Cannabis Use in Psychiatric Illness

The benefits and hazards of cannabis use for people with mental health issues have been widely debated. Decades of legal and political obstacles have limited much-needed cannabis research—especially large human clinical studies—that would help to validate or disprove the role of cannabis in treating several medical conditions. Furthermore, cannabis’ long-standing status as an illicit drug has focused much of the available evidence on its potential to cause negative psychiatric outcomes.

Recently, however, a more favorable public opinion along with improved access to medical cannabis has shifted some of the research focus toward the potential for cannabis to play a positive role in the treatment many psychiatric conditions, including anxiety, depression, obsessive-compulsive disorder, schizophrenia, and posttraumatic stress disorder (PTSD).

Although caution is advised before extrapolating evidence derived primarily from anecdotal reports, preclinical animal studies, and small clinical studies, reviewing the data with an open mind is equally warranted not only to help reduce the potential for unfounded bias but also to help stimulate more meaningful discussions about potential pros and cons of cannabis use in psychiatric illness. 

Complexity of Cannabis in Mental Health
The effects of cannabis on mental health are complex, and at times those effects appear to be contradictory; for example, cannabis can both help and cause anxiety. To better interpret the potential role of cannabis in treating psychiatric illness, it’s necessary to understand cannabis pharmacology and the factors that influence its impacts, including dose, route of administration (smoking vs oral), the strain of cannabis used, individual genetic variations, and type of product (full-spectrum or isolated components such as CBD only). 

Part of the complexity of cannabis resides in the fact that the cannabis plant consists of hundreds of different compounds, including cannabinoids (eg, THC and CBD), terpenes, flavonoids, and sterols. Each of these compounds not only possesses its own unique activity but also influences the effects of other compounds. For instance, terpenes provide the unique aroma of cannabis while working in tandem to either inhibit or activate the effects of other cannabis compounds. Also, CBD can attenuate many of THC’s more undesirable effects, including intoxication, sedation, and tachycardia. As a result, the expected effect of a cannabis product is highly dependent on the ratio of THC to CBD in a product. The synergistic effects that occur from all the compounds in cannabis working together is known as the “entourage effect.”

Different cannabis products can have varying effects on medical conditions. Full-spectrum cannabis products contain all compounds found naturally in the cannabis plant. Other products have been developed to contain only one isolated cannabinoid (eg, CBD-only products). As a result, it’s necessary to know what type of product (eg, full-spectrum, THC only, or THC and CBD) is being used to predict the expected effect a cannabis product may have on a medical condition. 

Cannabinoids’ effects depend on their interaction with one of two known cannabinoid receptors—CB1 and CB2. CB1 receptors are found abundantly in the brain and central nervous system, while CB2 receptors are found primarily in peripheral immune cells and tissues. Thus, THC’s primary interaction with CB1 leads to its intoxicating effects (euphoria), while CBD’s primary interaction with CB2 receptors leads to effects that are nonintoxicating and nonreinforcing.

Many of the effects of cannabis are “biphasic” and “bidirectional”—meaning low and high doses can have totally opposite effects.1 For instance, low doses of THC may help make one calm and relaxed while higher doses may induce anxiety.

Long-Term Risks of Cannabis Use
It’s prudent to discuss what’s known about the risks associated with long-term cannabis use. About 30% of people using cannabis meet the criteria for cannabis use disorder (CUD), which is characterized by a strong desire to use cannabis, using larger amounts than intended, continued use despite negative social and physical consequences, craving, tolerance, and withdrawal.2

Cannabis withdrawal can occur when cannabis is used frequently and then discontinued; symptoms are characterized by irritability, anxiety, depression, decreased sleep quantity and quality, and stomach pain.3

Chronic cannabis use may also cause THC-induced dysregulation of the dopaminergic systems, resulting in amotivational syndrome, which is characterized by apathy, lack of motivation, and poor educational performance.4 The THC component of cannabis is responsible for most of the concerns with cannabis use, and in general those concerns will be greatest in cannabis products high in THC and low in CBD.

