surprising then that cannabis use in kids and teens doubles the risk for psychosis and schizophrenia - Dialogues in Clinical Neuroscience, 2005.

The authors in the above study suggest that cannabis is not solely responsible for the higher rates of serious mental illness. They argue that young people with premorbid symptoms of future psychosis are much more likely to self-medicate with marijuana.

It's clear based on the information above that THC is the likely culprit in memory loss, IQ decline, and increased risk of mental illness. With this understanding, legalization of marijuana should be predicated on the production and sale of high-CBD strains with little or no THC.

Here is a recent article from The Guardian (UK) that suggests people are finally starting to understand that the benefits of marijuana are found in the CBD and not in the THC.

Cannabis and memory loss: dude, where's my CBD?

Legalisation presents an opportunity to promote cannabis rich in a chemical that protects against its negative effects

Dude, Where's My Car? CBD in cannabis is thought to protect against dependence, psychotic symptoms … and memory loss. Photograph: Sportsphoto/Allstar/Cinetext
It isn't often that science and pop culture overlap, but the two fields are in agreement when it comes to the familiar trope of the forgetful stoner.

A recent study published in Schizophrenia Bulletin is the latest to reveal the detrimental effects that cannabis can have on memory. The authors report that people dependent on the drug – both healthy individuals and patients with schizophrenia – show impairments in memory compared with healthy volunteers and non-smoking schizophrenia patients.

Even more striking, the cannabis-using groups had significant decreases in the volume of two brain areas that are important for processing rewards, learning and working memory – the thalamus and striatum – and these changes were linked to their memory problems. There was no evidence to connect cannabis use and schizophrenia – the authors simply compare the two groups. However, previous studies have found a higher prevalence of psychosis among regular cannabis smokers.

Reports of memory loss with long-term cannabis use are nothing new, and an influential paper published last year provided evidence that smoking marijuana has a deleterious effect on intelligence. In the investigation, the cognitive abilities of participants were tested several times over the course of 25 years. The researchers found that heavy cannabis users had significant decreases in intelligence and memory ability as they aged, not only compared with non-smokers, but also compared with their younger selves. Additionally, the earlier they started smoking pot, the bigger the cognitive decline.

Obviously these findings are worrying, especially given the recent spate of cannabis legalisations in states across the US and in countries such as Uruguay. However, before we all start worrying about the good people of Colorado and Washington, it might be helpful to look closer at what's actually in the cannabis we're smoking nowadays, and what ingredients are contributing to these cognitive deficits.

THC (tetrahydrocannabinol) is the primary psychoactive compound in cannabis and is what causes the subjective "high". This includes changes in perceptual sensations, a feeling of contentedness and increased appetite. However, THC is also linked to many of the potential negative consequences of cannabis use, such as dependence, psychotic symptoms, and impaired memory and cognition.

Another important component, CBD (cannabidiol, which works by increasing natural cannabinoid levels in the brain) is associated with the calming, anti-anxiety effects of the drug. In addition, CBD is thought to protect against many of the potential negative effects of marijuana, including dependence, psychotic symptoms and cognitive impairments.

The THC concentration in cannabis has increased by as much as 12% over the past 30 years, making the drug much stronger than it used to be. At the same time, there has been a significant depletion of CBD, sometimes to levels as low as 0.1%. "Skunk", as this new strain of high-THC/low-CBD marijuana is called, is flooding the illegal marijuana market, and it is this variety that is thought to be behind the rise in cannabis dependence diagnoses, links to schizophrenia, and cognitive deficits seen over the past decade.

The changing chemical make-up of cannabis appears to be partly accidental and partly deliberate. New strains are often bred to have higher levels of THC in them, increasing the drug's potency. However, modern growing techniques have also affected these chemical levels. For example, illegal growers have turned to indoor marijuana farms to avoid detection. Growing cannabis locally in such farms also circumvents the need to import the drug, and guarantees a more reliable harvest. However, the 24-hour lighting used in these farms inadvertently reduces CBD levels in the plant. Thus, these new strains are not only bred for higher potency, with elevated THC content, they are also lacking the protection provided by CBD against the drug's negative effects.

