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Canabidiolul – zeci de ani de cercetare şi utilizările clinice actuale

 Cannabidiol – decades of research and current clinical uses

Valentin Rădoi, Gabriel Cicu

First published: 15 noiembrie 2019

Editorial Group: MEDICHUB MEDIA

DOI: 10.26416/Psih.59.4.2019.2605

Abstract

While most of the research on cannabis has focused on delta-9-trans-tetrahydrocannabinol (THC), recently other cannabis constituents have sparked interest, culminating with cannabidiol’s (CBD) approval for the treatment of seizures in Lennox-Gastaut and Dravet syndromes. The aim of this narrative review is to discuss the possible therapeutic uses of CBD in psychiatry, with a focus on human clinical studies. Several other points of interest for the authors in this review will include the endocannabinoid system, the pharmacodynamics, pharmacokinetics, interactions and safety profile of this drug, as well as its legal status. CBD as a drug seems to be safe in adults and to have no or a low abuse potential. The current data indicate towards a possible use in different psychiatric disorders such as anxiety disorders, sleep disorders, post-traumatic stress disorder, schizophrenia and substance abuse disorders. Regarding anxiety, we consider that if the current findings are confirmed, CBD could be used in much the same way as benzodiazepines are currently used, with the advantage of a significantly lower or no risk of dependence, as well as a different, if not more favorable, side effect profile. However, it is important to note that bigger randomized controlled trials are required for each specific disease, research that could ultimately lead to meta-analyses which can offer high quality evidence. Legal changes regarding the status of CBD would ideally be made based on these studies.

Keywords
cannabidiol, cannabis, marijuana, endocannabinoid system, schizophrenia, anxiety disorders, social anxiety disorder, post-traumatic stress disorder, safety, adverse events

Rezumat

Deşi majoritatea cercetărilor referitoare la canabis s-au concentrat asupra delta-9-trans-tetrahidrocanabinolului (THC), recent alte componente ale canabisului au atras interesul, culminând cu aprobarea canabidiolului (CBD) pentru tratamentul crizelor din sindroamele Lennox-Gastaut şi Dravet. Scopul acestui review narativ este de a discuta posibilele roluri terapeutice ale CBD-ului în psihiatrie, accentul fiind pus pe studiile clinice umane. Alte puncte de interes ale autorilor pentru acest review includ sistemul endocanabinoid, farmacodinamica, farmacocinetica, interacţiunile şi profilul de siguranţă al acestei substanţe, precum şi statusul său legal. CBD-ul, ca medicament, pare a fi sigur la adulţi şi a nu avea sau a avea un potenţial redus de abuz. Datele curente sugerează posibilitatea folosirii sale în diverse tulburări psihiatrice, precum tulburări de anxietate, de somn, de stres posttraumatic, schizofrenie şi tulburări în legătură cu consumul de substanţe. În ceea ce priveşte anxietatea, considerăm că, dacă rezultatele actuale sunt confirmate, CBD-ul ar putea fi folosit în mod similar benzodiazepinelor, cu avantajul unui risc semnificativ mai scăzut de dependenţă sau al absenţei acestui risc, precum şi al unui profil de efecte adverse diferit, dacă nu chiar mai favorabil. Totuşi, este important de menţionat că studii clinice randomizate controlate sunt necesare pentru fiecare patologie în parte. Acestea ar putea conduce în final la metaanalize care pot oferi dovezi de înaltă calitate. Modificările legislative privind statusul CBD-ului ar fi, în mod ideal, realizate pe baza acestor studii. 

Introduction

The cannabis plant has a long history, its first medicinal uses dating back some 2800 years ago, in Asia(1). In the western world, it was used increasingly in medicine beginning with the 19th century(2). While delta-9-trans-tetrahydrocannabinol (9-THC) has garnered most of the research interest, recently other cannabis constituents such as cannabidiol (CBD) have been researched for therapeutic uses, culminating with the approval of an oral solution of CBD for the treatment of seizures in Lennox-Gastaut and Dravet syndromes(3).

