ADVICE ON MENTAL HEALTH: What Research Tells Us About Cannabis Use — And What Parents Should Consider

ADVICE ON MENTAL HEALTH - from Brain & Behavior Magazine, January 2022 issue

Q&A with Martin Paulus, M.D.

Scientific Director and President

Laureate Institute for Brain Research

Deputy Editor, JAMA Psychiatry

2000 BBRF Young Investigator

Martin Paulus has published over 300 scientific papers and has been funded continuously by federal grants since 1997. Among his current projects, he is a member of the NIMH’s Adolescent Brain Cognitive Development (ABCD) study, which is closely following some 11,000 youths from age 9–10 to adulthood to determine how the brain changes during the course of adolescence and how these changes put adolescents at risk for substance use. The Paulus lab is also engaged in several studies involving the impact of cannabis upon the brain, as well as research exploring the possible utility of pharmacological modifiers of the body’s own cannabinoid system to treat anxiety and depression.

Dr. Paulus, cannabis is a substance that until recent years was illegal. Today, many states have legalized cannabis, some for recreational use, some for “medicinal use” only. Either way, this represents a major shift. We wonder whether the trend to legalize cannabis is accompanied by a solid body of research that would assure the parents of an adolescent, for example, that the use of cannabis from an early age is harmless.

The short answer is that research to date is not able to support such a reassurance. I don’t want to be an alarmist, but it is crucial that we try to understand what research so far has revealed about cannabis, and in that context, to consider why people use cannabis and what its impacts are on the brain and behavior—both in adults and young people. Also, it’s important to try to distinguish among those who use cannabis. Research suggests that some people are likely at greater risk than others.

In your own research, we understand that you and colleagues are investigating the possibility of using modifiers of the body’s own, naturally occurring cannabinoid system to treat anxiety and depression. We will write at a later date about this very interesting work. In this conversation, we’d like to focus on cannabis that is derived from plants, and how ingesting it—whether by smoking it, vaping it, or eating it in the form of various foods or even cannabis-infused candies—may or may not pose risks for young people, in particular. After decades of public discussion and debate about cannabis, we’re curious: why hasn’t research managed to resolve the ambiguities about safety and risk?

There is much we still do not know, and there are reasons for this. As you noted, many of the states have moved ahead quite vigorously to legalize the use of cannabis and cannabis-based products such as those containing CBD (cannabidiol, a non-psychoactive component in cannabis). But there is a real disconnect between liberalized state laws and federal law.

Federal law still considers cannabis a Schedule I substance, considered to have a high potential for abuse and no currently accepted medical use. That’s the same designation that is given to LSD, heroin, cocaine, mescaline, and heroin. Because cannabis is still a Schedule I drug, it is very difficult to do federally funded studies with it. You need to have a special license from the Drug Enforcement Administration. These are hard to obtain. Also, the federal classification of cannabis means that researchers, when they are authorized to study it, have to obtain it from regulated federal sources. The National Institute on Drug Abuse (NIDA) makes cannabis available to researchers, but the concentration of THC is much lower, meaning it has much less effect on users compared with the cannabis that people regularly purchase and consume in various forms today. So you’re not really studying the same drug that people are using on a day-to-day basis.

Is the cannabis that is now being sold to the public different than the cannabis people consumed in the 1970s and 1980s?

Today’s cannabis is far more potent. THC is the main psychoactive ingredient in cannabis. Its concentration in street-use cannabis was in the single-digit percentage range in the ‘70s and ‘80s. But the formulation that people buy today in, say, Colorado or California, or even here in Oklahoma, is much more concentrated, with THC in the 20%–30% range.

We have heard that in some formulations of the product—the “concentrate,” for example—the THC content can be 70% or higher.

This is indeed true. The point is that the makeup of the drug itself has changed dramatically over the years. There are several things to consider about this. One is that when people say, “There’s nothing wrong with cannabis; I smoked it in the ‘70s, so I know it’s fine,” they are talking about a different era that may not be a good guide to potential risks of the cannabis in use today. Another is that not having access to the currently consumed form of cannabis due to federal classification is a real problem for research; it makes it very difficult to study the long-term health impacts, positive or negative, associated with cannabis consumption.

A bill has been drafted by several senators to “de-schedule” cannabis by removing it from restriction under the Controlled Substances Act. What are your thoughts on this?

This would be of great benefit to research because we would then have the chance to much more thoroughly research cannabis—which must be the basis of responsible recommendations to the public.

