The proposition that cannabis causes schizophrenia has existed since at least the early days of the anti-marijuana movement in America, as illustrated in the 1936 film Reefer Madness, in which a character descends into psychosis after smoking a joint.¹ The cannabis-schizophrenia connection intensified during the “War on Drugs,” which produced propaganda linking the herb to schizophrenia, as well as cancer and brain damage.² Fast-forward more than seven decades since the film, and the academic and mainstream media continue to refer to cannabis’s ability to cause and increase the risk of developing this serious mental illness.^3,4

The link between cannabis (Cannabis sativa, Cannabaceae) and schizophrenia, however, is much more complex and much less certain. Cannabis and the brain have an interesting and unique relationship, part of which remains a mystery to researchers even today. After more than two decades of scientific analysis, researchers know that the human body contains receptors that bind with tetrahydrocannabinol (THC) and other cannabinoids from the cannabis plant, and also has neurotransmitters that activate these receptors in much the same way. The body's receptors include the CB1 and CB2 receptors, and the endogenous cannabinoids, referred to as endocannabinoids, including anandamide and 2-AG.^5,6

Although this intricate endocannabinoid system of receptors and neurotransmitters — as well as the exact role played by the cannabis plant — is not yet fully understood, it clearly is involved in numerous physiological and pathological processes that are essential to human health. As Ester Fride and Ethan Russo, MD, wrote in the neuropsychiatry chapter of the 2005 book Endocannabinoids: The Brain and Body’s Marijuana and Beyond (CRC Press), “Endocannabinoids serve a modulatory function in many neurochemical and psychopharmacological processes, and deficiencies or excesses in any of these may produce manifestations of psychopathology.”⁵

Even more perplexing to scientists is the severe brain disorder called schizophrenia, which affects about 24 million people worldwide — approximately one percent of the population. According to the PsychCentral mental health web resource, “In spite of advances in the understanding of its causes, course, and treatment, schizophrenia continues to confound both health professionals and the public. It is easier for the average person to cope with the idea of cancer than it is to understand the odd behavior, hallucinations, or strange ideas of the person with schizophrenia.”⁷

Medical researchers believe that schizophrenia is tied to a genetic link as incidence among those with afflicted family members is increased by about nine percent.8 It is also thought that schizophrenia might be caused by the malfunction of a gene that creates important brain chemicals, as well as possible environmental triggers, and/or an imbalance of the neurotransmitters dopamine and glutamate. Scans of schizophrenia patients’ brains have revealed that they have larger center-brain ventricles and less gray matter, and post-mortem brain analyses have shown differences in schizophrenics’ brain cell characteristics — perhaps occurring during abnormal fetal brain development. Schizophrenia presents itself through a variety of symptoms, including hallucinations, delusions, thought and movement disorders, monotonous voice, and motionless face when speaking (referred to as “positive” symptoms), as well as social withdrawal, inability to make decisions, lack of emotion and motivation, etc. (referred to as “negative” symptoms and “cognitive deficits”).

Research

While a fair amount of scientific research has examined the relationship between cannabis and schizophrenia, most of this consists of laboratory, animal, epidemiological, or post-mortem human studies. Recognizing the “tremendous amount” of preclinical research on cannabis and schizophrenia, Martin Lee — author of the 2012 book Smoke Signals: A Social History of Marijuana – Medical, Recreational, and Scientific — noted the ethical implications of studying cannabis in humans.

“You’re not going to get experiments in the United States where the federal government will approve a researcher or a scientist giving marijuana to a schizophrenic, but you could do a survey of schizophrenics,” said Lee (oral communication, March 15, 2013).

Healthy Populations

Cannabis is well known to cause physiological and psychological side effects in almost all people who use it, particularly varieties that contain higher levels of THC. Thus, the concept that cannabis causes negative mental experiences is not ridiculous; anecdotal reports of momentary post-cannabis psychosis and hallucinations have been shared for quite some time.²

While the psychological side effects of cannabis can be similar to the symptoms experienced by diagnosed schizophrenics — such as visual illusions, paranoia, mood alterations, and memory deficits9 — cannabis-produced symptoms typically disappear after three to five hours.¹⁰

Still, the allegation persists that cannabis can cause schizophrenia, a disease in which psychotic symptoms typically last throughout a patient’s life. When experts discuss this cannabis-schizophrenia relationship, they make sure to differentiate between cannabis’s impact on healthy populations and cannabis’s impact on diagnosed schizophrenic patients and individuals with risk factors for developing schizophrenia.⁹ This important detail is often not provided in media reports on the topic.

