COMMENTARY

Cannabis and Cannabinoids: Weighing the Benefits and Risks in Psychiatric Patients

Diana M. Martinez, MD

December 18, 2020

This transcript has been edited for clarity.

Hello. I'm Diana Martinez. I'm a psychiatrist at the Columbia University Medical Center in the Department of Psychiatry. Today we'll be talking about the interaction between cannabis and psychiatric disorders. When I say "cannabis," this is really the same as marijuana. I use the term "cannabis" because this is a scientific term for the plant.

I'm going to start with a brief history of cannabis. It’s been used for centuries in India as both an intoxicant and a medication. Medicinal texts in China, dating back to about 100 BCE, described cannabis as being helpful for mood, appetite, gout, and rheumatism.

In the 1930s, William O'Shaughnessy, an Irish physician, joined the British East India Company and there he studied cannabis and submitted reports to medical journals on its ability to improve pain and rheumatism, to treat spasticity and tetanus, and to treat seizures. It became quite well known and widely used in England. Russell Reynolds, who served as a physician to Queen Victoria, argued that cannabis should be used for pain instead of opioids because morphine addiction was rampant at the time in Victorian England.

Even at the time when cannabis was placed into Schedule I, it was debated as being too harsh of a measure.

In the United States, cannabis was used medically and recreationally until it was restricted in 1937 and outlawed in the 1950s. In 1970, President Nixon signed the Controlled Substances Act and cannabis was placed into Schedule I. As you may recall, Schedule I is a class of medications that have a high potential for abuse with no accepted medical use. In other words, cannabis cannot be prescribed by physicians for any reason. Even at the time when cannabis was placed into Schedule I, it was debated as being too harsh of a measure.

Since 1970, there have been multiple petitions submitted to the DEA to move cannabis off of Schedule I so that it can be prescribed by physicians and studied more readily. However, this has not happened. Despite the federal law, cannabis has been approved in many states for medical and recreational use. At present, cannabis is approved for medical purposes in 36 states and for recreational use in 15 of those states.

Now I'm going to talk about cannabis as both an intoxicant and a medication. As physicians and psychiatrists, we know that many medications are both a therapy and a substance of abuse, such as opioids, amphetamines, benzodiazepines, ketamine, and I'll add cannabis to this list. As a result, these drugs, including cannabis, can have a therapeutic or detrimental effect. Cannabis has a potential to cause a substance use disorder or an addiction, and it can also worsen psychiatric disorders such as mood disorders, anxiety, and psychosis. We'll talk about this today. However, cannabis also has a potential to treat some psychiatric symptoms, and we'll discuss that as well.

The cannabis plant contains about 100 cannabinoids. The main ones that have been studied are THC, which is short for delta-9-tetrahydrocannabinol, and is the molecule in the cannabis plant that creates a high; and CBD, which is short for cannabidiol. CBD does not create a high, it has few subjective effects, and there's a lot of interest in CBD for treating different disorders, including psychiatric disorders.

When it comes to cannabis and psychiatric disorders, there are really two main questions. The first one is, does cannabis use worsen psychiatric symptoms in patients who use it? And the second question is, does cannabis cause mental illness in people who use it?

We'll start with the first question. Most of what I'll be talking about today with respect to cannabis use in patients with psychiatric disorders comes from a report published in 2017 by the National Academies of Sciences, Engineering, and Medicine (NASEM). It's called The Health Effects of Cannabis and Cannabinoids, and it really is a remarkable resource if you have any interest in reading further on this.

These are studies in patients who use cannabis themselves — this is THC-containing cannabis —looking at the outcomes or the effects that this might have on their psychiatric symptoms. We'll start with depression. Overall, there is a lack of data investigating an association between cannabis use and depression, meaning that we simply don't know if cannabis use in depressed patients either worsens or improves the disorder. It's simply a big question mark currently. There's moderate evidence of increased symptoms of mania and hypomania in patients with bipolar disorder who use cannabis regularly.

In anxiety disorders, there's limited evidence of an association between near-daily cannabis use and the increased symptoms of anxiety. In PTSD, there's limited evidence of an association between cannabis use and increased symptoms of PTSD in patients diagnosed with this disorder.

You'll note that this report uses terms like "limited evidence" and "moderate evidence." Limited evidence means that an association has been seen, but it is not strong and remains inconclusive. Moderate evidence says that there's stronger evidence and more supportive data; it's still not conclusive, but there's more of a concern.

Again, moderate evidence is in bipolar disorder with mania and hypomania, and there's only limited evidence showing that cannabis worsens anxiety disorders or PTSD.

There is some evidence showing an association between cannabis use and an increase in positive symptoms of schizophrenia among individuals with a psychotic disorder. There's no clear evidence of an association between cannabis use and worsening of negative symptoms of schizophrenia. There's actually moderate evidence of an association between cannabis use and better cognitive performance in individuals with psychotic disorders.

