Methods for optimizing the treatment of psychiatric disorders with cannabidiol and pharmaceutical compositions comprising cannabidiol

Abstract

Methods for optimizing the treatment of psychiatric disorders with cannabidiol and pharmaceutical compositions comprising cannabidiol are described.

Description

[Technical field]

[0001] The present invention relates to in vitro methods for optimizing the treatment of psychiatric disorders with cannabidiol, and pharmaceutical compositions comprising cannabidiol. [Background technology]

[0002] Mental disorders affect a large proportion of the world's population. One example of a mental disorder is schizophrenia. Approximately 1% of people worldwide suffer from schizophrenia. Due to the various forms of manifestation, the diagnosis of schizophrenia is not easy and the diagnostic criteria have been repeatedly revised. This results in differences in prevalence and incidence in the literature. Affected individuals suffer from positive and negative symptoms, including delusions, hallucinations, emotional and speech disorders, illogical thinking, belief in psychic powers, apathy, emotional blunting, speech deficits, lack of motivation, poor physical hygiene, and anhedonia. Compared to healthy individuals, positive symptoms are characterized by increased behavioral patterns and negative symptoms are characterized by decreased behavioral patterns. The severity of symptoms can be measured, for example, using the Positive and Negative Symptoms Scale (PANSS).

[0003] Moreover, schizophrenia is a disorder with complex nature. It involves several neurotransmitters, including dopamine, glutamate, serotonin, and endocannabinoids. None of the approved antipsychotic drugs can alleviate all symptoms. Therefore, there is still a need for improved pharmacological treatment and reduced side effects. Summary of the Invention [Problem to be solved by the invention]

[0004] Surprisingly, it has been found that a specific range of cannabidiol concentrations in the blood of a patient improves symptoms in patients suffering from psychiatric disorders. Furthermore, it has been found that certain preparations of CBD are particularly useful in treating subjects. [Means for solving the problem]

[0005] The present invention therefore relates to an in vitro method for determining the effectiveness of treatment of a subject with a psychiatric disorder by administration of cannabidiol, comprising determining in vitro the level of cannabidiol in a sample from said subject with said psychiatric disorder, wherein said treatment is deemed effective if the level of cannabidiol is at least about 25 μg / l.

[0006] Cannabidiol levels can be at least about 30 μg / l, at least about 35 μg / l, at least about 40 μg / l, at least about 50 μg / l, at least about 60 μg / l, at least about 70 μg / l, at least about 75 μg / l, at least about 80 μg / l, at least about 85 μg / l, or at least about 90 μg / l.

[0007] Cannabidiol levels should normally not exceed 1000 μg / l.

[0008] Cannabidiol levels can be up to 1000 μg / l, 900 μg / l, 800 μg / l, 700 μg / l, 600 μg / l, 500 μg / l, or 400 μg / l.

[0009] Cannabidiol levels can be determined about 3 to 5 weeks or about 4 weeks after the start of treatment, where the cannabidiol level can range from about 20 μg / l to about 400 μg / l, about 25 μg / l to about 360 μg / l, about 30 μg / l to about 200 μg / l, about 60 μg / l to about 120 μg / l, about 70 μg / l to about 110 μg / l, about 80 μg / l to about 100 μg / l, about 85 μg / l to about 95 μg / l, or about 90 μg / l.

[0010] Cannabidiol levels can be determined about 1 to less than 3 weeks or about 2 weeks after the start of treatment, in which case the cannabidiol level can range from about 20 μg / l to about 60 μg / l, about 25 μg / l to about 55 μg / l, about 30 μg / l to about 50 μg / l, about 35 μg / l to about 50 μg / l, or about 45 μg / l.

[0011] The methods may be useful for optimizing and / or monitoring the effectiveness of such treatments.

[0012] The psychiatric disorder can be a psychotic disorder.

[0013] The psychotic disorder may be selected from the group consisting of schizophrenia, delusional disorder, or schizoaffective disorder, preferably schizophrenia.