It should be noted that the majority of research into cognitive deficits and cannabis use has focused on heavy or dependent users, and there's little evidence that occasional smokers show any of the problems mentioned above. But with the recent changes in drug policy, the chances are that more people will be smoking cannabis than ever before, and the more potent and more popular high-THC/low-CBD marijuana that is available today will increase their risk of dependence.

The recent legalisation of recreational and medicinal marijuana in parts of the US has the potential to reduce significantly the harms caused through incarceration or criminal records for minor drug-related offences. However, it also provides an opportunity to reduce the cognitive and psychiatric harms linked to cannabis use. With this shift in drug policy, it is now possible for states to monitor the commercial production of cannabis, regulating the levels of THC and CBD present in the drug. To facilitate this, they could force growers to use strains with higher levels of CBD, and revert to more old-fashioned farming methods that don't use round-the-clock lighting.

These changes could help protect individuals from the damaging effects of the drug, prevent the development of dependence in new users, and maybe even help our favorite Hollywood stoners remember where they left their car.

Use of cannabis by adolescents in key developmental periods increases vulnerability to psychiatric disease and overlaps with biological changes in the endocannabinoid system. The endocannabinoid system is involved in a LOT of biological functions, including memory, appetite, energy balance and metabolism, stress response, immune function, multiple sclerosis, female reproduction, autonomic nervous system, analgesia, thermo-regulation, and sleep

Adolescence is associated with an increased incidence of psychiatric illness, and exposure to cannabis during this developmental window strongly predicts subsequent development of mood disorders, addictive disorders, and schizophrenia (A). Components of the endocannabinoid system appear as early as embryonic life, but maximal CB₁R mRNA expression occurs during adolescence.

When people advocate for legalizing marijuana and tout its healing benefits, most seem to ignore that there are years and years of research linking marijuana use, especially in adolescents and teens, to increased risk for mental illness and psychotic episodes.

The other thing that advocates of marijuana legalization overlook, or are ignorant of, is the tremendous increase in THC levels relative to CBD (cannabidiol), a trend that makes for a greater high and a greater risk and negative side effects. The black market has bred marijuana to be higher in THC and lower in CBD.

Medical marijuana, on the other hand, at least in San Francisco, is being bred for a higher CBD level and a lower THC level. From Wikipedia:

Cannabidiol (CBD) is one of at least 85 cannabinoids found in cannabis.[3] It is a major constituent of the plant, second to tetrahydrocannabinol (THC), and represents up to 40% in its extracts.[4] Compared with THC, cannabidiol is not psychoactive in healthy individuals, and is considered to have a wider scope of medical applications than THC,[5] including to epilepsy,[6] multiple sclerosis spasms,[7] anxiety disorders, bipolar disorder,[5] schizophrenia,[8] nausea, convulsion and inflammation, as well as inhibiting cancer cell growth.[9] There is some preclinical evidence from studies in animals that suggests CBD may modestly reduce the clearance of THC from the body by interfering with its metabolism.[10][11][12] Cannabidiol has displayed sedative effects in animal tests.[13] Other research indicates that CBD increases alertness.[14] CBD has been shown to reduce growth of aggressive human breast cancer cells in vitro, and to reduce their invasiveness.[15]

Anyway, this article offers pretty solid evidence for the risks in allowing adolescents and teens to smoke marijuana, which would likely be prohibited if and when marijuana becomes widely legal. Still, kids are going to smoke weed just like kids are going to drink their parents' beer.