The aim of this narrative review is to discuss the possible therapeutic uses of CBD in psychiatry, focusing on the pharmacodynamics, pharmacokinetics, interactions and safety profile of this drug. We will also cover the endocannabinoid system (eCB), as we consider that a short introduction is useful for understanding CBD. A succinct presentation of the legal status of CBD in the world will close the review.

The endocannabinoid system

The endocannabinoid system (eCB) includes cannabinoid receptors, endogenous endocannabinoids and their metabolic enzymes, and is involved in reward signaling, memory, cognition, mood, appetite, stress, pain, substance use and metabolic processes among others, as well as in migraine, fibromyalgia, irritable bowel syndrome, schizophrenia, multiple sclerosis, Huntington’s disease, Parkinson’s disease, anorexia, and chronic motion sickness(4-6).

Two cannabinoid receptors have been identified so far, CB1 receptors and CB2 receptors, with existing evidence which points towards the existence of other non-CB1 and non-CB2 cannabinoid receptors(7-10).

CB1 receptors are mainly located in neuronal tissues, especially in the basal ganglia, cerebellum, hippocampus and cerebral cortex. They are present, to a lower extent, in the hypothalamus and the spinal cord, and are almost absent in the respiratory centers of the brain stem(8,9). CB1 receptors have also been identified in the peripheral nervous system and in other tissues such as the testis, prostate, adrenal glands, bone marrow, heart, lung, thymus, tonsils and spleen, and in some immune cells, adypocites, hepatocytes and musculoskeletal tissues(6,8). CB2 receptors are mainly located in immune cells and tissues(8,9). These immune cells and tissues include B lymphocytes, macrophages, mast cells, microglia, natural killer cells, CD4 and CD8 lymphocytes, the spleen, tonsils and thymus(8).

These receptors play an important role in the release of messengers from neurons (CB1 receptors) and from immune cells (CB2 receptors)(4,7,8). As summarized by Howlett et al.(8), human, animal and in vivo studies have shown that, once activated, presynaptic CB1 receptors can modulate the release of numerous neurotransmitters, mainly resulting in the inhibition of their release: acetylcholine (Ach), dopamine (DA), D-aspartate (D-asp), noradrenaline (NA), gamma-aminobutyric acid (GABA), serotonin (5-HT), glutamate (Glu), and cholecystokinin (CCK). 

Several endogenous substances named endocannabinoids have been identified so far, including arachidonoylethanolamide (anandamide; AEA), 2-arachidonoylglycerol (2-AG), 2-arachidonylglyceryl ether (noladin ether), homo-a-linolenoylethanolamide, and docosatetraenoylethanolamide(7,8). AEA and 2-AG have been the most studied so far.

AEA is a partial agonist of both CB1 and CB2 receptors and 2-AG is a full agonist of these receptors(9-11). 2-AG is synthesized when needed, functioning as a retrograde messenger with an important role in inhibiting neurotransmitter release and, as such, it is involved in plasticity(9). AEA and 2-AG differ in their synthesis, degradation, receptor affinities and the way in which they influence synaptic plasticity, learning, memory and reward among others, with 2-AG having more diffuse effects and AEA more of a calibrator role(12).

Multiple studies in literature have linked AEA to pain(12-14) and neuropathic pain(15), vasorelaxation, cardioprotective effects(16), renal hemodynamics, fluid and sodium reabsorption, the renal sympathetic nervous system(17), blood pressure(16,17), emotional behaviour, anxiety, fear and stress(12,18,19), primary delayed ejaculation(20), spontaneous miscarriage, ectopic pregnancy and preeclampsia(21), weight loss, anger, anxiety and cardio-respiratory fitness following moderate aerobic exercise(22), substance abuse and the reward mechanism(12,23), defective processing of food cues following olanzapine treatment(24), synaptic plasticity, neuroprotection, learning, memory(12) and neurological damage following traumatic brain injury(25), but also to cardiovascular inflammation and oxidative stress(16).

2-AG has been linked to neuroinflammation and neuroprotection, synaptic plasticity, food intake and energy metabolism, pain, mood, stress, anxiety, addiction, reward, learning, memory, the immune, cardiovascular and gastrointestinal systems, and to cancer(9-12).