Before we go further, can you tell us a bit about how cannabis works? And about the body’s own cannabinoid system, called the endogenous cannabinoid system?

THC, the main psychoactive ingredient in the cannabis plant, is one of over 100 known compounds in the plant that affect the body in one way or another. CBD—cannabidiol—is the other main ingredient of cannabis, considered by some people to be “the good sister” of THC. It has no psychoactive effects and may have some therapeutic effects in the brain and body, although this remains to be proven. The human body has its own system that produces cannabinoids—the endogenous cannabinoid system. There are two cannabinoid receptors, CB1 and CB2, which are widely distributed throughout the brain. These receptors are where the cannabinoids made by the body “dock.” These receptors are also occupied when we ingest plant-based cannabis. I’ll return to this later, but for now I want to note that ingesting cannabis creates competition for the receptors with the body’s own cannabinoid system.

Why do we even have an endocannabinoid system? Why does the body make this substance?

That’s a good question, because it helps explain why people seek to supplement it by ingesting plant-based cannabis. There are many systems in the brain that have evolved over the eons to enable individuals to modulate their responses to the vast range of stimuli and situations that we confront. Think of the many neurotransmitter systems like dopamine and serotonin. Or CRH, the corticotropin-releasing hormone, which helps modulate the response to stress. Or norepinephrine, which is released when we need to pay attention to something. Each of these systems has specific pathways and receptors that make their effects possible. The endocannabinoid system is one of these many regulatory systems. It’s involved in our level of approach or avoidance toward an object or a situation that may make us anxious. In the slowdown period following exercise, for example, there’s an increase in the level of naturally occurring cannabinoids in the system. The system scales our readiness for relaxation in the context of the environmental conditions we are facing—as I said, one of many systems that help adjust the readiness of the brain to perform different operations.

What about the urge to smoke marijuana? What is behind the urge, biochemically?

Say I’m going out to a party and I know I will need to socialize, talk to people. That can cause some people to experience stress, anxiety. A person might worry, “Other people will be judging me.” Many people ingest cannabis to feel more relaxed when they feel stress.

Is it correct to say this comes from the experience of experimenting with cannabis and feeling the “high”?

Yes, but smoking cannabis, and especially the high-potency cannabis that is everywhere today, is like using a very blunt instrument to deal with stress. Cannabis with single-digit THC concentration is one thing— somewhat akin to taking an alcoholic drink. But smoking high-potency cannabis, some recent research has suggested, carries risks. People with mild anxiety might get some relief from ingesting cannabis, but taking high THC-concentration cannabis will flood the body’s cannabinoid receptors and may dysregulate the body’s own endocannabinoid system. Then, rather than reducing anxiety, you may end up becoming much more anxious.

It’s like two sides of the same coin. You ingest cannabis to deal with anxiety; but high-potency cannabis has the potential to make you even more anxious. Why?

A bit of biochemistry will help to explain this seeming paradox. The body’s own cannabinoid system is finely balanced, with action at the two receptors, one of which is active on the psychoactive side, the other the non-psychoactive side. THC affects one of the two receptors, the CB1 receptor. The body makes an enzyme called FAAH whose action reduces the level of endocannabinoids in the system. It attaches to endocannabinoid molecules and thus changes their shape, making it impossible for them to dock at the receptors.

This is how the body regulates the action of its own cannabinoids. When you ingest high-potency cannabis, the endogenous system says, “there’s too much coming our way; we have to try to limit the impact.” What’s the consequence? In response, the system down-regulates itself—it tries to become less sensitive so that you are not overly stimulated. But this creates a new problem. This means that the body’s own system, after the “high” has ended and when it next has to respond to stress, is starved of endocannabinoids. This can make one irritable; it is what happens when high-potency cannabis use leads to withdrawal. The user may be relaxed when ingesting the drug, but afterward may feel anxious, stressed, and irritable.

So you have bombarded the system by ingesting highpotency cannabis; the body’s own cannabinoid system has responded by down-regulating itself; and now you have dysregulated the system, creating an imbalance that only ingesting more cannabis can (temporarily) relieve.

Yes, this is the risk of becoming tolerant of high-potency cannabis with high THC concentration. Your irritability is the consequence of coming down from your high and then saying, “Okay, let me take some more, so I can feel good again.” The endocannabinoids you make naturally can no longer compete; they’re sort of side players now, and so what would naturally help you to relax—the body’s own cannabinoid system— doesn’t do that anymore. The body’s own system is very sensitive and quite subtle; it has evolved to balance itself.