“I don’t think we should say cannabis induces schizophrenia, and so we should discourage people from using cannabis because they’ll become psychotics,” said Andrea Giuffrida, PhD, an associate professor of pharmacology at the University of Texas Health Science Center in San Antonio, who researches this topic (oral communication, March 25, 2013). “Maybe some of them have a higher risk, but not the entire population.”

Researchers and proponents of the argument that cannabis does not cause schizophrenia in the general population often cite epidemiological data that shows a significant increase in cannabis usage during the last several decades while the rates of schizophrenia have remained largely static. As stated by the authors of a recent article titled, “Cannabis and Psychosis: What Causes What?,” “Most people who use cannabis do not develop schizophrenia, and many people diagnosed with schizophrenia have never used cannabis.”9

“As marijuana usage has increased in culture in the last 50 years, you haven’t seen that increase in schizophrenia,” said Lee. “If it was causing schizophrenia, you would probably see an increase, so the causal thing is just not there.”

But according to psychiatrists Patricia Gerbarg, MD, who has a clinical practice in New York City, and Richard Brown, MD, a professor at Columbia University, the lack of correlation could be explained in other ways. “For example,” they said, “improvements in prenatal nutrition and healthcare are more likely to lower the incidence of schizophrenia…. Also, there may appear to be a lack of increase in schizophrenia because of a lack of increase in the diagnosis of schizophrenia, which could be due to the many changes in diagnostic categories since the 1970s. Many cases that would previously have been diagnosed as schizophrenia, would now be diagnosed as Asperger’s or bipolar disorder” (email, March 16, 2013).

Some epidemiological surveys have shown that schizophrenic patients abuse cannabis more than any other illegal drug and also have cannabis usage rates higher than healthy population rates, which has been used as an argument that cannabis possibly causes or increases the chance of developing schizophrenia in otherwise healthy populations.11 But according to Dr. Giuffrida, this is just a correlation, which, he points out, cannot establish causality. He additionally noted the hypothesis that schizophrenic patients might use cannabis more because they are attempting to self-medicate.

“Whether they smoke more because they are schizophrenic or they are schizophrenic because they smoke more cannabis, we don’t know the direction of the connection,” he explained.

Further, a Swedish survey published in 1987 of almost 50,000 male participants conducted over the course of 15 years found that those who self-reported heavy cannabis use were 50 times more likely to be diagnosed with schizophrenia.12 But when these findings were reanalyzed and adjusted to account for other risk factors, the increased likelihood dropped to 6.7 times, and many of the participants who reported cannabis use also reported the use of other drugs that have the ability to precipitate psychosis.¹³

In examining the connection between cannabis and schizophrenia, researchers also study brain morphology. In a 2012 paper in the European Archives of Psychiatry and Clinical Neuroscience, a team of researchers from Germany and England analyzed 16 neuroimaging studies. The authors concluded that there is “no convincing evidence” that cannabis-related brain alterations happen before the onset of schizophrenia.¹¹ In fact, essentially none of the changes seen in the brains of schizophrenic patients using cannabis were observed in healthy individuals who used cannabis.

Some journals and other sources report that young people are especially vulnerable for developing cannabis-induced schizophrenia. A large-scale survey conducted in 2005 by Henquet et al. suggested that ingesting cannabis at a young age (14 to 24 years) was associated with an increased chance of developing psychotic symptoms,^14,15 but this data did not analyze the risk of developing full schizophrenia, and those with predisposed risks for psychosis were more likely to develop psychotic symptoms. According to an expert peer reviewer of this article, while extra caution is always advised in adolescents, there is still no evidence that permanent, schizophrenia-related de novo damage is done to young, healthy individuals.

“The work of Henquet is very interesting,” added Dr. Giuffrida, “but the assessment of cannabis use is based on an interview and consequently is not as precise as a study where cannabis is administered in a controlled fashion. I do believe we need more experiments before establishing a causal relation between cannabis exposure and schizophrenia development in the healthy population.”