The eCB system is complex and features a wide variety of interactions and roles that deserve further research towards a better understanding and clinical applications, such as the ones for which CBD is currently researched and used.

Pharmacodynamics, pharmacokinetics and interactions

Cannabis has over 500 constituents, such as 9-THC, CBD, delta-8-tetrahydrocannabinol (8-THC), delta-9-tetrahydrocannabinolic acid A (9-THCA), cannabinolic acid A (CBNA), cannabigerolic acid (CBGA), cannabispirone, b-cannabispiranol, dehydrocannabifuran, dihydrophenanthrenes, and cannflavin B(26-31).

CBD was first isolated in 1940, with its structure being described in 1963(32,33). Reported bioavailability following oral delivery presents some differences between sources and, in our opinion, still requires more study before it can be stated with certainty. However, the literature reports a bioavailability of 13-19%, respectively 6% after oral delivery of an oil-based capsule formulation(34-36).

CBD’s time to maximum plasma concentration (tmax) is 2.5-5 hours, the effective half life is 10-17 hours, the terminal elimination half life is around 56-70 hours, and the steady state is reached after two days(37,38). CBD’s concentration does not increase proportionally with higher doses yielding a lower concentration increase in the 5-20 mg/kg/day range(38). Also, high fat meals seem to increase the maximum concentration five times(38).

While in vitro studies have shown that CBD could be converted to 9-THC following exposure to a simulated gastric fluid at 37° C, human studies have not shown a detectable 9-THC concentration after CBD administration(36).

CBD is metabolized by cytochrome P450 (CYP2C19 and CYP3A) and uridine 5-diphosphoglucuronosyltransferase (UGT1A7, UGT1A9 and UGT2B7), with CYP enzyme inactivation in the short term and CYP enzyme induction in the long term. The literature suggests that CBD is an inhibitor of UGT1A9, UGT2B7, CYP2C8, CYP2C9 and CYP2C19. Therefore, it can increase the dose of common psychiatric drugs such as bupropion, diazepam and propranolol(38).

The producers of the first CBD drug approved for the treatment of seizures in Lennox-Gastaut and Dravet syndromes state, in regards to drug-drug interactions, that a dose reduction of the CBD product is suggested in case of moderate or strong CYP3A4 or CYP2C19 inhibitor use, and a dose increase of the CBD product is suggested in case of strong inducer of CYP3A4 or CYP2C19 use(39). Also, if the patient is prescribed, alongside CBD, a substrate of UGT1A9, UGT2B7 (e.g., lamotrigine, morphine and lorazepam), CYP2C8, CYP2D9 or CYP2C19 (e.g., diazepam), a dose reduction of the substrate will be suggested, while if, alongside CBD, the patient is prescribed or uses a substrate of CYP1A2 (e.g., caffeine) or CYP2B6 (bupropion), a dose adjustment will be suggested(39).

The administration of an enzyme inductor (rifampin) determined a 52% lower CBD concentration and the administration of a CYP3A inhibitor (ketoconazole) increased the concentration by 89%(38). However, another study(40) calculated the extrapolated doses required to inhibit cytochrome P450 enzymes, with these doses being in the range 4,900-1.28 million mg, which have not been used in medical practice(36,40).

A healthy volunteer study has shown that the pharmacokinetics of CBD are not modified when administered alongside valproate and that CBD does not change the pharmacokinetics of valproate(41). Due to CBD’s inhibition of CYP2C9, it is suggested that CBD increases international normalized ratio (INR) values when co-administered with warfarin(42). Omeprazole seems to not influence CBD’s concentration(38).

Although there is some contradiction, CBD appears to have a very low affinity for CB1 and CB2 receptors, with some studies suggesting that it is a non-competitive antagonist which acts through negative allosteric modulation or an indirect agonist at the CB1 receptor and an inverse agonist at the CB2 receptor(34,36,43-45). Due to this profile, CBD may counter some of the effects of 9-THC(43,44,46-48). A meta-analysis(44) has found a Ki=3245±803 nM for CBD at CB1 receptors, and a Ki=3612±1382 nM at CB2 receptors. 