[0014] Cannabidiol levels can be determined by liquid chromatography coupled with tandem mass spectrometry.

[0015] The levels can be determined every 12-48 hours, or can be determined about every 24 hours.

[0016] The levels can first be determined at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 days after the start of treatment with cannabidiol.

[0017] Cannabidiol may be administered to a subject at a dose of 5 mg to 1200 mg per day, 6 mg to 1200 mg per day, 7 mg to 1200 mg per day, or the cannabidiol is administered to a subject at a dose of 8 to 12 mg per kg of body weight per day.

[0018] If the determined level of cannabidiol is below the range set forth in claim 1, the dose of cannabidiol administered within a given period of time may be increased.

[0019] If the determined level of cannabidiol exceeds the range set forth in claim 1, the dose of cannabidiol administered within a given period of time may be reduced.

[0020] The dose of cannabidiol to be administered should be administered intravenously, orally, sublingually, nasally, rectally, topically or by inhalation, or the dose of cannabidiol to be administered should be administered as a capsule.

[0021] The present invention also relates to a pharmaceutical composition comprising at least 99% cannabidiol, without any added excipients, and having a particle size of less than 0.8 mm. The cannabidiol may be of plant origin or synthetic.

[0022] A capsule can contain the pharmaceutical composition.

[0023] The pharmaceutical composition or the capsule can be used for the treatment of psychiatric disorders, preferably schizophrenia. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] Cannabidiol (CBD) is a highly lipophilic cannabinoid derived from the cannabis plant Cannabis sativa. The well-known compound Δ 9 In comparison with -THC, it is non-psychotropic. The CBD used in the practice of the present invention can be plant-derived, i.e. extracted from a plant source, or synthetic CBD, i.e. chemically synthesized.

[0025] In the context of the present invention, CBD is preferentially chemically synthesized.

[0026] The present invention relates to an in vitro method for determining the efficacy of treatment of a subject with a psychiatric disorder by administration of cannabidiol, comprising determining in vitro the level of cannabidiol in a sample from said subject with said psychiatric disorder, said treatment being deemed effective if the level of cannabidiol is at least about 25 μg / l, this range may be defined as a target range.

[0027] The sample may be a blood sample of the subject.

[0028] Cannabidiol levels (target) can be at least about 35 μg / l, at least about 30 μg / l, at least about 35 μg / l, at least about 40 μg / l, at least about 50 μg / l, at least about 60 μg / l, at least about 70 μg / l, at least about 75 μg / l, at least about 80 μg / l, at least about 85 μg / l, or at least about 90 μg / l.

[0029] Cannabidiol levels should normally not exceed 1000 μg / l.

[0030] Cannabidiol levels can be up to 1000 μg / l, 900 μg / l, 800 μg / l, 700 μg / l, 600 μg / l, 500 μg / l, or 400 μg / l.

[0031] Cannabidiol levels can be determined about 3-5 weeks or about 4 weeks after the start of treatment, in which case the cannabidiol level can range from about 30 μg / l to about 360 μg / l, about 35 μg / l to about 200 μg / l, about 60 μg / l to about 120 μg / l, about 70 μg / l to about 110 μg / l, about 80 μg / l to about 100 μg / l, about 85 μg / l to about 95 μg / l, or about 90 μg / l.

[0032] Cannabidiol levels can be determined about 1 to less than 3 weeks or about 2 weeks after the start of treatment, in which case the cannabidiol level can range from about 20 μg / l to about 60 μg / l, about 25 μg / l to about 55 μg / l, about 30 μg / l to about 50 μg / l, about 35 μg / l to about 50 μg / l, or about 45 μg / l.

[0033] The methods may be useful for optimizing and / or monitoring the effectiveness of such treatments.

[0034] The psychiatric disorder can be a psychotic disorder.

[0035] The psychotic disorder may be selected from the group consisting of schizophrenia, delusional disorder, or schizoaffective disorder.

