Slate

Mellow, Paranoid, Happy, or Mean

By Brian Palmer

Why do people respond so differently to the same drugs?

Mean drunk or generous drunk?

Composite by Slate. Photos courtesy of Shutterstock.

Maureen Dowd, a 62-year-old Pulitzer Prize–winning columnist for theNew York Times, had a bad marijuana trip earlier this year. As part of her research into the legalization of recreational cannabis in Colorado, she ate a few too many bites of a pot-infused candy bar, entered a “hallucinatory state,” and spent eight paranoid hours curled up on her hotel room bed. Dowd used the experience as a jumping-off point to discuss the risks of overdosing on edible marijuana, which has become a major issue in pot-friendly states. It’s also possible, however, that Dowd just doesn’t handle cannabis very well. While pot mellows most people out, everyone has heard of someone who barricaded himself or herself in a dorm room after a few bongs hits in college. (Or maybe that someone is you.) Why do people react so differently to the same drug?

The question itself may be something of a fallacy. Cannabis is not a single drug—it contains dozens of compounds, and they appear to have varying, and sometimes opposing, effects on the brain. Tetrahydrocannabinol, or THC, and cannabidiol, or CBD, have been the subject of some intriguing research. In 2010, researchers showed that pretreating people with a dose of CBD can protect against the less pleasant effects of THC, such as paranoia. In a similar 2012 study, participants took pills that contained only one of the two chemicals, rather than the combination that you receive in cannabis. The subjects who took THC pills were more likely to suffer paranoia and delusion than those who took CBD.

The researchers went one step further to investigate which specific cognitive effects of THC are likely to lead to paranoia and other symptoms of psychosis. After taking either THC or CBD, participants watched a series of arrows appear on a screen and responded by indicating which direction the arrows were pointing. Most of the arrows pointed directly left or right, but occasionally a tilted arrow appeared. (Researchers called the tilted arrows “oddballs.”) Subjects who took the CBD had a heightened brain activity response to the oddballs. That’s the way a nondrugged person typically reacts—repetitions of the same stimulus don’t interest us, but a sudden change grabs our attention. The THC-takers had an abnormal response: They found the left and right arrows, which constituted the overwhelming majority of the images, more noteworthy than the oddballs. The researchers’ interpretation is that THC may undermine our ability to ignore routine, unimportant stimuli. Ignoring the ordinary is an important skill—we can’t function if every chirping bird or billboard grabs our attention and refuses to let go. Focusing obsessively on every meaningless detail in the environment may contribute to the paranoia that some pot users experience.

The differing effects of THC and CBD partially explain why some marijuana strains—which differ in the ratios and amounts of THC and CBD—are believed to provide giddy, excited highs, while others are thought to mellow the user, regardless of one’s personal neurological peculiarities.

Although both THC and CBD are present in marijuana, your brain may be more receptive to one of the chemicals than the other. Maureen Dowd’s brain may have a strong affinity for THC, while the mellower smokers may take up CBD more efficiently.

There is probably also a psychological element in addition to the neurochemical explanation. Consider the effects of alcohol. There are mean drunks, loud drunks, amorous drunks, withdrawn drunks, teary drunks, and many more kinds. There are no differences in the drug itself—unlike cannabis, alcohol has only one psychoactive substance—so there has to be another explanation.

There are scads of studies exploring the diverse effects of alcohol, much of it focusing on variations in alcohol-related aggression, but none of the studies are entirely satisfying. Psychological research rarely is. (That’s not a knock on psychologists or psychiatrists—it’s just a very tricky field.)

Top Comment

An old friend of mine, normally a nervous, sharp-tongued guy, gets completely mellow when he drinks. He pretty much stops talking and just smiles at the world like he's figured out the Secret of Life.  More...

-Mr. T & Sympathy

One theory is that some people don’t care very much about the consequences of their actions, even when they’re sober. When these people drink, they get aggressive, and their lack of foresight means they don’t bother to check their mean-drunk impulses. In a 2012 study, researchers at Ohio State showed that people who ignored consequences when sober got really excited about shocking their opponents in a drunken reflex competition. The study was widely publicized, but shocking a person in a laboratory setting is vastly different from punching someone in a bar. The legacy of the infamous Milgram experiment is also relevant—anyone participating in a psych experiment allegedly involving shocking other participants may well know it’s just pretend. Several other personality characteristics, such as anxiety levels, have been suggested as explanations for how people behave when intoxicated. Most of these studies are based on laboratory scenarios that don’t mimic well the drinking experiences you get in the wild.

