Title: Literature Review of Cannabidiol Effects on Schizophrenia
Authors: Saba Ahmed, MAMSc, Darya Connor, MAMSc, Mahrukh Kadri, MAMSc, and Arena Maleque, MAMSc
Introduction
Humans express endogenous cannabinoid receptors (CB1R) in most tissues, including the central nervous system (CNS). Cannabidiol (CBD) binds and antagonizes the CB1R in the CNS, potentially benefiting the neuropsychological disorder schizophrenia. Schizophrenia can manifest positive and negative symptoms. There are limited therapeutic options for schizophrenia, and many therapies have adverse effects. CBD is a potential treatment. Our goal was to scan and interpret the literature available on CBD as a possible treatment for schizophrenia patients.
Materials & Methods
A PubMed search with the phrase “cannabidiol effects on schizophrenia,” yielded 172 articles. Meta-analysis, Clinical Trials, and Randomized Control Trials (RCT) were selected to produce 19 articles. A total of four articles were selected that fit the following criteria: human trials, for schizophrenia only, using CBD without THC. One was a clinical trial, and the remaining three were randomized control double-blind studies. Searching on Sciencedirect, PsycARTICLES, PsycINFO, and ClinicalKey with the same keywords yielded results that did not apply to our search criteria.
Results
Boggs et al. (2018) studied the effect of CBD (600 mg/day for 6 weeks, N=36) on cognition. CBD did not improve cognition as measured by PANSS or MCCB (p=0.18). McGuire et al. (2018) compared the safety and effectiveness of CBD (1000 mg/day for 6 weeks, N=43) compared to placebo (N=45). The results were not statistically significant (p=0.068). Leweke et al. (2012) compared amisulpride (a D2 antagonist approved for acute and chronic schizophrenia) to CBD (200 mg to 800 mg/day for 4 weeks, N=42), and the results were not statistically significant (p=0.8). The study also indicated CBD was associated with fewer extrapyramidal symptoms. Zuardi et al. (2006) studied CBD monotherapy (40 mg to 1280 mg/day) in 3 treatment-resistant schizophrenia patients. One patient showed mild improvement, while the other two did not. In all studies, CBD was tolerated without any side effects.
Discussion
The overall trends between CBD vs. placebo or CBD vs. amisulpride produced no statistically significant difference. Additionally, CBD does not have adverse effects and seems to decrease positive symptoms (hallucinations and delusions) of schizophrenia. Another limitation is the wide discrepancies in doses of CBD. A large-scale trial would further clarify these findings.
Did you not feel compelled to perform a meta-analysis of the 4 trials? Is is possible that the results, especially of the last trial, may have been confounded by the use of Cannabis? Subjects who perceived that they were not getting the effects of CBD may have been more likely to obtain and use Cannabis from other outside sources, and therefore had increased risk of schizophrenia and its many lesser forms. You should revisit DSM-IV-TR and DSM-5 as the standards for psychiatric diagnosis, as they seem to have been confused in your presentation.
Thank you for your questions, Dr. Elliott! Although we would have liked to do a meta-analysis, it was not possible for the four trials since all the authors did not use standardized statistical analyses. For example, one study used total PANSS versus another used exclusion criteria for a PANSS score less than 60 at screening. Additionally, Leweke et al. excluded patients with Treatment-Resistant Schizophrenia (TRS), but the Zuardi et al. and Boggs et al. included patients with TRS.
In two out of four studies, Zuardi et al. and Leweke et al. used institutionalized patients, so it is unlikely that they would be able to obtain additional CBD or THC from other sources. Additionally, Leweke et al., and Boggs et al., used exclusion criteria to exclude patients who had a substance use three months before the study. The authors of the McGuire et al. the paper said that there was only one patient in the CBD group and two patients in the placebo group who tested positive for THC at baseline; because so few patients tested positive for THC, it was not possible to assess whether the effects of CBD were influenced by cannabis use. Moreover, McGuire et al. did not provide information on substance use throughout the study.