Cannabis use during adolescent development: Susceptibility to psychiatric illness

Benjamin Chadwick [1], Michael L. Miller [1], and Yasmin L. Hurd [1,2,3]

1. Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
2. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
3. James J. Peters VA Medical Center, Bronx, NY, USA

ABSTRACT

Cannabis use is increasingly pervasive among adolescents today, even more common than cigarette smoking. The evolving policy surrounding the legalization of cannabis reaffirms the need to understand the relationship between cannabis exposure early in life and psychiatric illnesses. cannabis contains psychoactive components, notably Δ9-tetrahydrocannabinol (THC), that interfere with the brain’s endogenous endocannabinoid system, which is critically involved in both pre- and post-natal neurodevelopment. Consequently, THC and related compounds could potentially usurp normal adolescent neurodevelopment, shifting the brain’s developmental trajectory toward a disease-vulnerable state, predisposing early cannabis users to motivational, affective, and psychotic disorders. Numerous human studies, including prospective longitudinal studies, demonstrate that early cannabis use is associated with major depressive disorder and drug addiction. A strong association between schizophrenia and cannabis use is also apparent, especially when considering genetic factors that interact with this environmental exposure. These human studies set a foundation for carefully controlled animal studies which demonstrate similar patterns following early cannabinoid exposure. Given the vulnerable nature of adolescent neurodevelopment and the persistent changes that follow early cannabis exposure, the experimental findings outlined should be carefully considered by policymakers. In order to fully address the growing issues of psychiatric illnesses and to ensure a healthy future, measures should be taken to reduce cannabis use among teens.

Full Citation: 
Chadwick B, Miller ML and Hurd YL. (2013, Oct 14). Cannabis use during adolescent development: susceptibility to psychiatric illness. Frontiers in Psychiatry: Addictive Disorders and Behavioral Dyscontrol, 4:129. doi: 10.3389/fpsyt.2013.00129

Introduction

Cannabis sativa is grown worldwide for its production of Δ9-tetrahydrocannabinol (THC), a psychoactive compound found in the recreational drugs marijuana and hashish. The pervasiveness of this drug worldwide, along with its relatively low lethality, has led many to believe that it is of little harm. Indeed, the use of cannabis currently exceeds that of tobacco smoking among adolescents in the United States (1) (Figure 1). Whether cannabis is harmless, and without significant physiological or mental health impact, is actively debated. Unfortunately, these discussions are often not guided by evidence-based data. Research focused on the relationship between cannabis and mental health is thus important especially considering that psychiatric illnesses are complex disorders with multiple factors contributing to vulnerability and eventual expression of the illness. Based on the accruing data to date outlined in this review, developmental cannabis exposure is an important contributing factor to psychiatric vulnerability (Figure 2A).

FIGURE 1

Figure 1. Cannabis consumption is widespread in adolescents. Prevalence of this drug’s intake exceeds other illicit drug’s in eighth through twelfth graders in the USA (A), and it recently surpassed cigarette use (B). Graphs based on data adapted from Johnston et al. (1)(A,B).
 
FIGURE 2

 

Figure 2. Developmental cannabis increases vulnerability to psychiatric disease and overlaps with ontogenic changes in the endocannabinoid system. Adolescence is associated with an increased incidence of psychiatric illness, and exposure to cannabis (arrow head) during this developmental window strongly predicts subsequent development of mood disorders, addictive disorders, and schizophrenia (A). Components of the endocannabinoid system appear as early as embryonic life, but maximal CNR1 mRNA expression occurs during adolescence (B). (Green line = cannabis-exposed and gray line = unexposed individuals.)

Cannabis and Developmental Pattern of Use

Psychiatric illnesses are developmental in nature – the 12-month prevalence of any psychiatric illness is ∼40% in adolescents (2), but ∼25% in adults (3) – making it significantly germane to the strong developmental pattern of cannabis use. A plethora of studies and national surveys monitored the patterns of cannabis use in multiple ethnic and geographic populations worldwide. In the United States, cannabis use is highly prevalent during adolescence (Figure 1), the developmental period when most people initiate use. There are over 6000 first-time cannabis users per day in the US, over 60% of which are under the age of 18 (4). Approximately 34–45% of ninth through twelfth graders reported cannabis use at least once in their lifetime and the pattern of subsequent use appears more or less intermittent with 23% of 12 graders reporting use in the past month (1, 5, 6). Data from wave I–III of the National Longitudinal Study for Adolescent Health recapitulate this pattern of wide spread yet occasional use in adolescents. While the majority of teens have infrequent use, still a significant percentage, 6.6%, report daily use. Determining the long-term impact of occasional and heavy cannabis use during active periods of brain development, such as adolescence, is of critical importance. To provide such insights, data garnered from epidemiological and experimental studies is reviewed in this article. The emerging evidence strongly suggests that cannabis exposure during adolescence increases an adult’s individual vulnerability to drug addiction and schizophrenia and may also produce long-lasting effects on anxiety and mood disorders.