There may a genetic basis for differing responses to alcohol. In a 2010 twin study, researchers attributed one-third of the variation in alcohol-induced aggression levels to genetic factors. The research was based on self-reporting, though, and the ability to estimate our own anger and aggression levels isn’t necessarily consistent from person to person.

Although the research hasn’t settled on simple explanations, it’s clear that some combination of personality traits, genetics, and experience affects how people respond to intoxicants. You can’t blame it all on the drug. Maureen Dowd’s rough night in Denver had something to do with the amount and kind of dope she consumed, as well as her own reaction to certain psychoactive chemicals. But her psychological makeup also likely played a role. I can think of a few people who might accuse her of an inability to consider the consequences of her actions.

Brian Palmer is Slate's chief explainer. He also writes How and Why and Ecologic for theWashington Post. Email him at explainerbrian@gmail.com. Follow him on Twitter.

SCIENCE NEWS

Legalization trend forces review of marijuana’s dangers

Pot may be far less risky than highly addictive drugs, but it's not harmless

BY LAURA SANDERS 

2:06PM, MAY 30, 2014

HIGH TIMES  Marijuana legalization advocates tout pot’s medicinal benefits and low addictiveness, while critics point to its neurological dangers. Research shows that the reality is somewhere in the middle.  

TANG YAU HOONG

Magazine issue: 

June 14, 2014

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SPONSOR MESSAGE

Some people think marijuana is nature’s gift to humankind: a nonaddictive drug, safe at any dose, that opens the mind, lifts the spirit and transports the user to a more profound reality.

“The illegality of cannabis is outrageous, an impediment to full utilization of a drug which helps produce the serenity and insight, sensitivity and fellowship so desperately needed in this increasingly mad and dangerous world,” a user named Mr. X wrote in the 1971 book Marihuana Reconsidered.

Close to 30 years later, Mr. X was revealed to be the legendary science communicator and astronomer Carl Sagan. His message still reverberates with many Americans, whose support for legalizing marijuana has tripled since 1989 — from 16 percent to 54 percent today. In Colorado and Washington state, voters legalized recreational marijuana use in November 2012. That formal embrace of marijuana may signal a growing shift in acceptance. Today, 21 states and the District of Columbia sanction medical use (up from 16 in 2010) and 17 have curbed punishments for possession of small amounts of recreational cannabis.

Marijuana as medicine is gaining support in studies, both to tamp down nausea and pain and to directly counter insidious diseases such as epilepsy, cancer and multiple sclerosis (SN: 6/19/10, p. 16). But what about for healthy people? Is marijuana really a safe way to rise above the tumult and distress of daily life?

Michele Leonhart, the head of the U.S. Drug Enforcement Administration, says no. In congressional testimony in 2012, she portrayed marijuana as a dangerous addictive drug on par with methamphetamines or heroin. Like other drugs cordoned off by her agency to a list called Schedule I, she said, marijuana has no medical use and a high potential for abuse.

Convinced of marijuana’s dangers, the DEA and vocal groups of police officers, educators and public health officials remain steadfastly opposed to the growing legalization movement. Legalization poses significant health and safety risks to Americans, they argue. This addictive drug wipes out memories, steals IQ points and triggers psychosis, leaving behind a zombie nation of slackers vegetating in their parents’ basements, opponents say. The consequences may be especially damaging for teens.

Who is right? The people who contend that marijuana is a misunderstood salve for the soul or those who claim it’s a dangerous narcotic that turns people into dimwitted potheads?

Turns out it’s neither. Though the research is far from definitive, the scientific evidence that does exist suggests that marijuana is far less dangerous than highly addictive drugs like heroin, methamphetamines and alcohol. But it is not harmless. Pot can probably cause permanent changes in the developing brains of adolescents. And though marijuana is not highly addictive, about 10 percent of users become dependent.

Altered states

Marijuana can speed up the heart, expand blood vessels in the eye and make the mouth feel cottony. It also has several targets in the brain.

Brain structure	Effect of marijuana on brain region
Amygdala	Can alter emotional states
Basal ganglia	Reduces motor activity; users may move less
Cerebellum	Can impair coordination
Cortex	May alter complex thinking, making it hard to pay attention or switch quickly between two tasks
Hippocampus	Memory center becomes less efficient, making it harder to learn and remember new information
Hypothalamus	Stimulates appetite, giving marijuana users the well-known "munchies" effect
Nucleus accumbens	Can make users want to use again by targeting this area, which is part of the brain's reward system

Source: K. Franson; Credit: Alila Medical Media/Shutterstock

It’s unlikely that existing research will be able to provide a clear-cut answer about whether legalization is a good idea. But in a way, that debate is already over. As popular sentiment shifts and laws become more lenient, marijuana becomes a bigger piece of the social fabric.
“We’re at this point, whether we like it or not, where things are changing, and they’re changing fast,” says Susan Weiss, associate director for scientific affairs at the National Institute on Drug Abuse (NIDA) at the National Institutes of Health. Her agency is funding studies to better understand the effects of marijuana, she says, so that the science can better inform public policy.