CBD interacts with the eCB system indirectly by inhibiting AEA reuptake and the fatty acid amide hydrolase (FAAH) enzyme which degrades AEA. CBD also inhibits adenosine uptake, blocks the equilibrative nucleoside transporter (ENT) and the transient receptor potential of melastatin type 8 (TRPM8), it acts on transient receptor potential (TRP) channels and on intracellular calcium, on GABAA receptors, glycine receptors, on µ and d opiod receptors and on G protein-coupled receptors (GPR) 18 and 55. CBD is a full agonist at the 5-HT1A receptor (while in vivo studies show that it is an allosteric modulator), a weak partial agonist at the 5HT2A receptor and a non-competitive antagonist at the 5-HT3A receptor, and an antioxidant(33-36,44,49-53).

An animal study did not find tolerance to CBD(36), while a human study of healthy recreational polydrug users showed that 750 mg of CBD had a low abuse potential, while doses of 1500 mg and 4500 mg had a subjective effect in comparison with placebo, which was still significantly lower than the effect of alprazolam or dronabinol(54).

Taking into consideration the myriad of actions and interactions in which CBD is involved, it is clear that it exerts its effects not only, or even not mainly, through its action at CB receptors, but through a complex interconnected mechanism. Further studies to clarify the pharmacokinetics and pharmacodynamics of CBD are required, as well as studies regarding its numerous potential interactions especially with psychiatric and neurologic drugs and with drugs that are known to modify the metabolism of other substances, such as carbamazepine.

CBD in psychiatry

CBD has been studied and used therapeutically in various psychiatric conditions, such as anxiety disorders, post-traumatic stress disorder, depression, psychotic disorders, autism spectrum disorders, Alzheimer’s disease, and Parkinson’s disease. Several reviews from the last years have summarized these findings from various points of view(4,33,38,43,45,52,55-59).

In this narrative review, we will focus upon human clinical studies done in anxiety disorders, post-traumatic stress disorder (PTSD) and schizophrenia, as well as substance use disorder, Alzheimer’s disease and affective disorders, while mentioning supporting evidence from preclinical, animal and healthy subjects studies.

Anxiety and post-traumatic stress disorder

The anxiolitic effect of CBD, probably mediated through CBD’s action on CB1 receptors, adenosine receptors and serotonin receptors, is observed at low doses, with high doses being anxiogenic or having no effect. This might be explained by the fact that the activation of transient receptor potential cation channel subfamily V member 1 (TRPV1) receptors at higher doses is mostly anxiogenic. Animal studies have confirmed that low doses (10 mg/kg) have an anxiolitic effect, while higher doses (100 mg/kg) have no effect. Human studies have shown that CBD doses of 300 to 600 mg are efficient in experimentally induced anxiety and in enhancing fear extinction in acute settings in healthy subjects(52,58,60).

‘Runner’s high’ is described as euphoria, anxiolysis, sedation and analgesia, and is associated with an increase in the opiod b-endorphin and in AEA plasma levels. Fuss et al. have shown that, in mice, CB receptors are responsible for the analgesia and anxiolysis effects associated with running(61).

CBD has also been shown to counter the psychogenic and anxiolitic effects of 9-THC(43,44,46-48).

The inverted U-shaped dose-response curve of CBD from animal studies has also been found in a public speaking test study of 60 healthy adults with the 300 mg dose, but not the 100 mg and 900 mg doses, decreasing subjective anxiety in the post-speech phase(62). In this study(62), as well as in previous studies(63), CBD (in a 300 mg dose) was less sedating than a benzodiazepine.

An online survey study of 2409 persons has shown that anxiety was one of the three most treated medical conditions with CBD, and respondents considered most frequently that CBD treated their medical condition(s) “very well by itself” or “moderately well by itself”(64).

People suffering from social anxiety disorder (SAD) are more likely to present cannabis dependence, which suggests that they use cannabis as a form of medication(58,65). In a study including veterans, anxiety was among the most frequently endorsed condition for cannabis use(66).

Bergamaschi et al.(67) compared the effect of CBD on never treated SAD subjects (n=12) to placebo (n=12) and to unmedicated healthy controls (n=12) in a simulated public speaking test. CBD (600 mg) was administered 90 minutes before the test. The CBD treated group presented reduced anxiety, discomfort and cognitive impairment, and reduced alert in their anticipatory speech. The cognitive impairment, discomfort and alert of CBD treated patients presented no significant differences when compared to the healthy controls.