At-Risk and Diagnosed Populations

Most researchers agree that because schizophrenia likely is brought on by a variety of “component causes,” one of which could include cannabis use, a healthy person with no risk factors is very unlikely to develop the disease from cannabis use alone.9,11,14 The situation is different, however, for individuals with predisposed risks.

Those at risk for developing schizophrenia include individuals with schizophrenic family members or those who exhibit symptoms of the prodromal stage (a precursor to a more full set of symptoms or disease), which typically consist of increased isolation and decreased motivation and appear a year before true schizophrenia symptoms.¹¹ Interestingly, recent research suggests that a mutation in the AKT1 gene also might put an individual at increased risk for developing cannabis-associated schizophrenia.16 These at-risk groups are cautioned against using cannabis as epidemiological evidence and survey data show that they have worse psychotic-disorder outcomes when cannabis is a factor.¹⁵

The aforementioned 2012 brain morphology literature review by Malchow et al. found just three studies on high-risk individuals, in which an “additional effect of cannabis use on brain structure” was suggested.11 These studies found that cannabis use was associated with a bilateral volume loss of the thalamus, a region of the brain that integrates and processes sensory and cognitive functions; increased thinning of the cortex, the largest region of the brain; and an increased volume of the brain’s fluid-filled cavities known as ventricles. (The latter of these studies, however, analyzed cannabis and alcohol in high-risk subjects.)

The review authors conclude that there is “some weak evidence that cannabis abuse could affect brain structures in high-risk subjects, but replication of these findings is needed. The results of the identified neuroimaging studies are heterogeneous and inconclusive,” for various reasons, including differing definitions of regional volume boundaries and differing volume extraction methods (when measuring content of the brain), as well as differing MRI techniques.¹¹

For patients who have been diagnosed with schizophrenia, the implications for using cannabis are somewhat better understood. Although few human clinical trials on cannabis and schizophrenics have been performed, epidemiological data and survey evidence indicate — and most experts agree — that ingesting cannabis can aggravate schizophrenia symptoms and/or increase their frequency.¹³ The few human studies found cannabis products (i.e., hashish, THC) to exacerbate symptoms, although these were temporary effects. According to Endocannabinoid’s neuropsychiatry chapter, “Taken together, most studies confirm the vulnerability hypothesis for cannabis use and schizophrenia. Thus, schizophrenia patients should probably not use cannabis because a psychotic episode can be induced in someone with a preexisting disorder and, indeed, increased hospitalization rates and symptom exacerbation have been demonstrated.”⁵

Malchow et al. noted that most brain imaging studies on cannabis and schizophrenia examined individuals with first-episode or recent-onset schizophrenia.11 Some of this research suggested that schizophrenic patients who used cannabis had subtle brain abnormalities, increased ventricle volumes, thinning of various cortical regions, decreased gray and white matter volume, and “altered brain structure in particular regions … with a high density of CB1 receptors.” The authors noted, however, that anti-psychotic medication has been strongly associated with reduced gray matter and that many of the studies included “comorbid patients consuming other substances than cannabis, for example, amphetamines, cocaine, and sometimes alcohol, making it difficult to focus on the effect of cannabis alone.”

“The results of these neuroimaging studies are again heterogeneous and remain inconclusive,” they wrote.

Researchers are beginning to understand that the connection between cannabis and schizophrenic individuals might lie in the human body’s mysterious and powerful endocannabinoid system. According to the authors of a 2008 article in Expert Review of Neurotherapeutics, “There are several lines of evidence suggesting that, at least in a subgroup of patients, alterations in the endocannabinoid system may contribute to the pathogenesis of schizophrenia.”15

Human studies have shown schizophrenics to have increased levels of anandamide and endocannabinoid-like molecules such as palmitylethanolamide, and these patients with higher levels of anandamide typically experience fewer psychotic symptoms.15 Additionally, frequent cannabis usage was found to decrease cerebral spinal fluid levels of anandamide, suggesting a possible explanation for why some schizophrenic patients sometimes have negative experiences after ingesting cannabis. Authors of additional studies have found a possible connection between lower levels of the endocannabinoid 2-AG and schizophrenia progression, as well as impaired endocannabinoid signaling associated with acute psychotic episodes.