Schizophrenia
Schizophrenia is a serious mental illness that affects how a person thinks, feels, and behaves. The onset of symptoms typically occurs in late adolescence/early adulthood. Symptoms can be categorized as positive symptoms (eg, hallucinations, delusions, paranoia), negative symptoms (eg, blunted affect, lack of motivation, emotional/social withdrawal), and cognitive deficits (eg, impaired memory/executive functioning, attention deficits, dementia).5

Cons of Cannabis in Schizophrenia
A plethora of evidence exists indicating cannabis (due to THC) can worsen schizophrenia’s positive symptoms. Furthermore, cannabis use may contribute to the development of schizophrenia in some individuals. A Swedish study found cannabis use during adolescence to be associated with a six-fold increased risk of developing schizophrenia.6 Another study found the initial diagnosis of schizophrenia to be higher in persons who used cannabis in the year before being diagnosed.7

Multiple factors are thought to contribute to cannabis-induced transient psychotic symptoms and schizophrenia. It’s likely that cannabis use causes disruptions in dopamine, gamma aminobutyric acid, and glutamate neurotransmission, leading to psychosis.5 Genetic variations between people may also explain why only a small proportion of people who use cannabis develop psychotic disorders such as schizophrenia. For instance, carriers of an AKT1 genotype are twice as likely to be diagnosed with schizophrenia.8 Also, persons with a COMT gene mutation are at increased risk of schizophrenia with cannabis use.9

Pros of Cannabis in Schizophrenia
Whereas cannabis use worsens positive symptoms, it’s less likely to worsen cognitive symptoms, and there’s some evidence that it may actually diminish some of schizophrenia’s negative symptoms.5

Normally, when individuals are exposed to a small stimulus (eg, a low-volume sound) that’s then immediately followed by a more intense stimulus (eg, a loud sound), they experience “pre-pulse inhibition,” which helps to minimize their startle responses. However, persons with schizophrenia have impaired pre-pulse inhibition and as a result they find it difficult to filter out the unnecessary environmental stimuli that can worsen their positive and negative symptoms. Because CBD has antipsychotic properties that can attenuate these disruptions in pre-pulse inhibition, it may have a role in the treatment of schizophrenia.10

CBD or cannabis with high CBD/low THC may also help improve sensory motor gating deficits—the inability to block out unnecessary stimulation (eg, constant humming from an air conditioner)—that are commonly seen in persons with schizophrenia.11

PTSD
Cannabis use has been widely reported as a coping strategy by PTSD patients, who often experience overwhelming excessive fear and anxiety along with frequent nightmares, panic attacks, hypervigilance, detachment from others, and self-destructive behavior.

The high concentration of cannabinoid receptors found in the prefrontal cortex, amygdala, and hippocampus play a significant role in fear acquisition and extinction.12 There’s strong evidence that disruptions of the endocannabinoid system in these areas contributes to PTSD symptoms. Impaired fear extinction is seen in CB1 knockout mice, which suggests that CB1 receptors play a critical role in the extinction of fear.13 In a recent study on fear and trauma, researchers from Yale determined that a genetic mutation of CB1 receptors appears to prevent some children from developing a healthy fear extinction.14 Their findings also noted that previous exposure to trauma did not affect fear extinction as much as did this genetic variation.  

Cons of Cannabis in PTSD
More frequent and problematic cannabis use has been reported in persons using cannabis to help cope with PTSD. 
An observational study of 2,276 participants admitted to VA treatment programs for PTSD evaluated the severity of PTSD at the time of admission and four months after discharge, as well as recorded their use of cannabis. Patients who reported using cannabis were found to have more severe PTSD than did those who had never used the drug. Furthermore, those who stopped using cannabis during treatment showed significantly reduced PTSD symptoms at follow-up compared with baseline. The study also found that those patients who started using cannabis during treatment were the most likely to exhibit violent behavior and addiction.15

Pros of Cannabis in PTSD
THC in low doses appears to be useful in persons with PTSD due to its ability to produce anxiolytic effects and reduce threat-related amygdala activation implicated in disruptive fear and threat-related processing in trauma-exposed individuals.15

It’s been theorized that cannabis helps PTSD patients by extinguishing the intensity associated with memories of trauma by improving their ability to “overwrite” traumatic memories with new memories in a process called “extinction learning.” In a review of cannabis literature from 1974 to 2020, Brazilian researchers found support for this theory, reporting that low doses of THC or THC combined with CBD were able to enhance the extinction rate of traumatic memories while also reducing overall anxiety. They also suggested that THC drives the extinction rate improvements through its activity at CB1 receptors, while CBD helps to reduce potential side effects associated with increasing doses of THC.16

Insomnia is common in several psychiatric conditions including depression, anxiety, and PTSD. There’s also evidence that cannabis-related benefits in PTSD, and in many other conditions, may be related to improvements in sleep. A study of patients receiving medical cannabis from a California dispensary evaluated specific coping use motivations, frequency of cannabis and alcohol use, and mental health among a convenience sample of 170 patients with PTSD. Patients with high PTSD scores (using the PTSD Checklist-Civilian Version) were more likely to use cannabis to improve sleep and for coping reasons more generally compared with those with low PTSD scores. Cannabis use frequency was greater among those with high PTSD scores who used cannabis for sleep-promoting purposes compared with those with low PTSD scores or those who didn’t use cannabis for sleep-promoting purposes.16 