A 400 mg dose of CBD reduced subjective anxiety in 10 never treated patients with SAD. Functional imaging has implicated limbic and paralimbic areas in this effect(68)

A study of 32 subjects with high paranoid traits who received 600 mg of CBD or placebo did not show an effect on anxiety or persecutory ideation(69).

Shannon and Opila-Lehman(70) reported the case of a 27-year-old patient with bipolar disorder and marijuana addiction. Following CBD augmentation of his treatment (24 mg initially, then 18 mg), there was an improvement in anxiety, a return to a regular pattern of sleep and a cessation of marijuana use.

A retrospective case series studied CBD augmentation in 72 patients with anxiety or poor sleep. Most patients received CBD 25 mg/day, with several patients receiving 50 mg/day or 75 mg/day and one patient receiving a final dose of 175 mg/day. After one month, 79.2% of patients presented an improvement in anxiety and 66.7% of patients presented an improvement in sleep. After two months, 78.1% of patients presented an improvement in anxiety and 56.1% of patients presented an improvement in sleep. This treatment was well tolerated in 95.8% of patients(71).

A case report described a positive effect on anxiety and sleep of CBD augmentation (25 mg CBD per day and 6-12 mg CBD administered when needed for anxiety) in a 10-year-old girl suffering from PTSD with no treatment side effects(60).

A retrospective case series of 11 patients suffering from PTSD described CBD augmentation. The mean starting dose was 33.18 mg (standard deviation [SD] = 23.34), with the mean CBD dose at 8 weeks (study end-point) being 48.64 mg (range: 2-100). Ten of the 11 patients presented an improvement on the patient-completed PTSD checklist for the DSM-5 (PCL-5) questionnaire, with the mean score decreasing by 28%(72).

While there is preclinical and animal study support for CBD’s anxiolitic effect, all clinical studies are small and several are either case reports, or retrospective case series. It does appear, however, that CBD, as an (add-on) drug, in low doses, probably in the range of 25-50-75 mg/day, improves anxiety, sleep and PTSD symptoms. These results warrant further larger and better quality studies for CBD in anxiety disorders and PTSD.

Schizophrenia

CBD presents an interest in schizophrenia due to findings that support “a cannabinoid hypothesis of schizophrenia” which states that there is a hyperactivity of the eCB, to the capacity of CBD to counter 9-THC induced psychosis, its agonist role at TRPV1, its effect on GABA release and glutamate activity, and its efficacy in ameliorating anxious and depressive symptoms, among others(45,57). CBD’s antipsychotic effect was proven in animal and in healthy volunteer studies(45). Its pharmacological profile resembles that of second-generation antipsychotics(45).

Animal studies have shown that CBD needs to be administered in higher doses than those used in anxiety studies in order to have an antipsychotic effect(45).

A first case report of CBD use in schizophrenia described CBD monotherapy for four weeks with a dose of up to 1500 mg/day which significantly improved scores on the Brief Psychiatric Rating Scale (BPRS) in a 19-year-old patient(73). Another monotherapy study including three treatment-resistant schizophrenia patients used a CBD dose of up to 1280 mg/day. While CBD was well tolerated and there were no side effects, only one patient showed mild improvement(74). An open-label study of psychosis, with a duration of at least three months in Parkinson’s disease (n=6), also evaluated CBD treatment. The patients presented a significant improvement in BPRS total score, four of the BPRS factor scores, Parkinson psychosis questionnaire (PPQ), total unified Parkinson’s disease rating (UPDRS), and clinical global impression improvement (CGI-I) scores at four weeks(75).

A double blind trial investigated the effect of a single administration of 300 mg and 600 mg of CBD in comparison with placebo on the Stroop Color Word Test (SCWT) in 28 schizophrenia patients who were not in an acute psychotic episode. The study included two sessions, CBD or placebo being administered only in the second session. The placebo and the 300 mg group presented a statistically significant improvement between the two sessions, while the 600 mg group presented a smaller improvement which only tended to statistical significance. There was no difference in the comparison between the 300 mg and the placebo group in the second session(76).