Your brain on pot

When a person tokes, eats or vapes cannabis, a wave of THC, or tetrahydrocannabinol, washes into the brain.

Thought to be the major psychoactive ingredient in marijuana, THC latches on to a protein in the brain called cannabinoid receptor type 1, or CB1. These receptors are sprinkled liberally throughout the brain, especially in the cortex, where thinking takes place; the basal ganglia, which helps control movement; the appetite-regulating hypothalamus; and the hippocampus, a structure involved in forming memories.

CB1 receptors are an important part of how the brain works, says neuroscientist Valerie Curran of University College London. “They’re not put there by God so we can all enjoy cannabis,” she says. “They’re put there because we have our own cannabis in our brains.”

The brain’s self-made cannabis consists of molecules called endocannabinoids, which hit the targets that cannabis hijacks. One of the primary endocannabinoids is named anandamide, after the Sanskrit word for bliss. The brain’s endocannabinoid system influences pain, memory, mood and appetite, and plays a role in helping the brain grow.

So when foreign THC taps into this system, the effects can feel profound, says psychologist Mitch Earleywine of the University at Albany in New York. “It’s got a novelty,” he says. “It’s got its own receptor system and its own set of effects. The fact is that not a lot of other substances hit that CB1 receptor.“ That’s how cannabis elicits its particular brand of euphoria and cognitive flexibility, says Earleywine, who also serves on the board of NORML, the National Organization for the Reform of Marijuana Laws, which pushes to legalize the drug.

Unlike some other reality-altering drugs, cannabis doesn’t seem to be lethal, even in high doses. “Can you die from alcohol just by drinking yourself to death? Yes, you can,” says pharmacologist Kari Franson of the University of Colorado Denver. “Can you die from marijuana just from ingesting too much or smoking too much? Well, not really. You pretty much have to fall down and hit your head to die from it.” (A paper published in the April Forensic Science International does describe the deaths of two presumably healthy young men from heart trouble under the acute effects of cannabis. But overall, deaths seem to be rare.)

Leaning green

From the 1960s until about four years ago, the majority of Americans thought pot should be illegal. Today, views have shifted, with 54 percent supporting the legalization of marijuana.

Source: Pew Research Center 2014

Marijuana may not be deadly, but there are some clear downsides. A mental juggling act called working memory, the ability to hold pieces of information in mind, is diminished in someone who’s high, 40 years’ worth of studies show. Marijuana use has been linked to cardiovascular problems, most recently in a paper in the April Journal of the American Heart Association thatdescribes heart problems in young cannabis users. Cannabis intoxication may double a driver’s risk of a car crash, scientists reported in 2012 in BMJ. And heavy smokers can show more signs of lung damage compared with nonsmokers, though whether that actually leads to more disease is unclear, according to a 2013 reviewpublished in the Annals of the American Thoracic Society.

“We’re worried about having another drug that’s highly prevalent and very accepted by society,” says Weiss of NIDA. The burden of problems will only get worse, she says, including altered brain development, poorer school and work performance and higher numbers of people who are addicted. Between 2009 and 2011, as use rates went up, the rate of emergency room visits for cannabis intoxication rose by 19 percent, according to the Drug Abuse Warning Network.

Addiction

The concept of addiction plays front and center in the debate. Marijuana proponents are fond of pointing out that the drug is less addicting than tobacco and alcohol, substances that are legal for adults. And that is correct. On a relative scale, marijuana just isn’t as addictive as other substances, says Franson.

“Think about those poor little rats pushing levers to get cocaine. They forgo eating, forgo sex, forgo everything because they just want to hit that lever,” she says. Marijuana’s addictive allure doesn’t compete with opiates, or even alcohol or tobacco. But that doesn’t let marijuana off the hook, she says. “It’s not the worst offender, but it still does have some of those addictive components,” Franson says.

