Cannabidiol (CBD) for schizophrenia: Promise or pipe dream?
Over the past few decades, it has become increasingly clear that cannabis use can increase the risk of developing a psychotic disorder and worsen the course of existing schizophrenia in a dose-dependent fashion.1-3 Beyond psychosis, although many patients with mental illness use cannabis for recreational purposes or as purported “self-medication,” currently available evidence suggests that marijuana is more likely to represent a harm than a benefit for psychiatric disorders4 (Box4-8). Our current state of knowledge therefore suggests that psychiatrists should caution their patients against using cannabis and prioritize interventions to reduce or discontinue use, especially among those with psychotic disorders.
Cannabis for psychiatric disorders
Data from California in 2006—a decade after the state’s legalization of “medical marijuana”—revealed that 23% of patients in a sample enrolled in medical marijuana clinics were receiving cannabis to treat a mental disorder.5 That was a striking statistic given the dearth of evidence to support a benefit of cannabis for psychiatric conditions at the time, leaving clinicians who provided the necessary recommendations to obtain medical marijuana largely unable to give informed consent about the risks and benefits, much less recommendations about specific products, routes of administration, or dosing. In 2019, we know considerably more about the interaction between cannabinoids and mental health, but research findings thus far warrant more caution than enthusiasm, with one recent review concluding that “whenever an association is observed between cannabis use and psychiatric disorders, the relationship is generally an adverse one.”4
Some critics have argued that the medical marijuana industry represents little more than a front for recreational use. In California and other states that have legalized recreational use, that claim has been rendered all but moot, although the public remains curious about the potential health benefits of cannabinoids and will likely continue to look to clinicians for advice. For those seeking guidance from evidence-based research, the existing state of knowledge can seem like a “Wild West” of anecdotal subjective reports, biased opinions, and uncontrolled clinical studies. Cannabis remains a Schedule I drug at the federal level, and quality clinical research has been limited to a relatively modest number of randomized controlled trials (RCTs), mostly involving FDA-approved cannabinoids rather than smoked cannabis. Randomized controlled trials that have involved smoked marijuana have generally involved low-potency delta-9-tetrahydrocannabinol (THC) cannabis that may not reflect the same therapeutic and adverse effects of the increasingly high potency cannabis now available on the street and in dispensaries.
In psychiatry, a few RCTs are underway exploring cannabis as a viable treatment for mental disorders (eg, posttraumatic stress disorder), but none have yet been completed or published. At best, retrospective studies to date have failed to support a consistent benefit of cannabis for any psychiatric disorder and at worst increasingly suggest a negative impact on psychotic, mood, and anxiety disorders.4,6 Meanwhile, synthetic cannabinoid receptor agonists (eg, “Spice” products) have come to represent a clear public health risk, with both medical and psychiatric toxicity.7
A more cautiously optimistic case for the therapeutic potential of cannabinoids in psychiatry could be made for cannabidiol (CBD), which may possess anxiolytic, antipsychotic, and neuroprotective properties.8 Based on its purported health benefits, it is possible that CBD may even gain widespread popularity as a food supplement. Because a pharmaceutically-manufactured form of CBD was recently FDA-approved for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome, off-label prescribing of CBD for psychiatric disorders can be anticipated. While there is not yet sufficient evidence about risks and benefits to justify CBD being recommended broadly in psychiatry, that same informational vacuum has not stopped eager patients from seeking approval for cannabis, and some physicians from providing it.
Despite that conclusion, because cannabis is classified as a Schedule I drug by the US Drug Enforcement Agency, clinical research investigating the risks and benefits of cannabis has been limited. It therefore remains possible that cannabis, or individual cannabinoids such as cannabidiol (CBD), may yet find a therapeutic niche in psychiatry. This article reviews evidence on CBD for the treatment of schizophrenia.
Cannabinergic drugs as potential antipsychotics
Although the bulk of evidence indicates a harmful effect of cannabis in individuals with or at risk for psychosis, there have been a few published cases of schizophrenia improving with dronabinol, an FDA-approved, synthetic form of delta-9-tetrahydrocannabinol (THC).9,10 THC is the constituent of cannabis that produces euphoric effects. These provocative findings have not been replicated in controlled clinical trials, but suggest at least the theoretical possibility of idiosyncratic benefits from THC for some individuals within the psychotic spectrum.
Still, given that most available evidence supports that THC has a harmful effect on psychosis and psychosis risk, researchers have instead performed randomized controlled trials (RCTs) to investigate a possible therapeutic role for medications that oppose the agonist effects of THC at cannabinoid type 1 (CB1) receptors. To date, 2 RCTs comparing rimonabant, a CB1 inverse agonist, with placebo (PLB) in patients with schizophrenia have failed to demonstrate any benefit for psychotic symptoms or cognitive deficits.11,12 A third trial examining rimonabant for people diagnosed with schizophrenia who were overweight found significant benefits for anxiety and depressive symptoms, but none for positive symptoms or the primary outcome of weight loss.13 While these results are discouraging, the role of THC in precipitating psychosis suggests that novel agents opposing the actions of THC on the cannabinoid system could have antipsychotic properties.14
Cannabidiol: An antipsychotic medication?
In contrast to THC, CBD has minimal euphorigenic properties and has recently been heralded in the popular press as a “miracle drug” with benefits for medical and psychiatric disorders alike.15 It has even been speculated that it could become a popular food supplement.16 In 2018, the FDA gave full approval to a pharmaceutically manufactured form of CBD (brand name: Epidiolex) as a novel treatment for 2 rare and severe forms of pediatric epilepsy, Lennox-Gastaut syndrome and Dravet syndrome,17 based on RCTs supporting its efficacy for these often refractory and life-threatening conditions.18-20
In psychiatry, there have not yet been enough robust clinical studies to support broad therapeutic claims for CBD as a treatment for any mental disorder.21 However, there is growing evidence that CBD has potential as an antipsychotic medication. In 1995, the first case report was published describing the efficacy of CBD, 1,500 mg/d, as standalone therapy in a single individual with schizophrenia.22 In 2006, the same research group followed up with a case series in which only 1 out of 3 patients with treatment-refractory schizophrenia improved with flexible dosing of CBD to a maximum dose of 1,280 mg/d.23
There have been 3 published RCTs exploring the efficacy of CBD in schizophrenia (Table24-26). The first study, published in 2012, included 39 adults with schizophrenia who were randomized to 800 mg/d of CBD or amisulpride (AMS), a second-generation antipsychotic that is popular in Europe but is not available in the United States.24 Over 4 weeks of randomized treatment, CBD resulted in as much improvement in overall symptoms and positive symptoms as AMS, and improvement of negative symptoms was significantly greater with CBD. Compared with patients treated with antipsychotic medication, patients who were treated with CBD had fewer extrapyramidal symptoms, less weight gain, and less prolactin elevation. This initial trial suggests that CBD might be as efficacious in schizophrenia as antipsychotic medication, without its burdensome adverse effects. However, this is the only RCT of CBD monotherapy published to date.