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Cbd oil used for schizophrenia

Cannabidiol versus risperidone for treatment of recent-onset psychosis with comorbid cannabis use: study protocol for a randomized controlled clinical trial

Cannabis use is an important risk factor for development of psychosis and further transition to schizophrenia. The prevalence of patients with psychosis and comorbid cannabis use (dual diagnosis) is rising with no approved specialized pharmacological treatment option. Cannabidiol, a constituent of the Cannabis sativa plant, has potential both as an antipsychotic and as a cannabis substituting agent.

The aim of this study is to evaluate the efficacy of cannabidiol versus a first-choice second-generation antipsychotic (risperidone) in patients with early psychosis and comorbid cannabis use.


The study is a phase II randomized, double-blinded, parallel-group, active-comparator clinical trial. We plan to include 130 patients aged between 18 and 64 years with a recent diagnosis of psychosis, comorbid cannabis use, and currently not treated with antipsychotics. The participants will be randomized to seven weeks of treatment with either cannabidiol 600 mg (300 mg BID) or risperidone 4 mg (2 mg BID). Participants will undergo clinical assessment after 1, 3, 5 and 7 weeks, telephone assessment the weeks in between, and a safety visit two weeks after end of treatment. The primary outcomes are cessation of cannabis use (self-reported) and psychotic symptom severity. The secondary outcomes include frequency and quantity of cannabis use, global illness severity, psychosocial functioning, subjective well-being, cognition, sleep, circadian rhythmicity, and metabolomics.


The results of this trial can potentially contribute with a new treatment paradigm for patients suffering from dual diagnosis.

Trial registration


Psychotic disorders are characterized by psychotic symptoms including disorganized thinking and speech, delusions and hallucinations [1]. Schizophrenia is the most severe psychotic disorder, characterized by positive (e.g., hallucinations and delusions) and negative symptoms (e.g., lack of initiative and motivation, social withdrawal, emotional blunting) as well as cognitive impairments (e.g., impaired memory and executive functions). Schizophrenia manifests in adolescence or early adulthood in most cases, resulting in marked loss of functioning and reduced quality of life [2]. Antipsychotics are the pharmacological treatment of choice for patients suffering from schizophrenia with clear evidence of symptom reduction and reduced risk of relapse [3]. Dopamine D2 receptor blockade is the common mechanism of action of antipsychotics, but antipsychotics also bind to other receptor types with varying affinity [4]. Consequently, antipsychotics are associated with a variety of adverse effects, such as extrapyramidal symptoms, hyperprolactinemia, metabolic disturbances and sedation [4]. Nonadherence toward the medication is a common challenge [3]. A recent review reported that the most important reasons for prematurely stopping therapy included substance abuse (36.1%), a negative attitude toward medication (30.5%) and intolerable adverse effects (27.8%) [3].

Use of cannabis is an important risk factor for development of psychosis and accentuates the severity of psychotic symptoms [1, 5]. The risk of subsequent transition to schizophrenia is associated with the amount and frequency of cannabis used [1, 2]. A recent meta-analysis found that 34% of cannabis-induced psychotic conditions transition to schizophrenia [6]. This was higher than for hallucinogens (26%) and amphetamines (22%). Furthermore, it has been reported that between 19 and 57% of patients with first-episode psychosis use cannabis [2]. The co-existence of psychosis and substance use disorder is commonly referred to as dual diagnosis. In the context of this paper, dual diagnosis denotes a diagnosis of psychosis with comorbid cannabis use. These patients are more likely to be admitted to the hospital, to be hospitalized for longer time periods, to require compulsory admission, and to be prescribed several different antipsychotic medications suggesting an increased risk of treatment failure [7].

People with comorbid substance use disorder are usually excluded from clinical trials which has led to a scarcity of evidence regarding the efficacy of antipsychotics in patients with dual diagnosis. A meta-analysis combining results from trials investigating efficacy of antipsychotics in people with psychosis and substance use disorder found that clozapine, risperidone and olanzapine were slightly superior to other antipsychotics in terms of symptom reduction [8]. Regarding reduction of substance use and craving, clozapine and risperidone were superior to other antipsychotic drugs. The authors reported a similar pattern of adverse effects in this population compared to people without substance use [8].

When reviewing the efficacy of psychosocial treatment for people with severe mental illness and substance abuse, the evidence is sparse and the studies are of low quality [9]. A single study of patients with psychosis and a comorbid use of cannabis found significant effect of motivational interviewing on the amount of cannabis consumed after 3 and 6 months, but this effect was not sustained after 12 months [9].

In the light of the limited treatment data available, best practice today includes integrated psychosis and substance use treatment without advocating for specific treatment practices [10].

The potential therapeutic benefit of cannabidiol for treatment of dual diagnosis

The Cannabis sativa plant contains approximately 100 active compounds (phytocannabinoids). The two major active components are the psychoactive Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) [11].