[0036] The method may preferably be used on a sample obtained from a subject suffering from schizophrenia.

[0037] The level of cannabidiol can be determined by gas chromatography combined with tandem mass spectrometry. However, any other method suitable for determining the level of cannabidiol in a subject's sample can also be used.

[0038] Samples can be obtained once after administration of CBD, or at defined, e.g. regular, intervals during treatment.

[0039] For example, the levels can be determined about every 12 to 48 hours, or can be determined about every 24 hours.

[0040] The levels may be first assessed at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 days after the initiation of cannabidiol treatment. Preferably, the levels are first assessed between 7 and 14 days, more preferably about 7 or about 14 days, after the initiation of cannabidiol treatment.

[0041] The treatment may include administering to the subject a dose of 5 mg to 1200 mg per day. For example, the dose may be 5 mg, 6 mg, 7 mg, 8 mg, 10 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900, 1000, 1100 mg, or 1200 mg per day, or any range of doses defined by the aforementioned doses. Preferably, the dose may be 600 to 1000 mg per day, for example, 800 mg to 1000 mg per day.

[0042] Alternatively or additionally, cannabidiol may be administered to the subject at a dose of 8 to 12 mg / kg body weight per day, for example 8, 9, 10, 11, or 12 mg / kg body weight per day.

[0043] The administration period can be at least 4 to 8 weeks, preferably at least 6 weeks.

[0044] CBD can be administered in any suitable pharmaceutical dosage form, for example, as a tablet, capsule, gel, injection, or combination thereof. Preferably, CBD can be administered as a capsule.

[0045] A pharmaceutical dosage form may contain about 5 to about 300 mg, 100 to about 300 mg, about 150 to about 250 mg, about 175 mg to about 225 mg, or about 200 mg of CBD. Several dosage forms may be combined to provide the required daily dose. For example, a pharmaceutical dosage form, such as a capsule, containing a predetermined amount of CBD, such as 200 mg, less than a predetermined total daily dose, such as 1000 mg, may be administered multiple times a day, preferably at equally spaced time intervals, for example 5 times a day.

[0046] If the determined level of cannabidiol is determined to be below the target range, the dose of cannabidiol administered within a given period of time can be increased. For example, the daily dose can be increased by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%, or between 10 and 100%.

[0047] The dose of cannabidiol to be administered within a given time period can be decreased if the determined level of cannabidiol is above the target range. For example, the daily dose can be decreased by at least 1%, 2%, 3%, 5%, 10%, 20%, 30%, 40%, or 50%, or between 1 and 50%.

[0048] The increase or decrease of the dose or daily dose can depend on the size of each dosage form.Dosage form is the smallest pharmaceutical unit administered to a subject, such as capsule, tablet, etc.For example, if 1000mg / day is administered in 5 dosage forms of 200mg per dose, the decrease or increase of one dose can be 200mg, thus 20%.Therefore, the increase or decrease depends on the dosage form used.

[0049] The dose of cannabidiol to be administered should be administered intravenously, orally, sublingually, nasally, rectally, topically, or by inhalation, preferably orally. In particular, the dose of cannabidiol to be administered is preferably administered as a capsule.

[0050] The present invention also relates to pharmaceutical compositions that are particularly useful for carrying out the above methods.

[0051] Thus, the present invention also relates to a pharmaceutical composition comprising cannabidiol without any added excipients and having a particle size of less than 0.8 mm. The composition may comprise at least about 99%, about 99% to about 99.9%, about 99.3% to 99.8% CBD. The cannabidiol may be synthetic or plant-derived cannabidiol.

[0052] By no excipients are added, it is meant that no excipients, such as, for example, lipids (eg, triglycerides) or any form or liquid, are added to and therefore not included in the composition.

[0053] In a preferred embodiment, a capsule can contain the pharmaceutical composition. The capsule is particularly a capsule that prevents the migration of liquid or lipids into the compartment formed by the capsule. A preferred material for the capsule is hydroxypropylmethylcellulose. The capsule can usually consist of two capsule pieces.