Endocannabinoid System

The psychoactive effects of cannabis, principally mediated by THC, occur via its interaction with the endocannabinoid system, which regulates numerous biological processes involved in development and neuroplasticity. The endocannabinoid system consists of lipid-derived ligands, receptors, and enzymes that orchestrate intercellular communication and intracellular metabolism. The most characterized endocannabinoid ligands – or endocannabinoids (eCBs) – include 2-AG and anandamide, which are presumably synthesized via phospholipase-mediated pathways. At least two G-protein coupled receptors, referred to as cannabinoid receptor-1 (CB₁R) and -2 (CB₂R), interact with these ligands. Additionally, recent evidence suggests that eCBs bind to ligand-gated channels, particularly TRPV1. In regard to the ligands, eCBs are synthesized from membranous precursors and immediately diffuse to nearby cannabinoid receptors, classically expressed on pre-synaptic terminals. Following these events, co-expressed enzymes, such as monoacylglycerol lipase (MGLL), α-β-hydrolase domain 6 (ABHD6), and fatty acid amide hydrolase (FAAH), degrade the ligand to terminate its signal (7, 8). Tightly regulated biosynthetic and degradative pathways ensure proper signaling throughout development, and the correct function of these processes depends on the temporal and spatial patterning of this system. Exogenously consumed cannabis produces supraphysiological effects at eCB-targeted receptors and thus usurp the normal endocannabinoid system (9).

The endocannabinoid system is critical for neurodevelopment and as such is present in early development, and maintains expression throughout life (Figure 2B), exhibiting a broad spatial distribution to regulate synaptic plasticity (10, 11). The CB₁R is found in numerous central nervous system structures as early as the eleventh embryonic day, and throughout the embryonic period this receptor is expressed in subcortical and cortical regions (12). In cortical projection neurons, CB₁R and local eCBs facilitate the fasciculation of descending efferents and thalamic afferents, orchestrating the tight coupling of these two tracts (13). During adolescence, the endocannabinoid system still facilitates neurodevelopment through its intricate involvement in neuroplasticity and synaptic function. Receptor levels of CB₁R in the prefrontal cortex and striatum fluctuate during adolescence depending on the specific brain region. For instance, there is a rapid, sustained increase in cannabinoid receptor binding during adolescence, particularly in the striatum, that is substantially reduced (by half) in early adulthood (14). In addition, the expression of the CB₁R gene (Cnr1) is highest during adolescence and gradually decreases by adulthood with the greatest decreases observed in limbic-related cortical regions such as the cingulate, prelimbic, and infralimbic cortices (15). Concomitant to developmental changes in the CB₁R, levels of anandamide and 2-AG, as well as FAAH enzymatic activity, fluctuate throughout adolescence in a region- and time-specific manner (16, 17). The distinct changes in CB₁R and other components of the eCB system during adolescence, some of which occur during a narrow time window, suggest that certain phases during this dynamic ontogenic period may incur different sensitivity to cannabis exposure. These observations highlight the fact that despite significant studies of CB₁R in the adult brain, there are still gaps of knowledge as to the role of CB₁R and the endocannabinoid system in the extensive pruning and development that is evident throughout adolescence.
 