The cannabinoid receptors (CB1 and CB2) are activated by THC and responsible for the psychotomimetic and addictive properties observed after smoking and ingestion of cannabis [12,13,14]. CBD does not bind to cerebral cannabis receptors and thus has a very different mechanism of action than THC. For the same reason, CBD does not possess euphoric or psychotogenic effects. The cannabinoid receptors are part of the endocannabinoid system, which is also comprised of endogenous cannabinoids and several enzymes which control synthesis and degradation of the endocannabinoids [11]. CBD indirectly affects the endocannabinoid system by impairing the degradation of anandamide (endogenous cannabinoid ligand), which modulates and stabilizes several neurotransmitter systems including the dopaminergic, glutamatergic and GABAergic system [15, 16]. Due to this globally stabilizing effect, CBD theoretically has the potential to reduce craving for cannabis. Likewise, CBD has documented antipsychotic and anxiolytic properties [11, 17, 18], and an anticipated sleep stabilizing effect [19], though the latter has not yet been investigated clinically. Since sleep disturbances play a dominant role regarding the risk of relapse versus remission of psychosis, knowledge about the effect of CBD on sleep disturbances and circadian rhythmicity is a central factor to explore when evaluating the clinical profile of CBD [20]. The pharmacological profile of CBD comprises additionally agonism of 5-HT1A receptors (as many antidepressants), inhibition of re-uptake of adenosine (which plays an important role in the regulation of sleep-wake) as well as antioxidative and anti-inflammatory effects [21].

Cognitive impairment is considered a core symptom of schizophrenia [22]. The potential effect of CBD on cognition has not yet been thoroughly studied. Meta-analyses and reviews have focused on the deleterious effects of THC on cognition, but it has been difficult to study the separate effects of CBD, because THC and CBD are often mixed in different ratios in available cannabis products [23, 24]. Data indicate that CBD counteracts the harmful effects of THC on cognition [23]. THC impairs cognitive functioning in general, but in particular verbal learning, memory and attention [23]. A recent trial investigating CBD as add-on to antipsychotic treatment in patients with schizophrenia found a non-significant increase in cognitive composite score and indication of improvement in motor speed and executive functioning [25].

Taken together, CBD has a multimodal mechanism of action making it potentially superior compared with traditional antipsychotic compounds whose antipsychotic effect is mainly mediated through dopamine D2 receptor blockade. The antipsychotic effect of CBD is thought to manifest via inhibition of the degradation of the endocannabinoid anandamide which subsequently antagonizes dopamine D2 hyperactivation [11] and thus represents a paradigmatic shift regarding treatment of psychosis.

Recent evidence

Two published pilot trials have examined the effect of CBD for psychosis. In one study, the effect of CBD was compared with amisulpride for treatment of patients with acute schizophrenia. The results showed that the antipsychotic effect of CBD and amisulpride was comparable, but CBD was associated with significantly fewer adverse effects, such as no increase in prolactin, no weight gain and no extrapyramidal side effects [17]. In another study, CBD was examined as add-on treatment to antipsychotic treatment in patients with schizophrenia, finding a significant reduction in psychotic symptoms together with a favourable side effect profile [25].

Two recent studies investigating the effect of CBD in patients with cannabis use disorder (and no psychotic disorder) found a significant decrease in the amount and frequency of cannabis use compared to placebo [26, 27].

No previous trials have examined the effect of CBD in psychotic patients with comorbid use of cannabis.

Research objectives and hypotheses

Patients with dual diagnosis can currently be offered few established treatment options. While the development of new antipsychotics in recent years has focused on established mechanisms of action, psychopharmacological alternatives introducing new mechanisms of action and delivering more efficient and better tolerable antipsychotics are urgently required. Based on the studies outlined above, we consider CBD with its putative mechanism of action as one of the most promising candidates to supplement current standards in the therapy of psychosis regarding both efficacy and safety. CBD has unique potential regarding dual diagnosis representing both a promising antipsychotic potential as well as a means to reduce the amount of cannabis use due to its cannabinoid substituting mode of action.

The aim of this study is to evaluate the efficacy of CBD versus a first-choice second-generation antipsychotic (risperidone) in terms of cessation of cannabis use and psychotic symptom reduction in patients with early-stage psychosis and comorbid cannabis use. We hypothesize that CBD will have superior efficacy compared with risperidone for both cessation of cannabis use and symptom reduction.


The study is a phase II randomized, double-blinded, parallel-group, active-comparator, clinical trial and planned in accordance with the latest version of The Helsinki declaration [28]. The study is approved by the Danish Ethical Committee of the Capital Region in Denmark (H-19010038), the Danish Data Protection Agency and the Danish Medicines Authority (EudraCT 2018–004893-84).

The trial is registered at (NCT04105231), and the conduct of the trial will be in accordance with the protocol. If any necessary modifications of the protocol are made during the trial period, they will be addressed in the publication of the trial results.


Patients will be recruited from psychiatric hospitals and outpatient clinics under The Mental Health Services in the Capital Region of Denmark, where doctors or nursing staff will inform relevant patients about the project and contact the study team if the patient accepts and might fulfil the eligibility criteria.

Information about the study medication and potential side effects are provided by a research physician or the principal investigator, who will also collect the written informed consent.

The study will be carried out at Mental Health Centre Glostrup that hosts Centre for Neuropsychiatric Schizophrenia Research. This research centre has extensive experience and knowledge in clinical research of psychosis and has an established efficient recruitment set-up.

To ensure steady recruitment to the trial, we will establish a network of committed clinicians from mental health care services across the capital region.

Participants will be compensated for their travel expenses to participate in the present trial. No other economic compensation for study participation will be offered.

When the participants are enrolled in the project, the treatment and monitoring will be carried out in collaboration with the psychiatric hospital or outpatient clinic taking care of the patient before and after participation in the trial. If the participant is not enrolled in an outpatient clinic by the time of inclusion, the project staff will refer the patient to an outpatient clinic upon completion of the trial.