It’s not clear what goes on in the brain to cause pot addiction, or why so many people escape it. Marijuana somehow reduces the number of CB1 receptors in the brains of people who smoke regularly, an effect that might contribute to addiction, scientistsreported in Molecular Psychiatry in 2012. But after a month of abstinence, the receptors bounced back to normal levels everywhere except the memory-forming hippocampus. Regular marijuana use might also influence an addiction-linked pathway that involves the neurochemical dopamine, though the details of that interaction aren’t clear. Studies, mainly on animals, suggest that over time, cannabis might change the feel-good parts of the brain, including the neurons that produce dopamine, in ways that prompt people to keep using it.

Average number of daily U.S.
emergency room visits for drug use in
teens ages 12–17

197

Alcohol, alone or with other drugs

165

Marijuana
 

74

Pain relievers

Source: 2011 SAMHSA Drug Abuse Warning Network

Those changes might explain why some people struggle to stop using marijuana. About one user in 10 becomes dependent, defined by criteria described in theDiagnostic and Statistical Manual of Mental Disorders. Those criteria include two key features: tolerance and withdrawal. 

Experienced marijuana users need to up their dose as they become tolerant. “You need more of the drug to have the same effect,” says Franson. Animal studies bear that out: Mice exposed habitually to THC need more and more of the drug to show the same motor deficits.

Marijuana withdrawal is even more contentious than tolerance. After stopping heavy marijuana use, some people — but not everyone — experience irritability, anxiety and loss of appetite. Still, those symptoms are mild compared with an opiate or alcohol withdrawal, Earleywine says. “If you tell an opiate addict you’re ‘addicted’ to marijuana, you’re probably going to get kicked in the crotch,” he says.

But if cannabis isn’t lethal and doesn’t cause debilitating withdrawal, then is habitual use really such a bad thing? The answer, it turns out, probably depends on the age of the smoker.

Trouble for teens

Scientists can’t say with confidence what marijuana does to the body and brain long-term, for several reasons. It would be unethical to randomly assign study participants to use an illicit drug for months, so the best scientists can do is look for associations — particular traits, abilities or limitations that appear more frequently in people who use cannabis. This approach leaves open all sorts of variables: People are from different backgrounds and smoke marijuana from different sources, for starters. The most these studies can offer is possible links.

One of the strongest links found so far comes from studies of young people. The teenage brain is still growing and refining its neural connections — a process that’s regulated in part by the brain’s natural endocannabinoid system. Marijuana use when the brain is vulnerable may interfere with its normal development. “The developing brain is at risk,” Franson says.

Young adults, ages 18-25, who used marijuana at least once a week were more likely than nonsmokers to have structural differences in two brain areas thought to be involved in addiction, the nucleus accumbens and the amygdala. The differences were more pronounced with increased use, researchers reported April 16 in the Journal of Neuro­science. Scientists don’t know whether these brain differences track with any behavioral deficits.

Adolescents who heavily use marijuana are more likely to perform poorly in school and drop out, though the effects of cannabis can’t be easily separated from other social factors. New Zealanders in one study who used marijuana heavily during their teens showed an IQ drop of about eight points by the time they’d reached age 38. Because the study began before the participants started using marijuana and ran for decades, the results offer some of the strongest evidence yet that marijuana contributes to an IQ decline. But even these results come with caveats and methodological limitations.

Coast-to-coast

In the last decade, a growing number of states have passed laws legalizing marijuana, both for medical and recreational use. The numbers are expected to rise. In April, Maryland became the 18th state to ease punishment for marijuana possession and the 21st to allow medical marijuana.

Source: National Conference of State Legislatures, NORML; Credit: Vectorapz™, adapted By E. Otwell

Marijuana’s long-term effects on people who start using the drug as adults are even less understood, but the hints provided from some studies suggest that it’s not as harmful as adolescent use. That same IQ study, for instance, found no decline in people who began using cannabis as adults.

A different study, published in the May Addictive Behaviors, looked at whether the cognitive effects of marijuana in adults go away when people stop using. “It’s generally known that the acute effects are there,” says study author April Thames of UCLA. “The question is, do these reverse over time?”
Most of the negative effects of marijuana — poorer attention, working memory and mental nimbleness — were absent in adults who had not used the drug for a month, Thames and her colleagues found. However, a person’s ability to plan and make complicated decisions was still impaired a month out.

The results offer just a “snapshot at the time we did the testing,” Thames says. They describe an association, not causation. “The question down the road is, what kind of implications does that have for everyday functioning?”

Scientists have largely failed to turn up compelling evidence that adult pot smokers risk permanent brain problems, Earleywine says. “Being stoned all the time is a strange way to live your life,” he says, but data just aren’t there to argue that a cannabis-fueled lifestyle is permanently harmful to the adult body and brain.