In summary, what does this mean? What can we say about the impact of cannabis use on the course of illness in psychiatric patients? Overall, we can say that the data are strongest, showing that patients with bipolar disorder could have a worsening of their hypomania or mania, and that patients with schizophrenia may have a worsening of their positive symptoms of psychosis. There is some limited evidence that heavy cannabis use might worsen anxiety disorders.

Overall, this really highlights the importance of clinical judgment. In some patients, cannabis use might have no impact on their illness. In other patients, it might have an effect. In patients who are refractory to treatment or stop responding to treatment, it is important for the clinician to consider cannabis use as a potential factor.

However, it's also important to understand why a patient might be using cannabis, especially regular use. Common reasons that patients care to use cannabis include chronic pain, anxiety, and insomnia.

In a clinical patient who's using cannabis and not responding, or no longer responding, to a previously effective treatment and you think that cannabis might be a factor, it's important to look and see if they're using cannabis to address symptoms like anxiety and sleep. Maybe the symptoms could be addressed with other therapies instead.

Can Cannabis Use 'Cause' Mental Illness?

We're going to switch gears and talk about cannabis use and the development of a mental illness. Again, I'm going to be referring to the report published by NASEM looking at this question. There is moderate evidence of a small but increased risk of developing depression in heavy cannabis users. There's also limited evidence of an association between cannabis use in regular or daily users and the development of bipolar disorder. There's moderate evidence of an association between cannabis use and the incidence of social anxiety disorder.

It's worth noting that these studies show an association between cannabis use and the development of a psychiatric disorder; however, we can't assume that cannabis use causes psychiatric disorders because we simply don't have data that show this.

There's been a lot of attention paid to the potential link between psychotic disorders and cannabis use, especially daily or high-potency THC. There have been studies that suggest that there's an association between cannabis use and an increased risk for psychosis and the symptoms of schizophrenia. Overall, the data indicate that patients at clinical high risk for a psychotic disorder who use cannabis are at risk for earlier onset of psychotic-like symptoms, poorer prognosis, and a greater likelihood of being diagnosed with schizophrenia.

Thus, cannabis use in clinically high-risk patients probably worsens the prognosis. However, as noted previously with depression, anxiety, and bipolar disorder, we can't assume that cannabis causes schizophrenia or causes a psychotic disorder.

With respect to cannabis use causing a psychiatric disorder, we can assume that the greatest risk of cannabis use is development of a substance use disorder. People who use cannabis are at risk of developing a substance use disorder and meeting the DSM-5 criteria, which include not meeting their obligations, engaging in risky behaviors, the development of tolerance, and failed attempts to quit.

It's worth noting that frequent cannabis use is associated with withdrawal symptoms, which include irritability, sleep problems, decreased appetite, cravings, and restlessness. Research studies have estimated the risk of developing a substance use disorder among cannabis users. Overall, these studies suggest that 9% of people who use cannabis will become dependent on it or will develop a substance use disorder.

However, this percentage increases to 17% in those who are using in their teenage years. Among teenagers, cannabis use is clearly more risky (compared with adults) with respect to developing a substance use disorder. It's also worth noting that teenagers with depression or ADHD have a very high risk of misusing drugs, especially cannabis and other drugs like alcohol. In a teenager who's using cannabis, especially on a regular basis, it's worth looking at underlying psychiatric symptomatology like depression or ADHD to see if this is driving their risky cannabis use.

Cannabis as Treatment

We're going to switch gears again and discuss the use of cannabinoids as potential treatments for psychiatric disorders. Previously, we talked about the risks of cannabis. Now we're going to see if cannabinoids used in a medical setting can serve as treatments for psychiatric disorders. Again, I'll mostly be referring to that report from 2017 from NASEM.

I'll start this discussion by saying that there's a tremendous shortage of reliable data, largely due to regulatory barriers, meaning that because cannabis is a Schedule I drug, there's a lack of studies that use a prospective, double-blind analysis, which is desperately needed to support the use of cannabis as a medicinal product.

Today, placebo-controlled studies have been done to an extent with the cannabis plant and cannabis extract, which usually contains CBD and THC mixed together, and the FDA-approved drugs dronabinol and nabilone. Dronabinol is delta-9-THC made in a pharmaceutical factory, and nabilone is a related molecule. Dronabinol and nabilone are very similar.

The strongest support for the medical use of THC includes pain, especially chronic pain, and this has been shown in studies using dronabinol and nabilone, the cannabis plant, and cannabis extract. It's been estimated that 5-20 mg of oral THC is about as effective as 50-120 mg of codeine. However, head-to-head studies comparing cannabis and opioids in the treatment of pain are few and far between.

The pain conditions that have been studied include neuropathy caused by diabetes or HIV, cancer pain, fibromyalgia, and multiple sclerosis. Cannabinoids have also been shown to be helpful in spasticity. With respect to the FDA-approved drugs, dronabinol and nabilone, these are FDA approved for chemotherapy-induced nausea and vomiting and appetite stimulation in AIDS.