A 57-year-old schizophrenic patient with a nine-year history of persistent hallucinations and negative symptoms received up to 1500 mg CBD for 9.5 weeks apart from her usual treatment. This led to a decrease in the Positive and Negative Syndrome Scale (PANNS) score from 117 to 68, the disappearance of her hallucinations, and to an improvement of her negative symptoms(77).

A double blind cross-over study included 29 first episode schizophrenia patients who never received antipsychotic treatment. 600 mg of CBD or placebo were administered once for 14 days, then the patients were switched. The 18 study completers presented a significant improvement in psychotic symptoms(57,78).

A randomized double blind clinical trial enrolled 42 acutely psychotic patients with schizophrenia. After at least three days with no antipsychotic treatment, the patients received either amisulpride, or CBD. The initial dose for both was 200 mg/day, with a possible increase in increments of 200 mg/day up to 800 mg/day for a total study duration of four weeks. Lorazepam in a dose of up to 7.5 mg/day was allowed. Both groups presented significant improvements in the PANNS total score, with no significant differences between the two groups, but the non-inferiority test was not statistically significant (p=0.27). BPRS results were similar and there were no differences in responders between the two groups as defined by an improvement of at least 20% in the PANNS score. The CBD group presented a better side effect profile, including extrapyramidal symptoms, weight gain, prolactin increase and sexual dysfunction(79).

Boggs et al.(80) conducted a randomized parallel group study of CBD (600 mg/day) or placebo augmentation. The study included 36 stable schizophrenic patients and lasted six weeks. Adding CBD to the patients antipsychotic treatment did not improve PANSS or MATRICS Consensus Cognitive Battery (MCCB) scores. Another study(81) included schizophrenia patients who received their antipsychotic medication alongside CBD (1000 mg/day, n=43) or placebo (n=45) for a duration of six weeks. The CBD group presented improvements of positive symptoms as measured on the PANNS scale, as well as improvements on the CGI-I and in cognition which were almost statistically significant.

Bhattacharyya et al.(82) included 33 individuals at clinical high risk (CHR) of psychosis and 19 healthy controls in a neuroimaging study. Sixteen (n=15 included in the study) patients received 600 mg of CBD, while the other subjects received placebo (n=16 included in the study). The study results have shown that CBD had a positive effect in brain regions related to psychosis, including parahippocampal, striatal and midbrain regions.

There have been other studies regarding CBD use in schizophrenia, with these studies being more often larger and of a better quality. While these studies used higher CBD dosages, it is encouraging that the side effect profile was good, especially in comparison to that of antipsychotics.

Other therapeutic uses

CBD – due to its capacity to modulate the eCB tone and regulate mesolimbic DA activity, as well as its effect on the serotonergic system – presents promise in treating various substance use disorders(4). Animal studies, case reports and/or human trials describe the CBD’s potential in relation to cannabis, tobacco, opiod and stimulant use disorder, as revealed by a recent review(4).

Regarding other psychiatric conditions, there is limited evidence which will be presented succinctly. In vivo and animal studies, as well as the anti-inflammatory and neuroprotective properties of CBD suggest it could be useful in Alzheimer’s disease(43). An online survey study of 2409 patients has shown that depression was one of the three most treated medical conditions with CBD(64). An animal study showed that sub-chronic CBD treatment had a mild antidepressant effect in diabetic rats(83). A case report of two bipolar patients in a manic episode did not show CBD to be efficient(84).

Safety profile

A 144-week epilepsy study(85) of add-on CBD, which included 607 children with a mean age of 12.7 years old, used doses that started at 2-10 mg/kg/day and went up to 25-50 mg/kg/day. The most frequent adverse events were somnolence (30%), convulsions (24%) and diarrhea (24%), with the most common serious adverse events being convulsions (14%), status epilepticus (9%), pneumonia (5%) and pyrexia (4%). Elevations of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) over three times the normal value were reported in 22 patients (15%) out of which 18 (82%) were also receiving valproic acid. Somnolence presented a higher frequency when CBD was associated with clobazam (38% versus 18%). Three percent of patients withdrew due to adverse events. 