The new reality

As researchers try to make sense of study results, the nascent marijuana industry is charging ahead in a Wild West capitalistic society. That’s worrisome, many scientists say. Policies should regulate the quality and strength of marijuana, and keep it away from children, Franson says.

In Colorado, where drug laws have been loosened, first for medical marijuana and then for recreational use, a growing number of children under 12 have been admitted to emergency rooms for acute marijuana intoxication, according to a study in the July 2013 JAMA Pediatrics. There ought to be tighter controls over shops, particularly those that sell marijuana-infused products like chocolates and cookies that entice children. Many marijuana retailers “look like sweets shops,” Curran says.

NIDA is keeping tabs on ER visits as well as the increasing levels of THC in cannabis seized by law enforcement agencies, and how marijuana legalization has affected the health of people in Colorado and Washington State.

Some researchers see the growing availability of marijuana as inevitable and are advocating ways to keep the drug out of the hands of young people.

No worries

As high school seniors think pot is less of a problem, mirroring adult attitudes, their use of the drug is going up. Marijuana use might be particularly risky for young brains, studies suggest.

Source: Monitoring the Future study, 2013, Univ. of Michigan

“Kids are growing up on a much more toxic form of marijuana than they would have done years ago,” Curran says. Today’s plants are very high in THC and low in a compound thought to counter its effects called cannabidiol, or CBD. THC levels in marijuana have increased from 3.4 percent in 1993 to 8.8 percent in 2008, according to a marijuana potency-monitoring project at the University of Mississippi. A more regulated market might keep the most potent marijuana out of the hands of young people, Curran says.

More accurate testing and labeling of marijuana products would help, many researchers believe. THC concentrations can vary from seller to seller and even batch to batch. “People need to know what they’re getting,” Franson says. “It’s just named these weird names.” Purple Urkel, Girl Scout Cookies and Super Silver Sour Diesel Haze are some of the options available in stores. Colorado is trying to improve labeling to describe important differences, which is particularly urgent for people who rely on certain doses of THC or CBD to treat medical conditions.

When marijuana is eaten, THC takes longer to reach the bloodstream, and its absorption rates can vary greatly. This imprecise delivery system can cause people to take much more than they intended. Proper labeling might help people better titrate their dose, Franson says.

Even Earleywine, who supports legalization, says he’s concerned about commercialization of marijuana. “America is so free market and wild that it’s going to take some reining in to make sure that no one is penalized for it and medical users have access, but it’s not sponsoring every sport event or on TV every five seconds,” he says. Current restrictions on cigarettes might be a good model for the burgeoning marijuana industry, he says.

Imperfect science leaves people on both sides of the marijuana debate wanting more. But in a way, the good-or-bad, yes-or-no argument is over: Marijuana is creeping across the country. That’s probably not catastrophic for adults, but for young people, the implications are more worrisome. Just how worrisome is something scientists are still figuring out. That knowledge may help ease the transition to an ever-greener world.

---

Editor's note: This article appears in the June 14, 2014 Science News under the headline: "High times: Legalization trend forces consideration of pot's dangers."

Citations

E. Jouanjus et al. Cannabis use: Signal of increasing risk of serious cardiovascular disorders. Journal of the American Heart Association. April 23, 2014. doi: 10.1161/​JAHA.113.000638
M. Asbridge, J. A. Hayden and J. L. Cartwright. Acute cannabis consumption and motor vehicle collision risk: systematic review of observational studies and meta-analysis. BMJ. February 9, 2012. doi: 10.1136/bmj.e536
D. P. Tashkin. Effects of marijuana smoking on the lung. Annals of the American Thoracic Society. Vol. 10, June 2013. doi:  10.1513/AnnalsATS.201212-127FR
J. Hirvonen et al. Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers. Molecular Psychiatry. Vol. 17, June 2012. doi: 10.1038/mp.2011.82.
H. H. van Hell et al. Chronic effects of cannabis use on the human reward system: An fMRI study. European Neuropsychopharmacology. Vol. 20, March 2010. doi: 10.1016/j.euroneuro.2009.11.010
J. M. Gilman et al. Cannabis use is quantitatively associated with nucleus accumbens and amygdala abnormalities in young adult recreational users. Journal of Neuroscience. Vol. 34, April 16, 2014. doiI:10.1523/JNEUROSCI.4745-13.2014
M. H. Meier et al. Persistent cannabis users show neuropsychological decline from childhood to midlife. Proceedings of the National Academies of Science. August 27, 2012. doi: 10.1073/pnas.1206820109
A.D. Thames et al. Cannabis use and neurocognitive functioning in a non-clinical sample of users. Addictive Behaviors. Vol. 39, Issue 5, May 2014. doi: 10.1016/j.addbeh.2014.01.019
G. S. Wang, G. Roosevelt, K. H. Heard. Pediatric marijuana exposure in a medical marijuana state. JAMA Pediatrics. Vol. 167, Issue 7, July 2013. doi:10.1001/jamapediatrics.2013.140
Z. Mehmedic et al. Potency trends of delta-9-THC and other cannabinoids in confiscated cannabis preparations from 1993 to 2008. Journal of Forensic Sciences. Vol. 55, Issue 5, September 2010. doi: 10.1111/j.1556-4029.2010.01441.x

