Cannabidiol as an Adjunctive Treatment for Schizophrenia
Cannabis is a complex plant with more than 100 types of cannabinoids. Its main psychoactive compound is Î´-9-tetrahydrocannabinol (THC), which activates cannabinoid receptors to produce its “feeling high” effects. Cannabidiol (CBD) is another cannabinoid that has attracted growing attention recently. Unlike THC, CBD does not bind to cannabinoid receptors and has shown different, sometimes counteractive, effects. Currently, there are more than 100 clinical trials registered on the ClinicalTrials.gov website on the potential therapeutic effects of CBD.
The FDA has recently approved the first cannabis plant-derived medication, Epidiolex (an oral solution of pure CBD), for treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome in patients aged 2 years and older. 1 Consequently, DEA scheduled Epidiolex in Schedule V of the Controlled Substances Act (CSA), the least restrictive schedule. 2 Though Epidiolex is only approved for the above rare seizure disorders, physicians may recommend it off-label for other conditions, based on their own judgment. It is important to note, however, that the only approved form of CBD is Epidiolex and off-label recommendation of other forms of CBD does not follow the same rules.
The evidence for cannabidiol
The association between cannabis use and psychosis is well-known in epidemiological studies, and a dose-response relationship is consistently reported with an odds ratios of 3.90 (95% CI, 2.84 to 5.34) for the risk of schizophrenia in heavy cannabis users. 3 However, use of cannabis strains with high CBD content has been associated with fewer psychotic symptoms. 4 Whereas THC produces acute psychotic-like symptoms in healthy volunteers, pre-treatment with CBD decreases the THC-induced psychotic symptoms and cognitive impairments. 5-7
The potential beneficial effects of CBD on cognition in patients with schizophrenia have critical importance, since cognitive deficits are common in schizophrenia (up to 75%-85% of patients), usually precede other symptoms, and respond minimally to the available pharmacological treatments.
The very first case report on the use of CBD as an antipsychotic medication was published by Zuardi and colleagues 8 (Table). In this study, a 19-year-old female patient with schizophrenia was treated with CBD up to 1500 mg daily for 4 weeks, which resulted in improvement of acute psychotic symptoms. Findings from a study in 2006 that looked at the effects of CBD as monotherapy for treatment-resistant schizophrenia in three individuals show that improvement was seen in only one patient. 9 A later study on the antipsychotic effects of CBD (at flexible doses up to 400 mg/d) on 6 individuals who had Parkinson disease showed improvement of psychotic symptoms over the course of 4 weeks. 10
Since then, the antipsychotic properties of CBD have been investigated in three clinical trials with mixed results (Table). In 2012, Leweke and colleagues 11 published the first double blind randomized controlled clinical trial on the therapeutic effects of CBD (600-800 mg/d for 4 weeks) compared with amisulpride on acute psychosis in individuals with schizophrenia (N = 42). The study concluded that CBD is as effective as amisulpride in treating psychotic symptoms and has fewer adverse effects, including less extra pyramidal symptoms and weight gain.
More recently, the effects of CBD on psychosis were explored in two double-blind randomized placebo-controlled clinical trials. McGuire and colleagues 12 used CBD as an adjunctive medication in treatment of acute psychosis in individuals who had schizophrenia or other non-affective psychotic disorders. Participants (N = 88) received either CBD 1000 mg daily (in two divided doses) or placebo in addition to their routine antipsychotic medications (continued unchanged during the study) for 6 weeks.
Compared with the placebo group, the CBD group showed greater improvement of positive psychotic symptoms over the course of the treatment. Mean improvement of PANSS positive score was 3.2 (SD 2.60) in the CBD group compared with 1.7 (SD 2.76) in the placebo group. Moreover, by the end of the treatment, more patients in the CBD group were rated as “improved” on the CGI-I scale compared with those in the placebo group (78.6% and 54.6%, respectively). Patients who received CBD also showed a trend-level improvement in their cognitive functioning, and a significant improvement of their motor speed compared with controls.
In a similar study, Boggs and colleagues 13 investigated the therapeutic effects of adjunctive CBD 600 mg daily (in two divided doses) compared with placebo in a 6-week double blind placebo-controlled randomized clinical trial, in individuals with chronic schizophrenia (N = 36). However, their results showed no significant differences between CBD and placebo on psychotic symptoms or cognitive performances.