Now let's look at the limited evidence and the more moderate evidence for THC. There's moderate evidence showing that THC improves short-term sleep outcomes in patients with obstructive sleep apnea, fibromyalgia, chronic pain, and multiple sclerosis.

There's some limited but promising evidence showing that dronabinol in Tourette syndrome can reduce the tics and obsessive symptoms. However, this has been shown in small studies and needs to be replicated in larger studies.

There's also a small study showing that nabilone may be helpful in treating PTSD. This was done in patients who had ongoing PTSD symptoms despite treatment, meaning that they were a refractory group of patients who weren't responding well to existing treatments and nabilone was added as additional pharmacologic agent. The results show that their nightmares and some of their PTSD symptoms improved. Again, this is a small study and is in need of replication.

With respect to cannabis and OCD, there have been two small studies performed. In one study, the smoked plant was compared with placebo, and both decreased symptoms in OCD. There was no difference between smoked cannabis and placebo. However, in a follow-up study, nabilone 1 mg taken twice a day, combined with exposure therapy, improved OCD symptoms. This is an interesting approach combining nabilone, which is synthetic THC, with exposure therapy and it saw a response. However, this was a small study that needs to be replicated in a larger group of subjects.

Now we'll talk about the medical evidence for CBD. Of course, the strongest data for CBD is in epilepsy caused by Dravet syndrome and Lennox-Gastaut syndrome, and that's been shown in a large, multisite clinical trial. However, when we're talking about CBD for psychiatric disorders, the data are more limited, but some studies have been done.

We'll start with schizophrenia. Research on the ability of schizophrenia to improve psychotic symptoms in schizophrenia is mixed. There have been three studies performed using different methods, and two of these studies showed promising results, whereas one did not. One was a negative study.

The studies that showed a positive effect used high doses of CBD, 800-1000 mg a day, which is actually similar to the dose that was used in childhood epilepsy studies. The negative study used 600 mg a day, which is a lower dose but still on the high side.

Of the two studies showing a positive outcome, one used CBD as an add-on therapy to the schizophrenic patients' existing regimens, meaning that the patients were symptomatic despite treatment and CBD was added to see if treatment could improve. The results show that CBT did decrease the positive symptoms of schizophrenia, although the effect size was modest.

The other positive study looking at CBD and schizophrenia compared it with amisulpride, and both groups improved. Both the CBD group and the amisulpride group improved in schizophrenic patients. However, there was no control group, so that is an open question with respect to CBD compared with amisulpride. Overall, I'd say that the data in schizophrenia are promising, but they're mixed and in need of replication.

There have been some very small studies looking at CBD for social anxiety disorder and substance use disorders. The studies in social anxiety disorder used one single dose of CBD, 400 ad 600 mg, and it showed an improvement in patients with social anxiety. However, this is, again, a small, limited study with one dose; larger studies need to be done with repeated dosing.

With respect to substance use disorder, there have been two studies looking at CBD, including one for opioid use disorder and the other for cannabis use disorder. The study in opioid use disorder showed that CBD reduced cue-induced craving for heroin, which was done in the lab with videos. Videos were used to incite craving for heroin, and it showed that CBD was more effective at inhibiting that than placebo. This is an intriguing result that needs to be followed up with repeat-dosing studies.

Another study has been done looking at CBD for cannabis use disorder. This study investigated 400- and 800-mg doses of CBD and showed that CBD increased abstinence over placebo, but the effect was small. In this study, participants decreased their cannabis use by 0.5 and 0.3 days per week. That's a half-day-a-week improvement in reducing their cannabis use, which was statistically significant, but at this point, we don't know whether this has a clinical impact on the actual diagnosis of a cannabis use disorder. This study will need to be replicated.

These are my thoughts on the promises of medical cannabis. The most promising immediate use, in my mind, is the use of THC for pain. THC has a potential to treat pain and could be added to the armamentarium of pain medications that we use today.

The risks of using THC for pain are intoxication and the development of an addiction. This is higher than the risk seen in other pain medications like NSAIDs but lower than the risk of opioids. THC may have promise as an antianxiety medication, perhaps in PTSD and OCD and maybe in other anxiety disorders. However, larger, carefully controlled studies are needed, and especially ones looking at THC plus behavioral treatments. Probably the most promising use of THC is to combine it with behavioral treatments.

With respect to CBD, there's a promising signal that it may be helpful in schizophrenia, anxiety disorders, and perhaps substance use disorders. Again, we need replication and we need larger studies.

I'll just come back to history. One of the greatest reasons why we don't have these studies is because both THC and CBD are Schedule I drugs. Although this is in the process of changing, it has certainly impeded research at this point. Nonetheless, there's a significant interest in studying cannabinoids as potential treatments for medical and especially psychiatric disorders.

Dr Martinez, a professor of psychiatry at Columbia University in New York, specializes in addiction research and conducts a master class on marijuana's effects on psychiatric disorders.

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