All study participants are covered by the general insurance for patients treated in public hospitals and by the general right to receive compensation for injuries due to pharmaceutical drugs.

Inclusion criteria

ICD-10 diagnosis of schizophrenia (DF20.X), paranoid psychosis (DF22.X), acute/intermittent psychotic disorder (DF23.X), schizoaffective psychosis (DF25.X), other/not specified non-organic psychotic disorder (DF28/DF29), or cannabis induced psychotic disorder (DF12.5)

Within the first 5 years after first-episode psychosis

PANSS ≥60 and score of ≥4 on ≥2 PANSS-Positive subscale items: Delusions (P1), conceptual disorganization (P2), hallucinatory behaviour (P3), grandiosity (P5), suspiciousness (P6)

Regular use of cannabis at least on a weekly basis during the past 3 months

Female patients of childbearing potential need to utilize a proper method of contraception

Exclusion criteria

Treatment resistance as defined by treatment (ever) with clozapine

Dependence syndrome of alcohol or psychoactive substances (DF1X.2) other than cannabis (DF12.2)

Psychotic disorder induced by alcohol or psychoactive substances (DF1X.5) other than cannabis (DF12.5)

Treatment with a long-acting injectable antipsychotic within the past 3 months

Treatment with an oral antipsychotic within the past 7 days

Use of self-administered CBD products during the trial

Patients involuntarily admitted

Pregnancy or lactation

Severe physical illness that might influence the ability to comply with the protocol

Criteria for discontinuation

Relevant information about health status as judged by the investigator after the baseline visit may justify a subsequent exclusion from the study. Relevant information could be information concerning inclusion or exclusion criteria or information that implies an increased risk for the subject in case of participation in the trial.

Reasons for exclusion from the trial:

Unacceptable adverse effect(s)

Insufficient effect of treatment on psychotic symptoms with a need of switching to another antipsychotic compound

Intercurrent physical disease that interferes with the protocol

Subjects are free to discontinue their participation in the study at any time. Subjects who are not willing to continue the study will be asked about the reason(s) for their discontinuation and about the presence of any adverse events. Dropouts will be seen and assessed by an investigator and the full follow-up test battery will be performed if the participant agrees.

Experimental intervention and comparison

Participants will be randomly assigned in a 1:1 ratio to receive 600 mg of CBD or 4 mg of risperidone, administered in two divided doses morning and evening. Trial duration is seven weeks. After the baseline visit there will be a visit after week 1, 3, 5 and 7 as well as brief evaluations of symptom/disease severity by telephone interview in between, i.e. week 2, 4, and 6. In addition, there will be a safety follow-up visit two weeks after the end of study (week 9). Efficacy will be assessed at the end of the trial, i.e. after seven weeks (Fig. 1).

Schedule of enrolment, interventions, visits and assessments. Abbreviations: AE: Adverse event. PANSS: Positive and Negative Syndrome Scale (rating scale – symptom severity). CGI: Clinical Global Impression scale (rating scale – global illness severity), Severity (S) and Improvement (I) scores. PSP: Personal and Social Performance Scale (rating scale – level of psychosocial functioning). SWN: Subjective Well-being Scale under Neuroleptic treatment (rating scale – well-being). BACS: Brief Assessment of Cognition in Schizophrenia (neuropsychiatric test battery). UKU: Udvalget for Kliniske Undersøgelser (rating scale – antipsychotic side effects). PSQI: Pittsburgh Sleep Quality Index (rating scale – subjective sleep quality)

According to the literature there is no need to titrate the dose of CBD. For risperidone, dose will start at 2 mg and after four days be increased to 2 mg BID. In clinical practice, risperidone is usually titrated within 2–7 days to 4 mg which is a dose that most subjects can tolerate with few adverse effects. To make the groups comparable, the dose of CBD will start at 300 mg once daily and after four days be increased to 300 mg BID. Participants can ingest the total dose once daily if they so prefer. If participants experience intolerable side effects after increasing the dose to two times daily after the first four days, it will be possible to reduce the dose to once daily after discussion and agreement with the investigator.

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No other psychotropic medication can be added during the trial except benzodiazepines at a maximum dose equivalent to lorazepam 6 mg daily.

Cannabidiol is delivered as an oral solution with a CBD concentration of 100 mg/ml. Risperidone is administered as encapsulated tablets of 2 mg each. Thus, the CBD solution will be dosed as 3 ml in the morning and 3 ml in the evening, equivalent to CBD 300 mg BID. The risperidone capsules will be dosed as 2 mg in the morning and 2 mg in the evening. Participants are requested to ingest the study medication with a meal to increase the amount of CBD absorbed.

The trial has a double-dummy design, and each group of participants will ingest either CBD solution and risperidone placebo tablets, or risperidone tablets and CBD placebo solution. The CBD solution and the CBD placebo solution will be identical in colour, taste, smell and viscosity, and the same will be true for the encapsulated risperidone tablets and the risperidone placebo capsules.

To enhance adherence to the medication, participants will receive a phone call on day 4 to ensure that the dose is doubled. Adherence will be evaluated by documenting the amount of medication returned at the end of the study and by measuring plasma levels of CBD and risperidone.