Addiction Vulnerability

A gateway drug hypothesis had long been proposed implying that adolescent cannabis use predisposes individuals to use other illicit drugs as adults, thereby increasing their vulnerability to substance use disorders (18) (Figure 2A). Although, the term “gateway” has sometimes been misinterpreted to imply that all individuals who use cannabis will directly abuse other drugs, this original hypothesis by Kandel (18) conducted on cohorts of high school students suggested that cannabis use is a critical illicit drug, intermediate in the transition from legal substance use (i.e., cigarettes and alcohol) to illicit drug use (i.e., heroin, amphetamines, and LSD). Over a quarter of individuals who progressed to illicit drug use had previous experience with marijuana while only 2–3% of legal drug users without marijuana experience progressed to illicit drug use. Subsequent longitudinal studies that tracked younger adolescents found that early cannabis use positively predicted cocaine and alcohol use across a 1-year period (19). Additional evidence that early-life cannabis consumption increases cocaine use later in life is supported by studies representing broad demographic populations (20), suggesting that these findings are likely generalizable.

Prospective longitudinal studies have also offered compelling evidence in support of the gateway drug hypothesis. A landmark 25 year-long study conducted on a birth cohort from New Zealand assessed associations between age of onset, and frequency of cannabis use, with the use and/or dependence of other substances (21). Even after controlling for a number of confounding variables, such as socio-economic background, other illicit substance use, family functioning, child abuse, and personality traits, early cannabis use was still significantly associated with subsequent drug abuse and dependence. Additionally this effect was age-related such that the association between cannabis use and the development of drug abuse and dependence declined with increasing age of initiation. An important strength of this study was that data collection extended beyond self-reports, and included parental interviews, medical records, psychometric assessment, and teacher reports. Twin-studies, which control for potential confounds such as genetics and shared environmental influences, have also confirmed that early adolescent onset of cannabis use increases the likelihood of developing drug dependence later in life (22).

One concern with human epidemiological studies is the inability to distinguish between casual and purely associative relationships. This is highlighted by a common-factor modeling study which suggests that correlations between cannabis and illicit drugs were principally attributed to other factors, namely an individual’s opportunity for and propensity to use drugs (23). Therefore, it has been argued that the transition from cannabis use to other drugs is not causal but is simply an expected sequence engaged by individuals that would normally go on to use other illicit drugs. Moreover, many teens who routinely smoke cannabis also use other drugs (e.g., alcohol and tobacco). While sequential transitions and the co-abuse of other drugs during such times could potentially contribute to enhance psychiatric risk, it is impossible to ignore the growing body of evidence that suggest a significant contribution of early adolescence cannabis specifically to the propensity to develop substance abuse disorders later in life even when controlling for other substances (21, 22) (Figure 3).

FIGURE 3

Figure 3. Cannabis use is associated with progression to use other illicit substances in humans. Twin-studies illustrate that cannabis users have an increased risk of developing substance abuse disorder compared to their discordant twin. Graph based on data adapted from Lynskey et al. (22) (A). Cross-sectional studies reveal that earlier and more frequent cannabis use further increases this risk. Graph based on data adapted from Fergusson et al. (21) (B).

Animal studies allow the possibility to directly test the causal relationship between adolescent cannabinoid exposure and subsequent risk for drug addiction, independent of subject-specific factors that confound human investigations. Although a weakness of animal studies is that they do not mimic the complex nature of psychiatric disorder, specific phenotypes relevant to such disorders can be examined. In contrast to most psychiatric disorders, modeling addiction in animals is very predictive of the human condition through the use of self-administration paradigms wherein animals control their own drug intake. Under such conditions, adolescent exposure to THC reliably increases heroin self-administration (24, 25). In a similar investigation, performed in slightly older rats (approximately late adolescence), THC pre-exposure increased heroin self-administration when the contingency for heroin was fixed, but not when the work necessary to acquire heroin was progressively increased (26). Such findings imply that adolescent THC exposure increases the hedonic, but not motivational, aspects of heroin-seeking. Limited animal investigations have examined the sensitivity of early THC exposure to other “heavy” drugs of abuse such as cocaine, but the existing studies to date do highlight the generally enhancing effects of adolescent cannabinoid exposure on future drug-seeking behaviors, and experimentally support the gateway drug hypothesis.