Anxiety
Cannabinoid receptors are expressed in all brain regions that are important for the processing of anxiety, fear, and stress. Cannabis has been found to help anxiety by stabilizing disruptive emotional responses associated with anxiety by increasing cannabinoid and oxytocin receptor activation and also through the rewarding effects seen with elevated dopamine.17

Cons of Cannabis for Anxiety Disorders
Cannabis is commonly used by persons to help cope with anxiety. However, anxiety and panic reactions are also common negative effects associated with acute cannabis intoxication, which may limit its usefulness for some individuals.18 And while cannabis has been shown to be an effective anxiolytic, its effects may only provide short-term benefit, as tolerance develops quickly. Rebound anxiety can also occur upon cessation, which can foster dependence if persons attempt to self-medicate for anxiety symptoms by increasing the dose and frequency of use.19

Persons using cannabis for social anxiety disorder (SAD) appear to be at higher risk of problematic use, including CUD, with dependence occurring at a rate more than twice that seen with cannabis use in other anxiety disorders, including generalized anxiety disorder, agoraphobia, and panic disorder.20

Pros of Cannabis for Anxiety Disorders
Researchers reviewing eight cross-sectional studies to evaluate the use of cannabis for anxiety concluded that evidence supports the anxiolytic effects of cannabis.21 

Although THC can increase anxiety at higher doses, lower doses decrease anxiety. This effect was described in one study in which participants were exposed to a well-validated psychosocial stress task. A low THC dose (7.5 mg) reduced the duration of negative emotional responses to the task and posttask appraisals. A high THC dose (12.5 mg) produced small but significant increases in anxiety, negative mood, and subjective distress.22

The anxiolytic effects of CBD—including its ability reverse the anxiogenic effects of THC—are widely known and reported. CBD’s anxiolytic properties occur at a wide range of doses. CBD doses of 300 to 600 mg have been shown to reduce experimentally induced anxiety in persons without anxiety disorder and also reduce anxiety in persons with SAD.23

As noted previously, cannabis use in persons with SAD can increase problematic cannabis use, including CUD. However, one study found that psychiatric outpatients with comorbid SAD and CUD reported better physical health, fewer limitations due to physical health, and a trend toward better adolescent and current psychosocial functioning than did those with SAD alone.24

Depression
Although depression and anxiety are separate conditions, they frequently occur together. As in anxiety, cannabinoids also improve emotional responses associated with depression by increasing cannabinoid and oxytocin receptor activation, and also through the rewarding effects seen with elevated dopamine.17

Cons of Cannabis in Depression
Several reviews have concluded that cannabis use is associated with increased depression risk, depressive symptoms (especially diminished motivation), or depression severity. Concerns with depression appear to increase with more frequent use and higher doses. Results from a meta-analysis of 14 longitudinal studies involving more than 76,000 persons that evaluated an association between cannabis use and depression found that cannabis use was associated with a modest increased risk of depression (odds ratio [OR]=1.17) while heavy cannabis use was associated with a stronger but still moderate increased risk for developing depression (OR=1.62).25 

Pros of Cannabis in Depression
A large number of persons report using cannabis to self-medicate for depression, with many reporting dramatic reductions in depression symptoms, at least in the short-term, as long-term benefit is less clear. THC and CBD interact synergistically with other cannabinoids, terpenes, and flavonoids to help alleviate symptoms of depression.

THC alone can affect dopamine, serotonin, and norepinephrine similarly to traditional antidepressants.26 However, unlike traditional antidepressants, which often take weeks to exert an antidepressant effect, one study found THC provided an immediate reduction in the intensity of depressive symptoms, with 95.8% of users reporting symptom relief. THC levels were the strongest independent predictor of symptom relief, while CBD levels were generally unrelated to real-time changes in depressive symptom intensity levels.

Final Thoughts
While concerns of dependence and cannabis use disorder shouldn’t be minimized, there’s growing evidence to support the idea that cannabis and cannabis-derived entities may provide new treatment options for many difficult-to-manage psychiatric conditions. 

— Mark D. Coggins, PharmD, BCGP, FASCP, is vice president of pharmacy services and medication management for skilled nursing centers operated by Diversicare in nine states and is a past director on the board of the American Society of Consultant Pharmacists. He was nationally recognized by the Commission for Certification in Geriatric Pharmacy with the 2010 Excellence in Geriatric Pharmacy Practice Award.

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