Outcome measures and assessments

Primary outcome measures

Cannabis cessation is defined as no use during the past two weeks and is assessed by participant self-report. The self-reported data are the primary outcome, which is in accordance with findings from several studies showing high reliability of self-reported consumption, compared to biometric assessments [29, 30]. The primary outcome will be supported by a sensitivity analysis, considering the concentration of THC in plasma (present or absent) at the end of the study. The concentration of THC in plasma varies in relation to the pattern of cannabis use [29]. With intermittent use, plasma levels mostly decrease within 24 h, but is dependent on the potency of the cannabis used. People with a chronic use can have increased levels for a longer period, in rare cases up to one month [29, 30].

Psychotic symptoms are measured with the Positive and Negative Syndrome Scale (PANSS) [31], using the positive subscale score. PANSS is a rating scale measuring schizophrenia symptom severity based on a semi-structured interview pertaining to the patient’s symptoms during the past week. PANSS is clinician-rated and includes 30 items with a seven-point rating that represents increasing levels of psychopathology. The PANSS includes three subscales: The Positive Scale (7 items), the Negative Scale (7 items), and the General Psychopathology Scale (16 items). The PANSS total and subscale scores are calculated by summing the ratings of all items on the total scale and each subscale (range for total: 30–210, range for Positive and Negative Scales: 7–49, and range for General Psychopathology Scale: 16–112). For this outcome, we use the Positive Scale, and lowest possible score is 7. To avoid an underestimation of the effect, we will, according to Leucht et al. [32], subtract the 7 points from the baseline score when calculating the percentage reduction from baseline.

Secondary outcome measures

Cannabis use is assessed by self-reported days of cannabis use per week by use of the time-line follow-back method [33]. To assess the quantity, items from The PSYSCAN Cannabis Questionnaire are used. These items include pictures of different amounts of cannabis to allow for an estimation of the quantity [34].

Response is defined by PANSS total score 25 percentile changes. The results will be presented as 25% percentiles, with proportion of participants with 1–24% PANSS total reduction, 25–49%, 50–74% and 75–100%, as suggested by Leucht et al. [32].

Symptomatic remission is defined according to the Andreasen et al. remission criteria [35]. The criteria define symptomatic remission as a rating of no more than mild in four core positive and four core negative symptoms on the PANSS (P1: Delusions, P2: Conceptual disorganization, P3: Hallucinatory behaviour, N1: Blunted affect, N4: Passive/apathetic social withdrawal, N6: Lack of spontaneity and flow of conversation, G5: Mannerisms and posturing, G9: Unusual thought content) that is sustained for ≥6 months [35]. Because of the duration of this study, the requirement of 6 months duration will not be considered.

Global illness severity is assessed with the Clinical Global Impression Scale (CGI), which is a clinician rated scale that assesses illness severity [36]. The main item ‘severity of illness’ is measured on a 7-point Likert scale (from 1 ‘normal, not at all ill’ to 7 ‘among the most extremely ill patients’). We will use the severity (CGI-S) score at baseline and improvement (CGI-I) scores at the following visits. Response will be defined as much improved or better on the CGI-I.

Psychosocial functioning is assessed using the Personal and Social Performance Scale (PSP) [37]. The PSP is a 100 points single-item clinician-rated scale, divided into four domains: socially useful activities, personal and social relationships, self-care, and disturbing and aggressive behaviours. It has a maximum of 100 points, divided into 10 equal intervals (< 30 = intensive support or supervision needed, 31–70 = disabilities of various degrees, 71–90 = mild difficulties, 91–100 = more than adequate functioning).

Neurocognitive functioning is assessed with the Brief Assessment of Cognition in Schizophrenia (BACS), which is specifically designed to measure treatment-related improvements in patients with schizophrenia [38]. The BACS includes assessments of the following domains: verbal memory, working memory, motor speed, verbal fluency, attention and processing speed and executive function.

Well-being is assessed with the Subjective Well-Being under Neuroleptics Scale, short version (SWN-S) [39]. It is a self-rated 20-item scale consisting of 10 positive and 10 negative items and is rated for the last 7 days. The total score ranges from a minimum of 20 (poor) to a maximum of 120 (excellent).

Circadian sleep-wake cycle is assessed using actigraphy, a wrist-watch-like device, which the participants will wear for the whole study duration. The actigraph measures movement and patterns of movement which are used to estimate circadian rest-activity rhythmicity [40].

Subjective sleep quality is assessed using the Pittsburgh Sleep Quality Index (PSQI) [41]. PSQI is a self-administered rating scale assessing sleep quality and severity of sleep disturbances, rated for the last month at baseline and since last visit subsequently. PSQI consists of 19 items and measures seven components of sleep: sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medications, and daytime dysfunction. The component scores each has a range of 0–3 points and they are added to yield one global PSQI score (range of 0–21 points) which distinguishes good sleep (PSQI total score ≤ 5) from poor sleep (PSQI total score > 5).

Objective sleep evaluation is assessed using polysomnography (PSG). PSG is the gold standard for assessing sleep disorders, sleep architecture, and measures of sleep continuity.


Blood samples are taken at baseline and at each visit to measure plasma levels of cannabinoids (CBD, THC and metabolites), risperidone and metabolomics.

Routine safety measures:

HDL, prolactin and liver function tests are measured at baseline and at 7 weeks follow-up.

ECG are taken at baseline, after 3 weeks and at 7 weeks follow-up.

Data on adverse events are collected at every visit, and by telephone in the weeks between. Patients can reach the researchers at any time in case of spontaneously occurring adverse events.

Pregnancy urine test at baseline.

All ratings will be performed by trained clinicians and research nurses.