Animal studies also provide specific insights about discrete neurobiological disturbances associated with developmental cannabinoid exposure. For example, adolescent THC increases inhibitory G-protein coupled signaling in the rodent midbrain, which by modulating dopaminergic projections, enhances mesolimbic dopamine, all adaptations strongly associated with enhanced reward (24). In addition, adolescent THC exposure increased mu opioid receptor function in the nucleus accumbens, a brain region central to reward and motivated behaviors, and these receptor impairments directly correlated to heroin intake (24). Moreover, increased gene expression of proenkephalin, an opioid neuropeptide that directly modulates heroin self-administration behavior, is also induced in the nucleus accumbens of adult rats with adolescent THC exposure (25). Enhanced cocaine self-administration has also been observed in female rats as a consequence of early-life exposure to the cannabinoid agonist CP-55,940 which was associated with altered striatal dopamine transporter binding in adulthood (27), and this transporter’s disturbance is highly implicated in addiction-related behaviors. Together these and other accumulating evidence in the literature emphasize that adolescent cannabinoids persistently change mesolimbic brain regions of the adult that sufficiently predict future self-administration behavior, a phenotype relevant to drug addiction vulnerability.
 

Negative Affect and Anxiety

Another major question regarding the impact of adolescent cannabis relates to its role in negative affective disorders, such as major depressive disorder (MDD), which are increasingly burdensome worldwide. While equivocal, several longitudinal studies demonstrate an association between MDD and early-life exposure to cannabis. A large multi-cohort longitudinal investigation that examined the effects of adolescent cannabis use on depression and anxiety showed that frequent adolescent cannabis use increased depression and anxiety in early adulthood (28). Furthermore measures of depression and anxiety during adolescence did not predict cannabis use in young adults suggesting that this relationship was not simply due to premorbid differences. Similarly, while individuals who used cannabis during early teens did not differ in depression, suicidal ideation, or suicide attempts during adolescence, by early adulthood these individuals had significantly higher incidence of suicidal ideation and suicide attempts (29). A consistent observation was reported in another large longitudinal investigation, which found that adults with early cannabis use had increased suicidal behaviors (30). Altogether these findings emphasize the important contribution of early cannabis exposure to MDD and suicidal ideation. Importantly, accumulating evidence also implies that both adolescent exposure and the continued use during adulthood are required for these associations (31, 32) suggesting that disease may be mitigated with cannabis cessation.

It is important to note that although most studies to date imply an association of early cannabis with negative affective disorders, the longitudinal cohort investigation by Harder et al. (33) did not find any difference in depression or anxiety either during early adolescence or at the last follow-up in adulthood. This inconsistency may be due to the study’s lenient definition of a “cannabis user,” which included any participant who ever smoked cannabis prior to age 17 (∼50% population). Although additional studies are needed to understand the long-term causative effects of adolescent cannabis on negative affect, a preponderance of the evidence accrued thus far strongly suggests a correlation between these two factors.

Future longitudinal studies are clearly still needed to examine the contribution of the developmental period of onset and cessation of cannabis to the risk of negative affect. In addition, in vivo neuroimaging in humans can also offer much needed neurobiological insights. Evidence already exists demonstrating volumetric impairments in the amygdala, a brain region central to affective and addictive disorders, in cannabis users during early (34), and late (35) adolescence. Similarly, structural changes in the hippocampus, which is linked to depression (36), has been reported in individuals with cannabis use during late adolescence (35, 37).

The use of animal models has also helped to fill gaps of knowledge regarding the direct link between early-life cannabis use and negative affect and anxiety. Such experimental studies have demonstrated that early exposure to cannabinoids directly leads to dysregulation of emotional processes and induces depressive-like phenotypes later in life. For instance, escalating doses of THC to adolescent rats decreases sucrose preference, a measure of anhedonia (38). Other behavioral strategies such as the forced-swim test used to measure depression-related symptoms also reveal a pro-depressive phenotype directly associated with adolescent THC (39), although these effects generally appear stronger in females (38, 40). These findings suggest that adolescent cannabinoid exposure could affect the liability to mood disorders later in life, and the potential gender differences may relate in those well-documented in human depression.