Mechanism of action
The exact mechanism of action is still unknown for CBD’s potential anti-psychotic properties. Unlike other antipsychotic medications, CBD does not greatly affect dopaminergic neurons, and unlike THC, it does not bind to cannabinoid receptors. However, CBD reportedly increases the CSF levels of anandamide, one of the main endocannabinoid ligands, by blocking its degrading enzyme, fatty acid amide hydrolase, or by competing with anandamide intracellular transporters. It is interesting to note that anandamide levels are negatively correlated with severity of psychotic symptoms, whereas increased anandamide levels in psychotic patients treated with CBD are correlated with clinical improvement. This may suggest that CBD contributes to amelioration of psychosis by increasing the endogenous levels of anandamide. However, further studies are needed to confirm this.
The current pharmacological treatment for schizophrenia is only partially effective and mainly for positive symptoms. This has led investigators to investigate new pharmacological targets and the endocannabinoid system has been one of the newest ones. Over the past few decades, increasing evidence has shown the presence of endocannabinoid system abnormalities in schizophrenia. 14 However, the current studies on the potential therapeutic effects of CBD are not conclusive and the mechanism of action is poorly understood. The discrepancies in clinical results could be related to different doses of CBD, stages of psychosis, or possibly heterogeneity of schizophrenia itself.
In addition to the potential therapeutic effects of CBD for schizophrenia, CBD may also have a role in preventing or treating the psychosis related to recreational use of cannabis in vulnerable individuals. Cannabis continues to be the most commonly used illicit drug in the US, and with the spreading legalization for medical and recreational purposes, a lower proportion of people perceive the risk associated with regular cannabis use. At the same time, there is a decreasing ratio of CBD-to-THC in street cannabis from 1:14 in 1995 to 1:80 in 2014. Low CBD content may affect the overall impact of frequent cannabis use on mental health, which may become evident in the future. When discussing the medicinal use of cannabis, it is important to distinguish CBD, with its potential beneficial effects, from THC, with its controversial adverse effects, especially on individuals with psychotic disorders.
Dr Bassir Nia is Assistant Professor of Psychiatry, Yale University School of Medicine, New Haven, CT. Dr Bassir Nia reports that she has no conflicts of interest concerning the subject matter of this article.
1. US Food and Drug Administration. FDA Approves First Drug Comprised of an Active Ingredient Derived From M arijuana to Treat Rare, Severe Forms of Epilepsy. 2018. https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm611046.htm. Accessed February 7, 2019.
2. US Drug Enforcement Administration. FDA-Approved Drug Epidiolex Placed in Schedule V of Controlled Substance Act. 2018. https://www.dea.gov/press-releases/2018/09/27/fda-approved-drug-epidiolex-placed-schedule-v-controlled-substance-act. Accessed February 7, 2019.
5. Martin-Santos R, Crippa JA, Batalla A, et al. Acute effects of a single, oral dose of d9-tetrahydrocannabinol (THC) and cannabidiol (CBD) administration in healthy volunteers. Curr Pharm Des. 2012;18:4966-4979.
6. Englund A, Morrison PD, Nottage J, et al. Cannabidiol inhibits THC-elicited paranoid symptoms and hippoc ampal-dependent memory impairment. J Psychopharmacol. 2013;27:19-27.
7. Bhattacha ryya S, Morrison PD, Fusar-Poli P, et al. Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology. 2010;35:764-774.
8. Zuardi AW, Morais SL, Guimaraes FS, Mechoulam R. Antipsychotic effect of cannabidiol. J Clin Psychiatry. 1995;56:485-486.
9. Zuardi AW, Hallak JE, Dursun SM, et al. Cannabidiol monotherapy for treatment-resistant schizophrenia. J Psychopharmacol. 2006;20:683-686.
10. Zuardi AW, Cripp JA, Hallak JE, et al. Cannabidiol for the treatment of psychosis in Parkinson disease. J Psychopharmacol. 2009;23:979-983.
14. Fakhoury M. Role of the endocannabinoid system in the pathophysiology of schizophrenia. Mol Neurobiol. 2017;54:768-778.
Is CBD Good for Schizophrenia?
Schizophrenia is a chronic psychotic disorder that affects a small portion of the world’s population. There is some evidence that CBD might aid in the treatment of neurological conditions such as schizophrenia.
Schizophrenia is a chronic psychotic disorder that affects a small portion of the world’s population. Symptoms typically manifest in early adulthood or late adolescence. Schizophrenia has several different symptoms, such as hallucinations and impaired brain functions.