Central randomization is performed by The Capital Region Pharmacy with computer generated, permuted randomization allocation sequence with block size unknown to the investigator. The Capital Region Pharmacy delivers consecutively numbered and labelled medication packages. When a subject is included, he/she is given the next consecutive corresponding medication package number. The Capital Region Pharmacy delivers sealed envelopes for each randomization number with information of randomization group.


Trial participants as well as trial staff are blinded to the allocated treatment. The blinding will be maintained by using similarly bottled CBD/placebo and similar capsules of risperidone/placebo. The Capital Region Pharmacy will perform the randomization and do the packaging and labelling of trial medication. The Capital Region Pharmacy holds the randomization code which will not be broken until all data are registered, primary analyses finished, and conclusions drawn. The randomization code will only be broken during the trial period in case of emergency if the investigator decides that knowledge about the trial medication will affect the treatment of a serious adverse event (SAE) or in case of a suspected unexpected serious adverse reaction (SUSAR).

Data collection and managing

Data will be entered in an electronic Case Report Form (eCRF) using the software RedCap which is hosted by the Capital Region and approved as research database by the Danish Data Protection Agency. The trial complies with Danish law on data confidentiality. Data storing and handling is reported to the Danish Data Agency.

RedCap is a web-based and secure database, with real-time entry validation and audit trails. Some clinical data will be entered directly into the eCRF in a RedCap database designed specifically for this study. Other clinical data will initially be registered on paper and then entered manually into the RedCap database. The entered data will be checked by a second person to avoid errors. Study medication will be logged and documented.

Only the investigators will have access to the final dataset. Access to the protocol, data and statistical code can be shared upon request.

Results of this trial, both positive, negative and inconclusive findings, will be published by the investigators in international journals and presented at national and international meetings and conferences.


The trial will be monitored by the Good clinical Practice (GCP) unit at Copenhagen University Hospital. Trial-related monitoring according to ICH-CGP (International Conference on Harmonisation-Good Clinical Practice) guidelines will be permitted including direct access to the eCRF/source data by the GCP unit. Study monitors from the GCP unit will check that the study procedures are followed correctly and are in accordance with the study protocol.

Due to the short duration of the trial and the minimal risk associated with the intervention, we will not establish a data monitoring committee.

Statistical analysis

The efficacy of the intervention with respect to the PANSS positive subscale at seven weeks follow-up is analysed using the univariate general linear model with the seven weeks value as the dependent variable (using the last observation carried forward) and the indicator of intervention, age and the baseline value as the independent variables. If the assumptions of the model cannot be fulfilled either directly or after transformation a non-parametric method will be used.

The efficacy of the intervention with respect to the proportion of participants who cease use of cannabis is analysed using a logistic regression model where logit(p) is the dependent variable, p is the probability of cannabis cessation (using the last observation carried forward), and a binary intervention indicator and age are the independent variables.

All analyses will be carried out with the intention-to-treat sample. As secondary analyses the per-protocol sample will be evaluated.

The secondary endpoints will be analysed along the same lines as for the primary efficacy variables.

Subgroup analyses will be performed according to gender.

A sensitivity analysis of the participants with negative plasma-THC at the end of treatment will be carried out.

Sample size estimation

We consider a relative difference between cannabis cessation proportion in the two intervention groups of 0,50 (i.e. risk ratio for cannabis cessation at follow-up in risperidone group vs. CBD group = 0,5) as a relevant clinical difference. This yields a sample size of 50 patients in each group with a two-tailed 5% significance level and 80% power. Subjects will be randomized in a 1:1 ratio to each intervention group.

We consider that an improvement of 6 points (delta) in the PANSS positive subscale is of minimum clinical relevance (MIREDIF). Leucht et al. defined a clinically meaningful change on the PANSS total scale to be 15 points [42]. Extrapolating this to the positive subscale yields an improvement of 6 points (delta) on the PANSS positive subscale as the MIREDIF. We assume that the PANSS positive score is approximately normally distributed in both treatment groups with a standard deviation of 5 points (sigma) [17]. Thus, with a sample size of 50 subjects, we will be able to detect a difference between groups of 4 points on the PANSS positive subscale, with alfa = 0.05 and a power of 80%.

We expect a drop-out rate between 20 and 30% [43] and thus we reckon that N = 130 must be included in the study.


This is the first study to investigate a potential new paradigm in the treatment of patients with psychosis and comorbid cannabis use. Patients with dual diagnosis are particularly difficult to treat and are generally afflicted by worse outcomes than patients with psychosis alone. The increasing potency of available cannabis is of global concern [44, 45], and the results of this trial will become increasingly important.

There is a lack of knowledge on the treatment of patients with dual diagnosis since research so far has focused on patients with psychosis without comorbid substance use disorder.

CBD has been used in trials of animals and humans in up to eight weeks in a dose of 1500 mg/day without complications, toxic effects or major adverse effects, furthermore no physical or psychological dependence was observed [16]. Two published trials have evaluated CBD for treatment of psychosis. In one study, CBD was given in a dose of 800 mg divided in 4 daily doses and was well-tolerated [17]. In another study, a CBD dose of 1000 mg divided in two daily doses was augmented to an existing antipsychotic treatment showing good tolerability [25]. A study investigating the most effective dose of CBD in the treatment of cannabis use disorder found insufficient effect of 200 mg, but significant effect of 400 mg and 800 mg compared to placebo [26]. Thus, we expect a total dose of 600 mg to be sufficient to obtain both acceptable efficacy and tolerability.