We apologize for the typo; Boggs et al. used DSM-IV-TR and not DSM-V-TR. The other three studies all used DSM-IV.
Thank you for investigating this interesting topic. As one of the judges for your poster, I was wondering if you have information about the dosage of CBD that is likely to cause impaired driving and how using this drug as a treatment for schizophrenia may affect the patients ability to operate a motor vehicle safely. Thanks!
That is a fascinating question, Dr. Rhodes! Our initial literature search indicated that sedation is a factor in CBD use. In our review, only Boggs et al. showed that 20% of the participants in the CBD arm reported “mild” sedation compared to 5% in the placebo arm; the other three studies did not. While we recognize that mild sedation can be dangerous when operating a motor vehicle, we believe in our research that we must judge CBD as other Schizophrenia medications. From common Schizophrenia medication such as Haloperidol to second-generation medications such as Abilify, most antipsychotic drugs instruct patients to avoid operating hazardous machinery, including automobiles, until they are reasonably confident that therapy will not affect them adversely. Thus, we would hold the same standards for CBD if its medicinal use were to be proven for Schizophrenia.
Although we could not find research to show the dosage level of CBD that causes sedation to affect driving, we did find an article that may be of interest to you. It compared tobacco use concurrent with placebo or CBD-rich marijuana. The authors state that 500 mg of CBD-rich marijuana (16.6% total CBD; 0.9% total THC) is comparable to a placebo in terms of reaction time, motor time, behavior under stress, and concentration performance. However, they still recommended that consumers refrain from driving for several hours after smoking CBD-rich marijuana.
Gelmi TJ, Weinmann W, Pfäffli M. Impact of smoking cannabidiol (CBD)-rich marijuana on driving ability. Forensic Sci Res. 2021;6(3):195-207. Published 2021 Sep 28. doi:10.1080/20961790.2021.1946924. https://pubmed.ncbi.nlm.nih.gov/34868711/
Thank you for your presentation. As a judge, I am curious how the dosages of CBD were determined as there are no federal guidelines or oversight on how CDB (or THC) levels of a product are measured. Also, was it determined in any of the studies if the CBD had any THC contamination?
Thank you for your questions, Dr. Habecker! The earliest research regarding CBD dosage we found was from Cunha et al., 1980. They used 3mg/kg per day for phase one and 200-300mg per day for phase two of their study, respectively. They specifically looked at the potential use of CBD as an antiepileptic drug. Today that has translated to one US FDA-approved prescription product Epidiolex, cannabidiol, to treat seizures caused by Dravet syndrome, Lennox-Gastaut syndrome, or tuberous sclerosis complex. The current product guidelines are to begin dosage at 2.5mg/kg twice daily with an increase in weekly increments of 5 mg/kg/week to a maximum dose of 25 mg/kg/day. This is similar to what we saw in our Schizophrenia and CBD studies. Our studies’ lowest dose was 600mg/day and the highest at 1280/day, both fall in Epidiolex accepted range. We believe the use of CBD for Schizophrenia is still preliminary, and therefore, for now, it seems to be based on previous research.
Two of our four studies indicate specific pharmaceutical companies that they obtained CBD from. Since all four were hospital-based studies, it would be safe to assume that they all received CBD from pharmaceutical companies. Thus, CBD contamination with THC would be unlikely in the study medication. In 2020, the FDA studied products that claimed to have CBD. Of the 102 products that indicated a specific amount of CBD, 18 products contained less than 80% of the amount stated, 46 products contained CBD within 20 percent of the amount stated, and 38 products had more than 120 percent of the amount indicated. Furthermore, of 147 products tested, 49% of them tested positive for THC. Thus, CBD use in consumer products is not reliable.
Report to the U.S. House “Sampling Study of the Current Cannabidiol Marketplace to Determine the Extent That Products are Mislabeled or Adulterated Report in Response to Further Consolidated Appropriations Act, 2020,” FDA. Jul 2020. https://hempindustrydaily.com/wp-content/uploads/2020/07/CBD-Marketplace-Sampling_RTC_FY20_Final.pdf