Although it is not a core symptom, people with schizophrenia also experience anxiety, and with the increasing popularity of CBD, many people wonder if it can be of any help against schizophrenia. In fact, using CBD oil for schizophrenia may become the norm, since CBD has been legalized in many areas.
However, there is insufficient evidence to prove that CBD could affect brain function in people with schizophrenia. Research does not suggest or support use of medical cannabis as a treatment for such people.
Despite that, some benefits of CBD for paranoia and related disorders have been observed anecdotally.
Is CBD an antipsychotic?
There is no scientific consensus concerning the best CBD oil for psychosis, as the research is still underway. However, there is some evidence that CBD might aid in the treatment of neurological conditions such as schizophrenia and Parkinson’s disease.
The first of the CBD schizophrenia clinical trials was conducted in 1995. The study subject was a 19-year-old female. The researchers gave her 1,500 milligrams of CBD every day for four weeks. They found that it improved her acute psychotic symptoms.
Later, a 2006 study looked at the effects of CBD in three individuals with schizophrenia. Only one of them experienced improved symptoms after using CBD. Until now, there have been mixed studies. Some show positive results, while others have found that CBD can worsen symptoms of paranoia.
More research on the subject is needed to come to any clear conclusion about any CBD oil schizophrenia treatments.
Can CBD oil replace antipsychotics?
It would be best if you never replaced your medicines with alternative treatments without first consulting with your doctor.
If such treatment is approved, though, it is also worth noting that CBD could have an antipsychotic effect, since it mimics the impact of these medications. In an animal trial, it was seen that CBD reduced hyperlocomotion, which stems in some cases from the stimulation of ketamine and amphetamine in people with schizophrenia.
CBD had this effect without also causing catalepsy, a seizure or trance-like state in which the body becomes rigid and loses sensation. The researchers noted that this mechanism of action was similar to the antipsychotic drug clozapine, which also works similarly and does not cause any motor side effects.
However, it is important to keep in mind that these findings are from an animal trial. Studies in human subjects will shed more light on the effects of CBD in humans.
How much is CBD needed for schizophrenia?
Since there is no clear evidence of the effectiveness of CBD, there is no standard CBD dosage for schizophrenia. In a human trial with 57 healthy male adults, the researchers found that 300 milligrams of CBD were enough to experience anxiety relief in participants.
When they lowered the doses, there was no effect. Similarly, a higher dose did not show this effect either. However, this research studies the effect of CBD specifically in schizophrenia patients who experienced anxiety.
Although the researchers proposed that the same response pattern could extend to other conditions, it is too early to say what the proper CBD dosage for schizophrenia is. If you want to try medicinal cannabis to relieve your symptoms, talk to your doctor. Do not buy non-prescription CBD online. Most studies use pure CBD, which is why they require a higher dose.
When you buy CBD from a manufacturer, it will also include other components of cannabis. These assist the function of CBD, so you need a lower dose. Discuss the dosage with your doctor instead of calculating it using scientific studies.
How does CBD interact with prescription antipsychotics?
Typically, CBD is thought to be safe. However, it can have some side effects, such as dry mouth, nausea, and anxiety, and it may cause liver damage if you use it at a high dose.
As for drug interactions, you have to be careful if you intend on using CBD. According to Penn State University, 57 drugs interact with cannabis and CBD in your body.
These medicines have a narrow therapeutic index, which means your doctor will prescribe them at specific doses. They are sufficient to be effective but not capable of causing harm. When you use them with CBD oil, CBD may render them ineffective or alter their function.
Some antipsychotic medicines can also interact with CBD. Thus, you should always consult with your doctor before using CBD or any alternative treatment method.
Health Solutions From Our Sponsors
Brazilian Journal of Psychiatry: “Cannabidiol presents an inverted U-shaped dose-response curve in a simulated public speaking test.”
European Journal of Pharmacology: “Cannabidiol inhibits the hyperlocomotion induced by psychotomimetic drugs in mice.”
Journal of Clinical Psychiatry: “Antipsychotic effect of cannabidiol.”
Journal of Psychopharmacology: “Cannabidiol monotherapy for treatment-resistant schizophrenia.”
Penn State News: “Cannabinoids may affect activity of other pharmaceuticals.”
The Journal of Psychoses and Related Disorders: “Schizophrenia, Consciousness, and the Self.”?
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