CBD Fights Schizophrenia, but with Different Dose Range for Different Symptoms

Schizophrenia is a chronic and in many cases permanently disabling mental disorder that affects about one percent of the world’s population. According to the World Health Organization, more than 26,3 million people suffer from the disease, 16,7 million are disabled and it is accounted for 30.000 fatal outcomes a year, half of which take place in South East Asia. 

Schizophrenia is characterized by episodes of psychosis between periods of a blunted emotional state and stupor. Symptoms that occur during episodes of psychosis are called ‘positive symptoms’ and include impaired mental activity, a delirium that consists of false beliefs, and is often accompanied by paranoia; and hallucinations, most commonly in the form of hearing prying voices. These symptoms are accompanied by anxiety, depression, and excessive activity, e.g. constant movement and agitation.

Negative symptoms of schizophrenia include blunted emotions, a decrease in the frequency of speech, a deterioration in the ability to plan, start or continue any activity, and a reduction in the perception of positive emotions or interest. These symptoms can cause severe problems in social interaction and daily life.

The third group – cognitive symptoms of schizophrenia include disorganized thinking, slow thinking, difficulty understanding, poor concentration, poor memory, difficulty expressing thoughts, and difficulty integrating thoughts, feelings, and behavior.

The opposite effects of THC and CBD

While there are strong links between excessive usage of THC, especially in adolescents, with triggering psychosis and schizophrenia, CBD has been found to have the opposite effect. Nonetheless, a significant proportion of patients don’t respond to traditional antipsychotics , that only target the positive symptoms, with little effect on negative or cognitive symptoms. On top of that, dopamine-acting antipsychotics are associated with a number of side effects, some of which can be severe.

These understandings have driven the attention of scientists to providing more scientific evidence on the effects of CBD on patients who suffer from schizophrenia.

In 1982, a study of the interactions between THC and CBD in healthy volunteers provided the first evidence that CBD might have antipsychotic properties. This finding was confirmed in 1995, when a study published in the Journal of Clinical Psychiatry concluded that CBD has an atypical antipsychotic profile.

Lately, in 2018, at the South London and Maudsley NHS Foundation Trust in London, United Kingdom, a clinical trial was conducted where 33 antipsychotic medication–naive participants at clinical high risk of psychosis and 19 healthy control participants were studied. The scientists used functional magnetic resonance imaging to inspect the effects of CBD on parahippocampal, striatal, and midbrain function – the three brain functions active in schizophrenia. Observing the level of activation in the left parahippocampal brain cortex, the study concluded that a single dose of CBD may partially normalize dysfunction in the medial temporal lobe, striatum, and midbrain in the individuals at clinical high risk of psychosis.

Very recently, in May this year, Antonio Waldo Zuardi and José Alexandre Crippa from the University of São Paulo published an article in the Psychiatric Times, where they discuss the current stage of scientific evidence that supports the use of cannabidiol in schizophrenia, anxiety, and Parkinson disease.

The article underlines the connection between cannabis and psychosis as having a centuries-long history, that goes back to 2700 BC, when Shen-nung pen ts’ao ching (Divine Husbandman’s Materia Medica), the world’s oldest pharmacopeia attributed to Chinese emperor Shen-Nung, stated that “. . . ma-fen (the fruit of cannabis), if taken in excess, will produce visions of devils . . . over the long term, it makes one communicate with spirits.”

In the 19th century, French psychiatrist Jacques-Joseph Moreau started using cannabis as an experimental psychotomimetic, a drug that mimics the symptoms of psychosis, and, apparently, it’s been used for that purpose in Western medicine to this day. Consistent scientific evidence indicates that the chronic and intense use of the plant, especially if started in adolescence, contributes to the occurrence of schizophrenia.

Great results with intermediate doses

After the study in 1982, which provided the first evidence that CBD might have antipsychotic properties, the same observation was confirmed in a study with THC administrated intravenously after oral pretreatment with CBD or placebo. In addition to blocking the psychotic symptoms induced by THC, CBD and THC demonstrated opposite effects. 

This led the scientists to carry out a pioneering study to test the effects of CBD on laboratory animals. The stereotypy induced in rats was clearly reduced by CBD, without producing catalepsy, the study has found. The next step was to evaluate the effects of CBD in a patient with schizophrenia. The patient was a chronically psychotic young female who has experienced many adverse effects from traditional antipsychotics, which presented the ethical justification for the first clinical test. After four weeks of treatment, the patient had a marked reduction in her psychotic symptoms.

The patient was given up to 1500 mg per day in two divided doses, with weekly reducing diazepam dose, which was being given for periods of great agitation and anxiety. The dose of diazepam was reduced from 16,3 to 5,7 mg per day. The improvements of her condition were observed in all the symptoms closely related to the psychosis, including thought disturbance and hostility-suspiciousness.

To date, three randomized controlled trials have evaluated the therapeutic effects of CBD in schizophrenia patients. The first one included 39 patients treated with either CBD (800 mg/d; n = 20) or the atypical antipsychotic amisulpride (800 mg/d; n = 19) for four weeks. Both drugs led to a similar significant reduction in both positive and negative psychotic symptoms, but fewer adverse effects were seen in the CBD group.

In the other two trials, the results were contradictory. Treatment with a dose of 1000 mg per day significantly reduced positive symptoms, while the other study with 600 mg per day found no significant symptomatic differences between CBD and placebo. It is possible that the explanation for the contradictory results lays in the difference in CBD doses.

Bell-shaped dose-response

The CBD dose-response relationship appears to have a particular feature, Zuardi and Crippa point out. In 1990, CBD was tested in a range of doses in rats with the elevated plus-maze model and was found to act according to a bell-shaped dose-response curve. CBD induced an anxiolytic-like effect only at intermediate doses. At a dose of 20,0 mg/kg, it was no longer effective.

The dose-response curve was also observed in healthy volunteers subjected to anxiety induced by the simulation of public speaking test and by public speaking in real settings. In the first situation, volunteers were asked to speak for a few minutes in front of a video camera, while in the second each subject had to speak in front of a group of other research participants. In both situations, treatment with CBD 300 mg was associated with significant decreases in anxiety symptoms, but this effect was not observed with lower or higher doses.

Zuardi and Crippa observed the same response pattern in preclinical tests using other models of induced anxiety, cognitive impairment, and schizophrenia-like behavior. The findings suggest that this inverted U-shaped curve response pattern may be extended to other therapeutic effects of CBD, with different effective doses and therapeutic windows for each condition.

The data from all three studies in schizophrenia patients suggest that the dose range to reduce psychotic symptoms (probably between 800 and 1000 mg/d), but not cognitive symptoms, should be higher than that used to induce anxiolytic effects (between 200 and 400 mg/d). However, the scientists point out that precise dose ranges for each condition or symptom are yet to be determined.

Reviewed by Sasha Bajilo, founder of ILESOL Pharmaceuticals, an industrial scale producer of CBD products and formulations. Expert on Hemp/Cannabis policy, member of the Croatian Ministry of Health regulatory commission for medical cannabis.