The Cannabis-Psychosis Link

Psychiatric Times is a community for physicians and healthcare professionals. Commenting is only available to qualified physicians and professional providers. - See more at: http://www.psychiatrictimes.com/schizophrenia/cannabis-psychosis-link/page/0/1?cid=G%20#sthash.nm3n0Jai.dpuf

The Cannabis-Psychosis Link

January 12, 2012 | Schizophrenia, Addiction, Alcohol Abuse, Psychotic Affective Disorders

By Marie-josee Lynch, MD, Rachel A. Rabin, MSc, and Tony P. George, MD, FRCPC

- See more at: http://www.psychiatrictimes.com/schizophrenia/cannabis-psychosis-link?cid=G+#sthash.f3kNav4B.dpuf

"Marijuana doesn’t count, does it?” Clinicians are familiar with this common reply when screening for drug use. Cannabis—the most common illicit substance—has managed to exempt itself from the hazardous reputation held by other illicit drugs.1 As mental health practitioners, it is our duty to educate our patients about the potential harms and consequences of cannabis use. This important task is complicated by the disagreement and uncertainty surrounding the nature of the interaction between cannabis and psychotic disorders.

While research suggests that cannabis use can induce an acute psychotic state, there is controversy about whether it may precipitate psychotic disorders, such as schizophrenia. In this article, we provide an update on the literature on this important issue, emphasize areas in need of research, and provide clinically useful recommendations.

More than 16 million Americans use cannabis on a regular basis, typically beginning in adolescence. Notably, it is estimated that approximately 4% of the population have a diagnosis of either cannabis abuse or dependence.1 A history of cannabis misuse is even more common in patients who are schizophrenic than in the general population; 25% of patients with schizophrenia have a comorbid cannabis use disorder. Cannabis use disorders are especially common in younger and first-episode patient samples and in samples with high proportions of males.2

Neurobiology

Marijuana contains more than 400 chemical compounds, including over 60 cannabinoids that contribute to its psychopharmacological effects. The primary psychoactive constituent of cannabis is delta-9-tetrahydrocannabinol (THC). Other plant cannabinoids include delta-8-tetrahydrocannabinol; cannabinol; and cannabidiol (CBD); CBD is the second major psychoactive constituent of cannabis.3 The ratios of these and other cannabinoids vary enormously in preparations of cannabis, and little information exists about the concentration of each of the particular cannabinoids in commonly used cannabis products. Concerns have been expressed regarding the large increase in the potency of cannabis and the surrounding health implications. In the 1960s, the THC content was thought to be in the range of 1% to 3%; today it can reach up to 20%.4

The endogenous cannabinoid system consists of 2 types of G-protein-coupled receptors: cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptors. CB1 receptors are the most abundant in the brain, while CB2 receptors predominate on immune cells. CB1 receptors are highly concentrated in brain regions implicated in the putative neural circuitry of psychosis and cognitive function. These include the hippocampus, prefrontal cortex, anterior cingulate, basal ganglia, cerebellum, and cortex, with lower levels present in the thalamus, hypothalamus, and amygdala. Activation of CB1 receptors mediates the behavioral and physiological effects of both endogenous and exogenous cannabinoids in the brain.4

An important role of the CB1 receptor is to modulate neurotransmitter release in a manner that maintains homeostasis by preventing excessive neuronal activity in the CNS.5 CB1 receptors are localized on presynaptic neuron terminals on both inhibitory and excitatory neurons, yet they predominate on γ-aminobutyric acid interneurons.6 It is the inhibitory neurons that are thought to mediate most of the effects of cannabinoids. In addition, the action of cannabinoids includes interactions, albeit indirectly, with the dopaminergic system.