[0054] The pharmaceutical composition or said capsules can be used for the treatment of mental disorders as mentioned above, preferably schizophrenia.

[0055] The pharmaceutical compositions may be administered according to the dosing regimen described above 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times per day.

[0056] 1. A method for producing a pharmaceutical composition, comprising: a. Providing synthetic CBD; b. transferring the synthetic CBD to a first capsule piece of a two-piece capsule; and c. contacting the first piece of the capsule with the second piece of the capsule to provide an intact two-piece capsule.

[0057] Preferably, the transferring is accomplished with a powder pipette. Preferably, the CBD is sieved after step a. and before step b. Preferably, the sieve used for sieving has a pore size of 0.8 mm, 0.7 mm, 0.5 mm or less. Thus, the sieved CBD may have a particle size of less than 0.8 mm, less than 0.7 mm, less than 0.5 mm, or less.

[0058] Working Example Example 1: Manufacturing of CBD capsules Synthetic CBD was produced by THC Pharm GmbH (The Health Concept, Frankfurt am Main, Germany).

[0059] The purity of the obtained CBD was determined to be at least 99% (99.35%).

[0060] It was found that synthetic CBD was produced in the form of flakes or / and particles with a very heterogeneous size distribution. In this form, it was not possible to efficiently prepare pharmaceutical formulations such as capsules. Therefore, the synthetic CBD was subjected to a sieving process.

[0061] The particle size of the CBD can be reduced using any known device for reducing the particle size of a solid. For example, the CB can be size reduced by a grinding or shearing device.

[0062] The CBD was sieved through a sieve with a pore size of 0.77 mm, which appears to be very useful in the preparation of pharmaceutical preparations of CBD, especially capsules containing CPC preparations.

[0063] The sieved CBD was used without any additives in the preparation of capsules.

[0064] In particular, the sieved CBD was aspirated into a powder pipette and then transferred into a first piece of a two-piece capsule using the powder pipette, and the CBD contents were expelled from the powder pipette. The capsule half was then closed with the second piece of the two-piece capsule.

[0065] No additional liquids (especially lipophilic liquids) were added at any step.

[0066] The CBD dose per capsule was 200mg.

[0067] The capsule material was hydroxypropyl methylcellulose (HPMC).

[0068] Example 2: Clinical trial and its evaluation data The data used for this research question were obtained from the clinical trials, CBD-CT1 (ClinicalTrials.gov Identifier: NCT00628290) and CBD-PT (ClinicalTrials.gov Identifier: NCT00309413), all overseen by the same principal investigator (PI). Further information about the three included trials is provided in the following sections.

[0069] Active pharmaceutical ingredient (API) grade CBD used to manufacture the investigational products according to Good Manufacturing Practice (GMP) guidelines was purchased from THC Pharm GmbH (Frankfurt am Main, Germany). For CBD-CT1 and CBD-PT, the Pharmacy Department of the University Hospital Cologne (Cologne, Germany) was the manufacturer of the investigational products according to the German Medicines Law (AMG).

[0070] Clinical Trial CBD-CT1 "Evaluation of the antipsychotic efficacy of cannabidiol in acute schizophrenia" was a double-blind, controlled, randomized, phase II study with a parallel group design, conducted from March 2001 to November 2004 (ClinicalTrials.gov Identifier: NCT00628290). The Ethics Committee of the Medical Faculty of the University of Cologne approved the trial on June 8, 2000, application number 00-074.

[0071] A planned number of 42 patients with schizophrenic psychosis were randomized into two treatment groups and treated for 4 weeks with either CBD (n=21) or amisulpride (standard of care, n=21). All randomized patients met all of the following inclusion and exclusion criteria: age 18-50 years, male and female, sustained inpatient hospitalization, specific DSM-IV diagnosis, initial Brief Psychiatric Rating Scale (BPRS) score ≥ 36, understanding of the study objectives and course of the study, legal capacity, no pregnancy or lactation, reliable method of contraception.