“My preferred hypothesis is that frequent and intense cannabis smoking [reduces] an endogenous protective mechanism, mediated by anandamide, resulting in an increased risk for precipitation of psychosis,” said Daniele Piomelli, PhD, PharmD, a professor of anatomy and neurobiology at the University of California at Irvine (email, March 22, 2013). “Please note that anandamide is not the only endocannabinoid present in the brain and that this theory does not rule out the possibility that other endocannabinoids (e.g., 2-AG) might be pro-psychotic.”

In explaining why cannabis and endocannabinoids might not act in the same way, Dr. Giuffrida pointed to the different pharmacologic profiles of THC and anandamide. “For example, when you smoke cannabis and take in THC, you activate all the cannabinoid receptors in the brain. But when you elevate anandamide, the elevation does not happen all over the brain but happens in specific brain areas.”

Interestingly, the CB1 receptor is expressed in high levels in the prefrontal cortex — the region of the brain responsible for cognitive and emotional functions and thought to be the “primary dysfunctional area” in schizophrenia — as well as in other brain areas relevant to schizophrenia, such as the basal ganglia, hippocampus, and the anterior cingulate cortex.8,15 Some post-mortem studies have found schizophrenic patients’ brains to have even-further increased binding levels of the CB1 receptor.

“But again,” said Dr. Giuffrida, “whether this is a contributing factor to develop schizophrenia is unknown at this time.”

Dr. Giuffrida reiterated that cannabis can sometimes help certain schizophrenia symptoms, which might explain why some patients might self-medicate with the herb.

“We know that, in schizophrenic patients, cannabis intake can make positive symptoms worse. But, on the other side, there is some work showing that the cannabinoids have a beneficial effect on the negative symptoms of schizophrenia, so they make people interact more with each other. But what happens with marijuana, especially if you are a psychotic individual, the more you use cannabis, the worse your symptoms become over time. So it can be helpful in the beginning, but definitely not in the long run.”

Therapeutic Role of CBD

While THC, the compound in cannabis responsible for the euphoric “high,” is known to increase the severity of psychotic symptoms in schizophrenia patients, another cannabinoid in cannabis — the non-psychoactive cannabidiol (CBD) — has been shown to be therapeutic for schizophrenia symptoms.

Based on CBD’s known anti-anxiety activity, researchers conducted a small pilot study on CBD in 42 patients with paranoid schizophrenia in 2012. This Phase II, double-blind, four-week trial compared CBD treatment with the antipsychotic drug amisulpride and found that CBD improved symptoms as well as the pharmaceutical — and that it produced fewer negative side effects.17

“It’s a small study so we have to see if the data is replicated in larger groups of people,” said Dr. Giuffrida, noting that CBD “is definitely one of the most exciting areas in the cannabinoid field.” He explained that although CBD’s activity within the brain is not yet completely understood, this compound is pharmacologically different from THC in that it does not bind to the CB1 receptor in the brain, whereas THC does. Additionally, he said some animal and human studies show that CBD boosts levels of the endocannabinoid anandamide, and elevated anandamide seems to have a beneficial effect on schizophrenia.

“These results suggest that the inhibition of anandamide activation may contribute to the anti-psychotic effect of cannabidiol,” said Dr. Giuffrida, “which possibly represents a completely new mechanism of treatment for schizophrenia.”

Conclusion

While CBD presents an exciting possibility as a novel schizophrenia treatment, additional research must be conducted to validate early studies. Likewise, more human research on cannabis’s impact on schizophrenia would greatly broaden scientists’ and medical professionals’ understanding of this interesting and complex relationship. Based on the available evidence — which includes epidemiological studies, surveys, brain morphology analyses, and a few human studies — most experts accept that cannabis intake could have negative impact on individuals who have schizophrenia and that those vulnerable to developing schizophrenia can have psychotic episodes if they ingest high doses of cannabis.

“So there definitely is something there,” said Dr. Guiffrida. “However, this is probably one of the components that may contribute to schizophrenia. It is not the cause of schizophrenia. And so I don’t think we have yet enough evidence to say that cannabis causes schizophrenia, and this is particularly true for the healthy population.”

References

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