THC is a partial agonist at the CB1 receptors, where it has modest affinity and low intrinsic activity. In contrast, CBD shows very little affinity for CB1 receptors. Moreover, the precise molecular mechanism of action of CBD remains unclear. The main endocannabinoids are anandamide and 2-arachidonylglycerol. In contrast to classic neurotransmitters, endocannabinoids can function as retrograde synaptic messengers—they are released from postsynaptic neurons and travel backward across synapses, activating CB1 on presynaptic axons and suppressing neurotransmitter release.

Cannabinoids produce an increase in the dopaminergic activity in the mesolimbic reward pathway, which plays a pivotal role in mediating the reinforcing effects of most drugs of abuse. The increased dopaminergic drive elicited by the cannabinoids could underlie the abusive property of the drug and increases in positive psychotic symptoms induced by THC.7 Recurrent cannabis use produces prolonged and excessive stimulation of the CB1 receptor, and this is thought to disrupt endocannabinoid system function.8 Several lines of evidence exist to suggest a role for cannabinoids and their receptors in the pathophysiology of schizophrenia. It has also been proposed that this CB1 receptor overstimulation may be a contributing factor in triggering THC-induced psychosis.9

The cannabis-psychosis link

Many studies have explored the link between cannabis and psychosis (Table). In a systematic review, Moore and colleagues10 surveyed the literature on this topic. They looked at population-based longitudinal studies as well as nested case-control studies that assessed the impact of cannabis use on the later development of psychosis. The “psychosis” outcomes required the diagnosis of a primary psychotic disorder or affective psychosis, or the occurrence of delusions, hallucinations, or thought disorder during the study period. Results from 7 cohort studies showed a 40% increased risk of psychosis in cannabis users compared with nonusers. The data also revealed a dose-response effect—the risk of psychotic symptoms was increased approximately 50% to 200% in those who used cannabis frequently compared with nonusers.

What is already known about the link between cannabis use and psychosis?

There is strong evidence to support the hypothesis that cannabis consumption is a risk factor for the development of psychotic symptoms and schizophrenia.

 

What new information does this article provide?

This article emphasizes the negative effects of cannabis use in young populations and in those who may confer a genetic risk. We further believe that even in the face of enhanced cognitive function among cannabis-using patients with established schizophrenia, this cannabis use worsens the clinical course and overall prognosis of the disorder.

 

What are the implications for psychiatric practice?

While scientists attempt to clarify the relationship between cannabis and psychosis, it is important that we take the link between cannabis and psychosis seriously by definitively assessing patients for cannabis use. Clinicians should be educating their clients about the potential dangers of using cannabis and the potential bene­fits of quitting.

Critics of this hypothesis believe that cohort studies have inherent limitations that prevent any clear conclusions from being drawn. McLaren and colleagues11 evaluated the methodological strength of the existing cohort studies. The definition of psychosis was a recurrent limitation in the studies. Many studies used psychotic symptoms, not diagnoses, as their outcome, which may not be of clinical significance. Moore and colleagues10 also noted this limitation and attempted to correct for it by separately analyzing the 2 studies that required the diagnosis of a primary psychotic disorder. Interestingly, they found an odds ratio of 2.6 for the development of psychotic disorders in those who had ever used cannabis compared with nonusers. Important confounding factors, such as noncannabis drug use, a family history of psychosis, and unmeasured vulnerability to psychosis, were not adequately controlled in these studies.11

Age at onset of psychosis and cannabis use

Certain risk factors have been reported to interact with cannabis use to increase vulnerability to developing psychosis. One suspected important variable is the age at which cannabis use is started. The age effect was first noted in a Swedish conscript cohort study that demonstrated that cannabis use by age 18 led to a 6-fold increase in the risk of schizophrenia later in life.12 It is unclear, however, whether the psychotic symptoms predated the cannabis use.

To clarify this issue, the Dunedin Multidisciplinary Health and Development Study conducted a prospective longitudinal study of adolescent cannabis use, taking into account psychotic symptoms that occurred before cannabis use.13 The data were compiled from a birth cohort that consisted of 1037 individuals born in Dunedin, New Zealand. Information about psychotic symptoms was obtained at age 11, and drug use was assessed by self-reports at ages 15 and 18 and by a standardized interview schedule at age 26. Two psychosis-related outcomes were measured—the presence of symptoms of schizophrenia and the diagnosis of schizophreniform disorder.

The results showed that those who had used cannabis by ages 15 and 18 had more schizophrenia symptoms than controls, a finding that remained significant after controlling for the presence of psychotic symptoms at age 11. However, the increased likelihood of schizophreniform disorder at age 26 was no longer significant after controlling for psychotic symptoms at age 11. Taken together, this suggests that early cannabis use confers higher risk of psychosis.