[0072] CBD was administered as an oral dose in capsule formulation. The dose was increased from 200 mg / day to 800 mg / day (4 x 200 mg) during the first week and maintained at this level for the remainder of the study period. In the event of severe undesirable effects, the dose could be irreversibly reduced to 600 mg / day starting on day 15. Collection of blood samples to quantify CBD trough plasma concentrations and completion of the PANSS were performed at baseline, day 14, and day 28. Dose application, blood sampling, and PANSS assessment followed the time schedule shown below. Additional treatment with 7.5 mg lorazepam per day was permitted during the entire study period.

[0073] Of n=21 patients treated with CBD, 4 were excluded from the analysis. Three patients did not have CBD plasma concentrations measured at any time point, and one patient had a significantly higher CBD plasma concentration at day 14, which questioned efficacy. Another 3 patients dropped out after day 14, and no further CBD plasma concentrations and PANSS scores were available. Data from dropout patients up to day 14 are included in the analysis. A total of 17 patients are included in the analysis.

[0074] The method used to measure CBD plasma concentrations in this study is described in Schreiber D. Auswirkungen von Cannabiskonsum auf das endogene Cannabinoidsystem: Entwicklung einer LC-MS / MS-Analytik zur Messung von Endocannabinoiden im Serum. Bonn: Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn; 2007.

[0075] Clinical Trial CBD-PT This is a Phase II placebo-controlled randomized crossover trial of the antipsychotic properties of cannabidiol (ClinicalTrials.gov Identifier: NCT00309413). On July 28, 2005, this trial, application number 04-153, was approved by the Ethics Committee of the Medical Faculty of the University of Cologne.

[0076] Eighteen patients diagnosed with schizophrenia or schizophrenia-type disorder should be included in the study per the protocol. Dropouts had to be replaced by new patients, so a total of 29 patients were randomized from February 2006 to June 2008. All randomized patients complied with all the following inclusion and exclusion criteria: age 18-65 years, male and female, specific DSM-IV diagnosis, initial BPRS score ≥ 36, not pregnant or lactating, reliable contraception, no lack of accountability, no other relevant interferences, no treatment with depot antipsychotics in the past 3 months, no serious internal or neurological diseases, no QTc prolongation, no acute suicidal ideation and no danger to others by the patient. Ten patients started CBD treatment initially and 19 patients received placebo. Treatment lasted for 4 weeks. A first period of 2 weeks of CBD or placebo treatment was followed by a second period of 2 weeks of placebo or CBD treatment, respectively. There was no washout period between the two treatments. CBD was given as an oral dose of 600 mg / day (3 x 200 mg) in capsule formulation. In case of severe undesirable effects, the dose could be irreversibly reduced to 400 mg / day. Blood samples for quantification of CBD plasma concentrations were taken at baseline and on days 7, 14, 21, and 28. PANSS was applied at baseline and on days 14 and 28. Dose application, blood sampling, and PANSS assessment followed the time schedule shown below. Additional treatment with 5.0 mg lorazepam per day was allowed during the entire study period.

[0077] A total of n=11 patients dropped out during the study period. Seven patients dropped out during the first period of placebo treatment. They were not treated with CBD and therefore were excluded from the analysis of this research project. One patient dropped out during the second period of CBD treatment, but before any CBD plasma concentrations were measured and was therefore also excluded from the analysis. Another three patients dropped out but had at least one or two CBD plasma concentration measurements and could be included in the analysis. Data from a total of 21 patients are included in the analysis.

[0078] The method used to measure CBD plasma concentrations in this study is described in C. Schaefer: Exploration of the Endocannabinoid and Evaluation of Fettssaureethanolamide in Patients' Serum with a Borderline Personalized Examination and / or Posttraumatic Behavior: Validation of a LC-MS / MS Method. Cologne: University of Cologne; 2015.