Altered anxiety-like behavior as a consequence of adolescent cannabinoid exposure is also apparent in experimental animals though the relationship is not straightforward per se. Anxiogenesis or anxiolysis has been reported depending on the period of cannabinoid exposure and the specific task used to model anxiety. For example, chronic exposure to cannabinoid agonists – such as THC, CP-55,940, or WIN-55,212-2 – during mid- to late-adolescence, increases social anxiety as measured with a social recognition task (41–44). Other measurements of stress that do not rely on social interaction, such as the open-field and elevated plus-maze tests, indicate varying degrees of anxiolysis, not anxiogenesis (41, 45, 46). These anxiolytic effects were observed after mid- to late-adolescent exposure, whereas earlier, pre-pubertal exposures (PND 15–40) were anxiogenic (47). Consistent with the notion of critical periods, persistent alterations in anxiety almost exclusively occur after early-life exposure and not in animals exposed as adults (39).

Few animal experimental studies have specifically focused on examining neurobiological mechanisms associated with regulation of emotion in association with adolescent cannabinoid exposure. Of the studies, Page et al. (48) demonstrated that administration of the cannabinoid agonist WIN-55,212-2 to adolescents, as compared to adult rats, more profoundly and persistently disrupted cells in the locus coeruleus, a midbrain region that contains noradrenergic neurons and is implicated with depression and anxiety. Similarly, adolescent animals treated with WIN-55,212-2 exhibit altered midbrain neuronal firing characteristics that were not observed in adult-exposed rats (39). Specifically, the cannabinoid treatment resulted in hyperactivity of the noradrenergic neurons concomitant with hypoactivity of serotonergic cells (39). Such neuroadaptations would be predictive of enhanced anxiety and depression-like behavior as a consequence of early cannabinoid exposure.
 

Schizophrenia and Schizoaffective Disorders

Although a small fraction of teens that use cannabis develop schizoaffective disorders, a number of epidemiological studies repeatedly demonstrate elevated risk to develop these psychiatric disorders in association with early-life cannabis use. Longitudinal studies assessing the relationship between early-life cannabis exposure and schizotypal personality disorder demonstrated that early adolescent use increases adulthood symptomatology (49). Moreover, the presence and severity of schizophrenic endophenotypes, such as psychotic symptoms and prepulse inhibition, were predicted by adolescent cannabis use (50, 51).

The first longitudinal studies demonstrating an association between cannabis use before adulthood and schizophrenia were conducted in Swedish conscripts (52, 53) Although no information was known about the individuals before conscription, subjects reporting previous cannabis use at the time of conscription were significantly more likely to be diagnosed with schizophrenia later in life. These findings were replicated in multiple studies emphasizing the reproducible relationship between adolescent cannabis use and increased schizophrenia symptoms in adulthood (54, 55).

Although it is challenging to model schizophrenia in animals, phenotypes related to this disorder may be studied. Animals exposed to cannabinoids during adolescence demonstrate increased schizoaffective-like phenotypes, such as impaired sensorimotor gating, which, similar to humans, results in decreased prepulse inhibition (45). Consistent with the notion that developmental cannabinoids induce a schizophrenia-like phenotype, acute administration of the anti-psychotic haloperidol normalized prepulse inhibition in the cannabinoid-exposed rats (47).