These findings may be explained as follows: Adolescence represents a sensitive period of neurodevelopment, with the brain more vulnerable to the effects of cannabis. Alternatively, the heightened risk may simply be a consequence of greater cumulative cannabis use, since these subjects began using it at a younger age. These theories are not mutually exclusive, and the latter explanation is consistent with the previously mentioned dose-response relationship observed in many studies.

Genetic vulnerability

A subsequent study conducted with the Dunedin cohort investigated whether specific genes increase the risks associated with early cannabis use.14 The researchers examined the role of the catechol-O-methyltransferase (COMT) gene, whose link with psychosis has been the focus of many studies. The COMT gene encodes the enzyme responsible for the synaptic metabolism of dopamine. A functional polymorphism of this gene, Val158Met, has been shown to slow the breakdown of dopamine, which potentially increases the risk of psychosis.15,16 The results of the study showed that the presence of the valine polymorphism was not significant unless coupled with adolescent cannabis use.13

Persons with Val/Val or Val/Met genotypes and adolescent cannabis use were at increased risk for schizophreniform disorder (with respective odds ratios of 10.9 and 2.5), while individuals with Met/Met genotypes were not. These findings implicate genetic factors as important contributors to the cannabis-psychosis link, but they are in need of replication.

Impact of cannabis use on the course of schizophrenia

The extent to which cannabis use might alter the clinical course of schizophrenia remains a point of contention within the literature. Intuitively, one may expect cannabis to have a negative impact on the expression and course of schizophrenia. Findings suggest that patients with schizophrenia who use cannabis experience increased psychotic symptoms, are more likely to have relapses, have a greater likelihood of rehospital­ization, and experience poorer ther­apeutic response to antipsychotic medication than patients who are cannabis-naive.17,18 Furthermore, pre-onset cannabis use may trigger an earlier age of onset of psychosis, which is of critical importance given the negative prognostic features associated with earlieronset.19 These effects have been reported to be dose-dependent.

It is interesting to note that other studies have been unable to confirm these adverse findings after controlling for potential confounding factors, which include but are not limited to alcohol and drug use, premorbid functioning, and family history. Moreover, it has been suggested that patients with comorbid cannabis use constitute a clinically distinct subgroup of schizophrenia patients.

In this respect, cannabis use may trigger the onset of psychosis in vulnerable individuals in whom a psychotic disorder otherwise may not have developed. As a result, these patients have a better prognosis, exhibit fewer negative symptoms, have better social skills, and have an enhanced treatment response compared with nonusers. In addition, a recent meta-analysis demonstrated that patients with lifetime cannabis use disorders have superior cognitive function compared with nonuser counterparts.20

These conflicting findings may be due to the varying levels of THC/CBD found in street cannabis. The fact that these constituents have divergent properties may explain the manifestation of different psychological symptoms among users. In fact, CBD may actually attenuate some of the unwanted psychopharmacological effects of THC, because it may have anxiolytic and antipsychotic properties.21 Furthermore, CBD has been shown to have neutral or even procognitive effects.22

Conclusions

Despite all of the uncertainties surrounding the cannabis-psychosis link, we are left with the task of translating these results into clear recommendations for our patients. The evidence suggests that cannabis is associated with an increased risk of psychosis when it is used frequently. Whether cannabis can trigger a primary psychotic disorder that would not have otherwise occurred is unclear. However, in most individuals who use cannabis, psychosis does not develop, which suggests that the increased risk must be related to other vulnerability factors (genetics, frequency, or age of onset of cannabis misuse).

Cannabis also seems to negatively alter the clinical course of schizophrenia. While meta-analyses suggest better cognitive function among cannabis-using patients, this may be a reflection of a higher-functioning subgroup of schizophrenia patients. Accordingly, cannabis-using patients who achieve abstinence may demonstrate improved symptoms and cognitive performance.

The first step in communicating this information to our patients consists of screening for cannabis use and obtaining a thorough substance use history. Psychoeducation and early interventions for young patients who may be vulnerable to psychosis should be used, and motivational interviewing and cognitive-behavioral therapy should be considered to encourage reduction and cessation of use.

There are no accepted pharmacological treatments for cannabis use disorders, yet several potential agents are under investigation. Future studies that control for both environmental and biological risk factors are needed to more clearly elucidate the mechanisms linking cannabis misuse to psychosis.

REFERENCES

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