[0079] Data Extraction and Preparation The clinical trials, CBD-CT1 and CBD-PT, focused on the antipsychotic effects of CBD and not on the PK properties. Therefore, documentation of the time points when CBD was administered and blood samples were taken was limited and not included in the electronic data. Information on possible dose reductions due to adverse events, for example, was also missing in the electronic data. In collaboration with the PI, time points were entered based on the ward's standard routine. Study drug application was set at 9:00 AM, 12:30 PM, 6:30 PM, and 10:00 PM, and blood sampling was scheduled at 8:45 AM. PANSS assessment was also timed to 8:45 AM. The loss of precision due to standardizing the time was considered acceptable because the time interval between administration and blood sampling was long and therefore small deviations would not have a large impact. Information on the actual applied dose or reduced dose was updated in collaboration with members of the PI's research group. Electronic data was adjusted based on annotations in archived patient case report files and other paper-based documents.

[0080] In two patients, CBD-CT1 and CBD-PT, baseline CBD concentrations were missing and 20 patients had baseline values ​​above the local lower limit of quantification (0.12 μg / l). After consultation with the PI, these values ​​were replaced with 0, since all patients with a positive drug screen were excluded from the trial according to the study protocol. Baseline values ​​above 0 may result in errors in the procedure, for example, when blood samples were taken after dose application. The replacement is therefore considered equivalent to the imputation of a pre-dose measurement that was not performed.

[0081] Positive and Negative Symptoms Scale The Positive and Negative Syndrome Scale (PANSS) is a psychopathological scale developed to assess the severity of symptoms in patients with schizophrenia. The scale was first described in 1987 by Kay et al. (see Kay SR, Fiszbein A, Opler LA. "The positive and negative syndrome scale (PANSS) for schizophrenia". Schizophrenia bulletin. 1987;13(2):261-276) and contains 30 questions that are a combination of the 18-item BPRS and the 12-item Psychopathology Rating Schedule (PSYRATS) (Leucht S, Kane JM, Kissling W, Hamann J, Etschel E, Engel RR. "What does the PANSS mean?" Schizophrenia research. 2005;79(2-3):231-238). All questions are rated on a 7-point scale ranging from 1=no symptoms to 7=very definite symptoms. Thus, the PANSS total score (sum of all 30 items) can range from 30 to 210. Here, it is applied that the lower the PANSS score, the better / healthier the patient is.

[0082] The original three-factor solution suggested by Kay et al. for the PANSS used in CBD-CT1 and CBD-PT includes a positive scale, a negative scale, and a general psychopathology scale. The positive scale includes delusions, disorganized thinking, hallucinations, agitation, grandiosity, suspiciousness / paranoia, and hatred. Apathy, emotional withdrawal, poor communication, passive / unemotional withdrawal, difficulty with abstract thinking, stereotyped, lack of spontaneity, and conversation flow are part of the negative scale. The general psychopathology scale includes somatic concerns, anxiety, guilt, tension, monotony, abnormal posture, depression, reduced mobility, incoordination, abnormal thought content, disorientation, poor attention, lack of judgment and insight, mood swings, poor impulse control, preoccupation, and active social avoidance.

[0083] The scale takes approximately 50 minutes for a trained interviewer to complete.

[0084] result In the CBD-CT1 and CBD-PT trials, the psychopathological state of schizophrenic patients was assessed using the PANSS at baseline and on days 14 and 28.

[0085] The results of the descriptive analysis of both the total score and the three PANSS subscores are shown in Table 1. All mean scores decreased over time with an increase in standard deviation. The same can be observed for the change in scores from baseline (see Table 1). Both the mean change and the corresponding standard deviation increased over time for all scores presented, thereby indicating an improvement in psychopathology at the population level.

[0086] A descriptive analysis of the observed CBD plasma concentrations is shown in Table 2.