Since not all cannabis users develop schizophrenia, early cannabis use likely interacts with other factors to facilitate the emergence of this disease (56). Accumulating data in recent years highlight that the association between early cannabis exposure and vulnerability to schizophrenia is related to individual genetics. Pioneering studies by Caspi et al. (57) demonstrated that the relationship between adolescent cannabis use and schizophreniform disorder, as well as the presence of various psychotic symptoms, was attributable to the presence of a functional polymorphism in the catechol-O-methyltransferase (COMT) gene. This enzyme degrades catecholamines, such as dopamine, and this functional variant (COMTvaline158) catabolizes this neurotransmitter more rapidly than the methionine allele (58). In cannabis users, schizophreniform disorder is predominantly observed in persons with at least one copy of the polymorphic COMT gene (59–61). Moreover, clinical laboratory experiments show that THC’s acute psychotomimetic effects are moderated by this COMT SNP with THC-induced psychotic-like experiences and cognitive impairments being more pronounced in individuals with the valine158 allele (62). Animal models also confirm a link between the genetic disturbance of COMT and developmental cannabis such that adolescent THC exposure in transgenic mice lacking endogenous COMT synergistically impacts behaviors relevant to schizophrenia (63). Overall, these human and animals studies highlight the significant association between early cannabis exposure and schizophrenia, supporting the so-called two-hit hypothesis which posits that both genetics and early environmental factors enhance individual risk to psychiatric illnesses.

Phytocannabinoids and Psychiatric Vulnerability

It is important to emphasize that while most studies focused on THC to understand the long-term impact of cannabis, the plant produces at least 70 cannabinoids (64). To date the most studied phytocannabinoid aside from THC is cannabidiol (CBD), the second major constituent of the cannabis plant. Interestingly, in contrast to THC, CBD appears to have more protective effects relevant to addiction, cognition, and negative affect. For example, CBD inhibits drug-seeking behavior associated with heroin-relapse in rats (65), reduces cigarette intake (66), and inhibits morphine reward (67). It also has anti-psychotic properties (68, 69) and reduces anxiety behavior in rodents (70) and humans (66). Most of these investigations, however, were carried out in adults. No published study to date has examined CBD in relation to adolescent development and subsequent behavioral consequences in later life. As such, it remains to be explored whether the potential positive effects of CBD on brain function seen in adults would also be evident with adolescent exposure. One intriguing consideration about CBD relevant to the developing brain is that cannabis plants today ingested by teens are grown for high THC, but low CBD content (71). This significant change in the THC:CBD ratio could reduce a normally apparent protective constituent of cannabis. The fact that so little is known about CBD and the developing brain highlights the need for research about this and other phytocannabinoids to more fully understand the impact of cannabis to psychiatric vulnerability.

Conclusion

The high prevalence of cannabis use among teens and the increasing number of states in the USA that legalize cannabis for both medicinal and recreational purposes are concerning given the surprisingly limited information known about the impact of cannabis on the developing brain and individual susceptibility. Though a causative relationship cannot be determined between marijuana’s glamorization and its increasing use in teenagers, important lessons can be learned from the major inroads made in reducing cigarette use in youths such as interventions through campaigns that made smoking less socially accepted. Based on the current evidence available from human and animal models, it is evident that cannabis use during adolescent development increases risk of psychiatric diseases such as drug addiction and schizoaffective disorders with genetic interactions. No convincing data exist to support one “common cause” that exclusively predicts which individuals using cannabis as teens will progress to addiction and psychiatric disorders later in life versus those who do not. Psychiatric diseases, such as those discussed in this review, are complex and multifactorial. Indeed, the complex transition from early cannabis use to subsequent psychiatric illness involves multiple factors such as genetics, environment, time period of initiation and duration of cannabis use, underlying psychiatric pathology that preceded drug use, and combined use of other psychoactive drugs. Whether the early onset of cannabis use relates to preexisting pathology that is then exacerbated by the drug is still debated. Additionally, it remains uncertain whether there exist specific critical windows of vulnerability during different phases of adolescent development relevant to the long-term trajectory of risk in adulthood. Longitudinal investigations, making use of neuroimaging and genetics, alongside concurrent studies in animal models are needed to fully elucidate molecular mechanisms that could provide novel treatment interventions for individuals with psychiatric disease and comorbid adolescent cannabis use.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References available at the Frontiers site