One of the tasks of current research is to discover more about the impact of high-potency cannabis on the natural balance, and what the potential impacts are, and how these might affect different users. We want to know who is at risk, when, and why.

In your work for JAMA Psychiatry, you have edited several papers on cannabis over the last two years. Please tell us about what these have revealed about these and related questions. Then perhaps we can consider “best advice,” based on this evidence.

In June 2020, we published a paper based on research led by Kent Hutchinson, Ph.D., of the University of Colorado. He has done some fantastic work, doing something very difficult to do, which is using the real cannabis product—the cannabis that people actually use. The study involved 121 healthy volunteers, who were randomly assigned to groups that purchased and then consumed either relatively lowpotency cannabis or a kind of cannabis we call “concentrate,” with a much higher THC content.

We read in that paper that in the “lower-potency” cannabis group, the THC concentration ranged from 16% to 24%—much higher than the single-digit THC percentages in the cannabis commonly used decades ago. In the “concentrate” group, which Dr. Hutchinson and colleagues note is “made by extracting plant cannabinoids into a form with a much higher THC concentration,” THC content was a remarkable 70% to 90%. Even though these concentrates are in widespread use, “there are virtually no data on the relative risks associated with using these higher-strength products,” the researchers note.

They found that in the short-term, cannabis use in both groups resulted in acute delayed memory impairment as well as impairment in balance. These effects are well known. More surprising was that the lower- and higher-concentration types of cannabis resulted in similar levels of intoxication, as measured by the reports of the participants themselves.

This seems counterintuitive. But the researchers’ commentary in the paper echoes what you told us about the biochemistry. They note that high-potency users may develop a tolerance to the effects of THC. The similar levels of intoxication would suggest that the cannabinoid receptors might become saturated with THC in high-potency users, meaning that beyond a certain level, there’s a diminishing effect of additional THC.

Yes. And so one important implication of this study is that high-potency users may be at a higher risk for developing cannabis-use disorder because of increased exposure to THC. This is important because in Colorado and other places, concentrates have become popular. So for me, it’s a cautionary tale; we need to know more about the longterm consequences of exposure to highpotency cannabis.

Tell us about the second of the JAMA Psychiatry papers you edited.

Published in May 2020, it comes from researchers in England, who looked at mental health consequences of highpotency cannabis use in adolescents. In over 1,000 participants, 141 (13%) reported using high-potency cannabis. After adjusting for variations in the lowvs. high-potency users, the researchers found that there was a significant elevation in anxiety disorders among the users of high-potency cannabis. We’ve discussed why this might be the case: the system down-regulates itself after being flushed with so much THC; this dysregulation impairs the function that the system normally plays in relaxing us— resulting in anxiety.

The same paper also noted that use of high-potency cannabis was associated with increased frequency of cannabis use. So, this paper adds to the potency question a question about frequency. If you use highpotency cannabis a lot, you may be at increased risk of developing cannabis-use disorder.

That’s right.

And now tell us about a third paper, from Denmark, published in JAMA Psychiatry in September 2021. It takes up the very important question of whether there is a relationship between cannabis use and schizophrenia.

It’s a pretty remarkable study because it covers the entire Danish population— the national health records of over 7 million people. This gives you enormous sensitivity to detect relationships that otherwise you wouldn’t be able to detect. Also, the researchers were looking over a period of time—all people born before the end of 2000 who were alive and reached their 16th birthday at any point between 1972 and 2016.

The records enabled them to see that there was both an increase in cannabis use in this period, and also a slight increase in the prevalence of schizophrenia.

They were able to conclude, after doing a great deal of statistical work accounting for all kinds of variables with the ability to distort the analysis, that about 8% of the schizophrenia cases in Denmark over the period covered by the study could be causally related to cannabis use.

What does this mean? We know that schizophrenia is a complex disease with a strong genetic component and a developmental component—both in utero and early childhood. It also has a social component, having to do with what your brain is exposed to as you go through life. All these things matter. All of this suggests that there is a certain threshold of risk factors (let us assume it varies among individuals)—a threshold beyond which a person develops schizophrenia. For example, you may have a certain genetic risk, you may experience some developmental event when still in utero, and you may have grown up in a high-stress environment. If you had two of these you may not develop the illness but if you had two and you also used cannabis you may develop schizophrenia. In this hypothetical, which I mention for explanatory purposes, the additional cannabis added to the existing risk factors leads to an active disease process.