The duration of this trial is set to seven weeks. Earlier studies of the efficacy of CBD on psychosis have lasted four to six weeks [17, 25]. Using this duration, it has been possible to show an effect of CBD which was steadily increasing during the entire treatment period but did not find a plateau [17, 25].

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The profile of CBD allows for a new and revolutionary paradigm for treating dual diagnosis patients with a potentially substantial impact on the course of illness and the level of functioning. Consequently, CBD has the potential to counteract the transition of acute psychosis to more chronic conditions. The results may have a possible major advantage for current and future patients.

Trial status

The inclusion begins in May 2021.

Protocol version 4.0 04-12-2020.

Availability of data and materials

This manuscript does not contain any data. After study completion and after publication of planned primary and secondary analyses the analysed dataset will be available from the corresponding author upon reasonable request.


Brief Assessment of Cognition in Schizophrenia (neuropsychiatric test battery)

Bis in die, twice a day

Cannabinoid receptor 1

Cannabinoid receptor 2

Clinical Global Impression scale (rating scale – global illness severity), Severity (S) and Improvement (I) scores

electronic Case Report Form

Good Clinical Practice

International Conference on Harmonisation-Good Clinical Practice

Minimal relevant difference

Positive and Negative Syndrome Scale (rating scale – symptom severity)

Personal and Social Performance Scale (rating scale – level of psychosocial functioning)

Pittsburgh Sleep Quality Index (rating scale – subjective sleep quality)

Serious Adverse Event

Suspected Unexpected Serious Adverse Reaction (SUSAR)

Subjective Well-being Scale under Neuroleptic treatment (rating scale – well-being)

Udvalget for Kliniske Undersøgelser (rating scale – antipsychotic side effects)


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Chemerinski E, Ho BC, Flaum M, Arndt S, Fleming F, Andreasen NC. Insomnia as a predictor for symptom worsening following antipsychotic withdrawal in schizophrenia. Compr Psychiatry. 2002;43(5):393–6.

Hahn B. The potential of Cannabidiol treatment for Cannabis users with recent-onset psychosis. Schizophr Bull. 2018;44(1):46–53.

Miyamoto S, Fredrik Jarskog L, Wolfgang Fleischhacker W. New therapeutic approaches for treatment-resistant schizophrenia: a look to the future. J Psychiatr Res. 2014;58:1–6.

Broyd SJ, Van Hell HH, Beale C, Yücel M, Solowij N. Acute and chronic effects of cannabinoids on human cognition – a systematic review. Biol Psychiatry. 2016;79(7):557–67.

Colizzi M, Bhattacharyya S. Does Cannabis composition matter? Differential effects of Delta-9-tetrahydrocannabinol and Cannabidiol on human cognition. Curr Addict Rep. 2017;4(2):62–74.

McGuire P, Robson P, Cubala WJ, Vasile D, Morrison PD, Barron R, et al. Cannabidiol (CBD) as an adjunctive therapy in schizophrenia: a multicenter randomized controlled trial. Am J Psychiatr. 2018;175(3):225–31.

Freeman TP, Hindocha C, Baio G, Shaban NDC, Thomas EM, Astbury D, et al. Cannabidiol for the treatment of cannabis use disorder: a phase 2a, double-blind, placebo-controlled, randomised, adaptive Bayesian trial. Lancet Psychiatry. 2020;7(10):865–74.

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CBD for Schizophrenia: Can Hemp Oil Help with Schizoaffective Disorder?

Although cannabis has got a bad rap when it comes to psychotic disorders such as schizophrenia, the latest research findings indicate that the plant has been largely misunderstood. Studies suggest CBD may actually offset the development of schizophrenia and curb the episodes of psychosis. Better yet, it appears that the other major cannabinoid, THC, may not necessarily trigger the condition — at least not as a direct cause.

Today we’ll focus on the potential CBD treatment for schizophrenia. We’ll cover the recent studies on this subject, explain the mechanism of action, and debunk a few myths about cannabis and mental health.

Using CBD for Schizophrenia: Does It Make Sense?

Cannabis is a complex plant with 115 identified cannabinoids. Depending on the chemotype, cannabis strains may be THC-dominant and CBD-dominant.

Marijuana is known for significant amounts of THC, while hemp boasts higher concentrations of CBD and only traces of the intoxicating cannabinoid.

There are also terpenes, which influence the effect profile of each strain.

The majority of CBD oils available for sale are made from hemp, so their effects revolve around the benefits of CBD supported by other compounds in the plan. A growing body of scientific evidence suggests CBD may relieve anxiety, inflammation and pain, sleep disturbances, and balance mood.

The FDA has recently approved the first cannabis plant-derived medication, Epidiolex. It contains pure CBD and is recommended for treatment-resistant seizures. However, doctors may prescribe Epidiolex off-label for other conditions, such as schizophrenia.

What to Know About CBD and Schizophrenia?

There is a clear link between cannabis use and psychosis, as noted by epidemiological studies. However, a higher risk of schizophrenia has been associated with strains that have high THC content, and studies have notoriously mentioned a dose-response relationship for the risk of schizophrenia in cannabis users. This isn’t the case for high-CBD strains.

THC produces acute psychotic-like symptoms in healthy individuals after a certain dosage threshold is breached — but CBD decreases the THC-induced psychosis and cognitive impairment.