[0087] To verify this impression of improvement, the PANSS was analyzed using repeated measures analysis of variance. The normal distribution assumption at each time point (baseline, day 14, day 28) was checked with the Shapiro-Wilk test (Sam S. Shapiro, Martin Bradbury Wilk: "An analysis of variance test for normality (for complete samples)", Biometrika, 52(3 / 4), 1965, pp. 591-61). A significant within-individual effect of time was detected for all four PANSS scores (p<0.001), thus confirming statistically significant changes in the PANSS over time.

[0088] [Table 1]

[0089] [Table 2]

[0090] We also evaluated the correlation between CBD plasma concentrations and changes in PANSS scores 14 days after the start of CBD administration.

[0091] [Table 3]

[0092] In general, a 50% change in PANSS score relative to the baseline score after 4-6 weeks of treatment is expected to indicate a significant improvement in PANSS score (see Correll CU, Quantifying clinical relevance in the treatment of schizophrenia, Clinical Therapeutics, Vol. 33, No. 12, 2011, B16-B39).

[0093] Since the PANSS score(s) address symptoms experienced or observed in the preceding 7 days, the minimum required observation period is 1 week. A 2-week treatment period is considered the minimum reliable period to avoid overlap with observation of early symptoms. Therefore, we analyzed the treatment effect after 2 weeks of treatment. Due to the shortened treatment period analyzed, a 25% change rate of the PANSS score relative to the baseline score(s) indicates a significant improvement in the PANSS score. We found that a CBD plasma concentration of at least about 25 μg / l results in the required change rate of the PANSS score(s).

Claims

1. 1. An in vitro method for determining the efficacy of administering cannabidiol to treat a subject with a psychiatric disorder, comprising: determining in vitro the level of cannabidiol in a blood sample from said subject having said psychiatric disorder; The method, wherein the treatment is deemed effective if the level of cannabidiol is between 30 μg / l and 85 μg / l.

2. 2. The method of claim 1, wherein the cannabidiol level is at least 35 μg / l, at least 40 μg / l, at least 45 μg / l, at least 50 μg / l, at least 60 μg / l, at least 70 μg / l, at least 75 μg / l, or at least 80 μg / l.

3. The method of claim 1 or 2, wherein the method is useful for optimizing and / or monitoring the effectiveness of the treatment.

4. The method according to any one of claims 1 to 3, wherein the psychiatric disorder is a psychotic disorder.

5. 5. The method of claim 4, wherein the psychiatric disorder is selected from the group consisting of schizophrenia, delusional disorder, or schizoaffective disorder.

6. 6. The method of any one of claims 1 to 5, wherein the level of cannabidiol is determined by liquid chromatography combined with tandem mass spectrometry.

7. The method of any one of claims 1 to 6, wherein the level is determined every 12 to 48 hours, or every 24 hours.

8. 8. The method of any one of claims 1 to 7, wherein the levels are first determined at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 days after the start of treatment with cannabidiol.

9. 9. The method of any one of claims 1 to 8, wherein the cannabidiol is administered to the subject at a dose of 5 mg to 1200 mg per day, or the cannabidiol is administered to the subject at a dose of 8 to 12 mg per kg of body weight per day.

10. 10. The method of any one of claims 1 to 9, wherein if the determined level of cannabidiol is below the range of claim 1, the dose of cannabidiol administered within a predetermined period of time is increased.

11. 11. The method of any one of claims 1 to 10, wherein if the determined level of cannabidiol exceeds the range of claim 1, the dose of cannabidiol administered within a predetermined period of time is reduced.

12. 12. The method of any one of claims 1 to 11, wherein the dose of cannabidiol administered is administered intravenously, orally, sublingually, nasally, rectally, topically, or by inhalation, or wherein the dose of cannabidiol administered is administered as a capsule.

13. The method of claim 12, wherein the administered dose of cannabidiol is administered as a capsule containing at least 99% cannabidiol and containing no added excipients having a particle size of less than 0.8 mm.

Images