To clarify what you just said about a threshold: the Danish study tried to account for all of the background factors, and then looked at the incidence rate of schizophrenia across the population. They wanted to know how many of the cases during the study period could be attributed to the potential risk factor of cannabis use.

Yes. And, as we discussed, when you expose yourself to high-potency cannabis, the endocannabinoid system changes; the stress and relaxation systems are imbalanced. That is on top of whatever environmental, social, developmental, and genetic factors affect you as an individual. What this paper suggests is that the extra push provided by the unbalancing of the endocannabinoid system may put some people—8% in this study—over the edge and into schizophrenia. And that is a tragedy. I say this having worked with many firstepisode schizophrenia patients.

Is there a lesson in this, then, even though this result needs to be verified in other populations?

What you want to tell a parent is: “Listen, I am not saying everybody who uses high-potency cannabis will develop schizophrenia,”—not by any means. But if you notice certain aspects of your child, odd behaviors, difficulty with differentiating between real and imagined events, having few friends, or having a difficult time experiencing positive feelings, you need to consider that cannabis might make these symptoms worse, not better.

It may be that an unhappy or anxious adolescent may be looking for something to make them feel better. In fact, as we have noted, using high-potency cannabis may make a problem like anxiety worse because it dysregulates the brain even further and in some number of cases, not a trivial number if this third study is right, it may contribute to a process that results in schizophrenia.

Regarding the risk of high-potency cannabis raising the risk not of schizophrenia but of cannabis use disorder, how would you characterize cannabis? Where would you place it on the scale of addictiveness?

Ten years ago, I would have put it on the low end of the scale because of the relatively lower potency of the drug then in common use. Today we confront a changed situation.

As far as parents are concerned, I think it is useful to think about the question of why adolescents start to use cannabis. Clearly, there’s a social component; “I’m part of a group and they’re using it, so I’ll try it.” Another motivation is to address a problem. Something doesn’t feel quite right; the child wonders, “How can I feel better?” Through trial and exploration, they come to cannabis. And they might say, “When I smoked it, I felt pretty relaxed. I didn’t feel bad. It must be a good thing.”

For the parent, I think it is the latter situation that you want to be alert to. When the child is not feeling right, not feeling good, is searching for something. That’s when I think it’s important to have a conversation about “What’s happening?” “What is not feeling right?” “Is it excessive anxiety? Are you having odd thoughts? Mood swings? Unable to sleep?” You want to try to find out what drives the child to think that cannabis is really doing something for them.

How general is this advice?

As I have noted, we still need to do more research, with the kind of cannabis product that is now in common use. It is also crucial to remember that everyone’s brain is a little different. We have to allow for the possibility that for some people, the endocannabinoid system may be so fragile that it may be problematic to take any cannabinoids at all. We don’t know yet who these people are and that points again to the need for more research. We especially need to identify those people for whom cannabis might put them over a threshold and into a tragic illness.

We want to have empirical evidence about the responsible use of cannabis. If we do find that there’s significant potential of negative consequences for some people, then we have to be prepared to say, “At these doses and this frequency, at this potency, we need to be very, very careful.” Like with alcohol: some people are able to consume alcohol on a regular and recreational basis and maintain function over periods of time. Some people cannot. We need to identify, for cannabis, who these people are.

All the more because I don’t think we can turn the tide back. It appears that cannabis, recreational cannabis, will be legal in most states within the next 10 years. It’s going to be available and people are going to use it. We have to know what it does to us so we can act responsibly.

For parents, what is your suggestion based on what we know today?

Somewhat similar to what I say regarding the use of computer and smartphone “screens” and social media, which have created a lot of worry. What I always say is: “Find out what your kid is doing and why, and how it makes them feel. By understanding that process, you can, as a parent, have a lot more insight and can potentially judge if there is or is not a problem. I should say, at the same time, that in a study I did with Dr. Susan Tapert at UCSD, in which we looked at cannabis users in high school, the striking thing to me was that in most cases the parents had no idea. The kids were using and the parents did not know.

This is a major missed opportunity. It’s really important between parents and children to know what is happening and why; what the experience is like; and to do this in a non-judgmental way. To judge or to lecture accomplishes nothing. It shuts down the conversation.

Written By Peter Tarr, Ph.D. And Fatima Bhojani

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