Patients with schizophrenia suffer from cognitive deficits — they affect up to 85% of the sufferers, so the potential positive effects of CBD on cognition have critical importance.

Below we shed more light on how CBD may help with schizophrenia.

Antipsychotic Properties of CBD

A case study published by Zuardi and colleagues found that CBD may successfully treat schizophrenia. The authors tested a dose of CBD up to 1500 mg daily for 4 weeks, which improved the acute psychotic symptoms (1).

Findings from a 2006 study that analyzed the efficacy of CBD as monotherapy for treatment-resistant schizophrenia in three individuals show that only one patient responded positively to the treatment, but the dosage might’ve been inadequate (2). A later study on the benefits of CBD for schizophrenia tested flexible doses up to 400 mg daily on 6 patients with Parkinson’s disease, finding improvement of psychotic symptoms in all participants over the course of 4 weeks.

Since then, CBD has been investigated for its antipsychotic properties in three clinical studies with contradictory results.

For example, a 2012 double-blind randomized controlled trial on the therapeutic effects of CBD showed that the cannabinoid was as effective as amisulpride, a common antipsychotic drug, in treating the symptoms of schizophrenia. On top of that, CBD had fewer side effects; it caused no weight gain and resulted in less extrapyramidal symptoms (4).

CBD was also tested as an adjunctive medication in the treatment of acute psychosis in people with schizophrenia and non-affective psychotic disorders. After 6 weeks of taking 1000 mg of CBD daily, the CBD group showed greater improvement of positive psychotic symptoms compared to the placebo group. At the end of their therapy, more patients in the CBD group were evaluated as “improved” on the CGI-I scale compared with the controls. Patients who took CBD also showed trend-level improvements in their cognitive performance and motor speed (5).

A similar 2018 study investigated the therapeutic effects of 600 mg CBD daily — divided into two doses — in comparison with placebo in a 6-week double-blind placebo-controlled randomized clinical trial. However, the lower dose didn’t have a significant impact on the psychotic symptoms and cognitive performance of the participants compared to the placebo group (6).

How Does CBD Work for Schizophrenia?

Despite being supported by several epidemiological and clinical studies, the mechanism of action behind the antipsychotic properties of CBD remains unknown. Unlike other antipsychotics, CBD doesn’t directly affect dopaminergic neurons. It also doesn’t bind to cannabinoid receptors like THC.

However, CBD does indirectly increase the CSF levels of anandamide, one of the main endocannabinoids, by blocking its metabolizing enzyme, fatty acid amine hydrolase (FAAH). Interestingly, anandamide levels show a negative correlation with the severity of psychotic symptoms, whereas increased levels of anandamide have been found to improve them clinically after a CBD treatment.

This may hint to CBD as the potential mediator in the management of psychosis through the aforementioned boost of the endogenous levels of anandamide. However, further research is needed to confirm this theory.

Over the past few decades, medical researchers have been exploring the endocannabinoid system as the potential therapeutic target for mental disorders (7). The current pharmacological treatment for schizophrenia is only partially effective and doesn’t tackle the negative symptoms. This has led scientists to search for new pharmacological targets — and the findings from the ECS studies are very promising.

However, there’s a discrepancy in clinical results regarding CBD’s efficacy in treating schizophrenia and psychotic episodes. They could stem from different doses of CBD, stages of psychosis, and heterogeneity of the condition.

Risk and Side Effects: Can CBD Cause Psychosis?

There’s currently no evidence that CBD can cause psychosis. In order to do that, the cannabinoid would have to induce intoxication, elevating anxiety, and paranoia in the dose-response pattern. CBD has been repeatedly shown to reduce anxiety, help with the symptoms of PTSD, addiction, and improve people’s response to stress. CBD has a balancing effect on the nervous system, reducing the hyperactivity and increasing the hypoactivity of neurotransmitters when needed.

CBD is a safe substance. Studies have tested doses as high as 1,500 mg daily without dangerous side effects. That being said, there are a few mild reactions you may experience when you take too much CBD at a time:

  • Dizziness
  • Changes in appetite
  • Dry mouth
  • Diarrhea
  • Fatigue

There’s also a risk of CBD-drug interactions, so make sure to consult your doctor prior to buying CBD oil if you want to avoid them.

The relationship between cannabis use and schizophrenia refers to how THC affects the brain.

But are you sure you have been taught the truth? Let’s take a brief look at the effects of THC on people predisposed to schizophrenia.

Does THC Cause Schizophrenia?

THC is an anti-inflammatory compound with antidepressant-like properties. In low and moderate doses, it also has a relaxing effect on top of inducing an altered state of mind, such as euphoric mood, giggles, and tranquility. However, doses of THC that score higher than your tolerance may aggravate anxiety and trigger bouts of paranoia, especially in those who are sensitive.

Studies conducted in the past have shown a correlation between cannabis use and a faster onset of schizophrenia in people with a family history of the condition. However, the conclusion might have been too hasty, as the latest research shows.

A study performed by Harvard University has analyzed all contributing factors besides cannabis use, pointing to the hereditary burden as the main trigger of schizophrenia in cannabis users. According to the research team, cannabis can only spur the onset of schizophrenia, but it’s not a trigger per se.

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In other words, if a person is predestined to have schizophrenia, they will develop it sooner or later.

According to Dr. Musa Sami, a researcher and psychiatrist from King’s College in London increased cannabis use would need to positively correlate with the severity of psychosis, which hasn’t been proven by any study to this day.

Finally, Italian scientists from the University of Calgary have recently tested whether cannabis use will further harm the brain structure of rats that were prenatally exposed to an inflammatory agent that disrupts dopamine signaling and causes behavioral symptoms of schizophrenia. To their surprise, exposure to THC during adolescence seemed to protect the rats’ brains. The authors of the study hypothesized that THC’s anti-inflammatory effects were responsible for offsetting schizophrenia (8).

How Much CBD to Take for Schizophrenia?

The studies we’ve covered above have tested how pure CBD affects the mental health of the participants. However, most people use full-spectrum CBD products, where CBD is only one of over 400 compounds. These compounds influence the way CBD affects the body and brain, so doses may vary between people. Whole-plant extracts require a lower dose than CBD isolates, for which most studies have used a daily dose of 600 to 1,000 milligrams.

If you’re using a full-spectrum or broad-spectrum CBD oil, it’s best to start with a low dose, say, 15 mg once or twice a day with food. If you don’t feel a difference in your symptoms after one week, increase by 10–15 mg and reassess the effects. Once you’ve found your optimal dosage, you can stick to it — there’s no risk of increasing your tolerance to CBD over time.

Do Your Research Before Buying CBD for Schizophrenia

The CBD market is regulated due to the current classification of hemp-derived products. As health supplements, CBD extracts aren’t subject to any standardization when it comes to quality and labeling. Although the market has positively evolved over the years, there are still many fly-by-night vendors churning out poor quality products with less CBD than advertised. Some of them may contain more than 0.3% THC; others may be contaminated with pesticides, solvent residue, and other impurities.

For this reason, you should always check how the company grows, tests, and processes its CBD products.

The best source of CBD is organically grown hemp. Hemp plants are dynamic bio accumulators, so they easily absorb everything from the environment they grow in. Organic farming ensures that you only get the good substances in the source material.

Another important factor on your checklist should be the extraction method. Premium-quality CBD oils are extracted using pressurized CO2; this method produces pure extracts with consistent potency throughout the batches. It doesn’t use additional heat or solvents, so you’re getting a product with a complete cannabinoid profile.

Last but not least, look for certificates of analysis or COA. This shows that each batch is tested by a third-party laboratory. Independent laboratories analyze the potency of the product and look for common contaminants, such as heavy metals, pesticides, or solvent residue.

Summarizing the use of CBD for Schizophrenia

CBD can be used to manage schizophrenia thanks to its therapeutic effects on psychotic symptoms. It may also have a role in preventing or treating cannabis-induced psychosis in vulnerable individuals who consume high-THC strains.

High CBD content may positively affect our mental health — not only by curbing psychosis but also by reducing anxiety and improving the body’s response to stress. Studies investigating the efficacy of CBD in mental disorders have found that the cannabinoid has a calming effect on the nervous system but without the dangerous side effects of commonly prescribed antipsychotic medications.

Clinical trials on CBD and schizophrenia have brought mixed results, most likely due to the discrepancy in dosages. If you’re considering taking CBD oil to improve the symptoms of your condition, make sure to consult a holistic psychiatrist who will have a good understanding of CBD and cannabis in general. Doing so will help you determine the effective dosage and avoid negative CBD-drug interactions.


  1. Zuardi, A W et al. “Antipsychotic effect of cannabidiol.” The Journal of clinical psychiatry vol. 56,10 (1995): 485-6.
  2. Zuardi, Antonio Waldo et al. “Cannabidiol monotherapy for treatment-resistant schizophrenia.” Journal of psychopharmacology (Oxford, England) vol. 20,5 (2006): 683-6. doi:10.1177/0269881106060967
  3. Zuardi, Antonio Waldo et al. Op. Cit.
  4. Leweke, F M et al. “Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia.” Translational psychiatry vol. 2,3 e94. 20 Mar. 2012, doi:10.1038/tp.2012.15
  5. McGuire, Philip et al. “Cannabidiol (CBD) as an Adjunctive Therapy in Schizophrenia: A Multicenter Randomized Controlled Trial.” The American journal of psychiatry vol. 175,3 (2018): 225-231. doi:10.1176/appi.ajp.2017.17030325
  6. Boggs, Douglas L et al. “The effects of cannabidiol (CBD) on cognition and symptoms in outpatients with chronic schizophrenia a randomized placebo-controlled trial.” Psychopharmacology vol. 235,7 (2018): 1923-1932. doi:10.1007/s00213-018-4885-9
  7. Leweke, F Markus et al. “Role of the Endocannabinoid System in the Pathophysiology of Schizophrenia: Implications for Pharmacological Intervention.” CNS drugs vol. 32,7 (2018): 605-619. doi:10.1007/s40263-018-0539-z
  8. Lecca, Salvatore et al. “Δ9-Tetrahydrocannabinol During Adolescence Attenuates Disruption of Dopamine Function Induced in Rats by Maternal Immune Activation.” Frontiers in behavioral neuroscience vol. 13 202. 6 Sep. 2019, doi:10.3389/fnbeh.2019.00202
Livvy Ashton

Livvy is a registered nurse (RN) and board-certified nurse midwife (CNM) in the state of New Jersey. After giving birth to her newborn daughter, Livvy stepped down from her full-time position at the Children’s Hospital of New Jersey. This gave her the opportunity to spend more time writing articles on all topics related to pregnancy and prenatal care.

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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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