Another study in Dravet syndrome(86) used doses of up 30 mg/kg/day (mean dose: 21.2 mg/kg/day) for 264 children (mean age: 9.8 years old), with a mean duration of 274 days. Adverse events were slightly more frequent in children who received a modal dose of at least 20 mg/kg/day. The most common adverse events were diarrhea (34.5%), pyrexia (27.3%), decreased appetite (25.4%) and somnolence (24.6%). Elevations of ALT or AST were reported in 17.2% of patients, all of them also receiving valproic acid; 6.4% of patients withdrew due to adverse events.

A meta-analysis of 550 epilepsy patients (mean age between 7 and 16 years old in the included trials) with CBD augmentation (5 mg/kg/day, 10 mg/kg/day or 20 mg/kg/day) found the following side effects significantly associated with CBD: somnolence, decreased appetite, diarrhea, and increased AST and/or AST. Drug withdrawal, treatment discontinuation, treatment discontinuation due to adverse events, and adverse events were more frequent in the CBD than in the placebo arm(87).

Another meta-analysis of CBD, as well as CBD:THC extract, cannabis sativa, dronabinol and other cannabinoid formulations has found a relative risk (RR) of 1.24 (95% Confidence Interval [CI]; 1.13 to 1.36) of adverse events and of 2.55 (95% CI; 1.48 to 4.38) of serious adverse events in comparison to placebo(88). Other serious adverse events mentioned in literature pertaining to CBD use in epilepsy include severe diarrhea and thrombocytopenia(89).

It is important to note that these studies included a children population which was diagnosed with a form of epilepsy, receiving concomitant medication and a high dose of CBD. Considering a 70-kilogram human, the maximum doses in the first two of these studies(85,86) would have been 3500 mg and 2100 mg, higher than the doses used in the schizophrenia trials and the doses used in anxiety trials.

CBD did not determine respiratory depression, cardiovascular compromise or a significant change in temperature, heart rate, respiratory rate, blood pressure and oxygen saturation in a study(90), and had no effect on mean arterial pressure or heart rate at 300 mg and 600 mg doses, with a slight increase in heart rate at 900 mg dose in another study(91)

As reviewed by Mandolini et al.(55), CBD does not seem to alter embryonic development according to an in vitro study and does not induce catalepsy in animal studies. Apart from the vital signs already mentioned in human studies, CBD did not affect glucose levels, pH, PCO2, PO2, hematocrit, K+ or Na+ levels in animal studies. Human studies of chronic CBD administration have not shown EEG, EKG, clinical, psychiatric, blood or urine tests changes. Due to CBD’s inhibitory action in the immune system, there is a risk of progression of human immunodeficiency virus-1 (HIV-1) infection, tumor genesis and metastases, exacerbating allergic inflammation of the lung, and increasing the risk of HIV-1 infection(55).

In hepatic impairment subjects (n=8 for mild and moderate; n=6 for severe; n=8 for controls), a single dose of 200 mg of CBD did not determine serious adverse events, although a lower starting dose and slower titration would be recommended in case of moderate or severe hepatic impairment(92). The producers of the first CBD drug approved for the treatment of seizures in Lennox-Gastaut and Dravet syndromes recommend lower doses in moderate hepatic impairment (1/2 of the usual dose) and severe hepatic impairment (1/5 of the usual dose)(39). They also recommend baseline ALT, AST and bilirubin levels, as well as at one, three and six months after treatment initiation, and periodically thereafter and more frequent dosing in patients who also receive valproate(39).

In healthy adult subjects, single CBD doses of up to 6000 mg or multiple doses of up to 1500 mg were well tolerated, with no severe or serious adverse events and no trial discontinuations(37).

In a healthy volunteer study which assessed the interaction between CBD (1500 mg/day) and clobazam, stiripentol or valproate, there were no serious adverse events, deaths or clinically significant safety findings, with 7.8% of subjects discontinuing the study due to adverse events(41).

Most reviewed studies state that CBD is safe in adult patients. The described side effects are most often mild or moderate, but we would state that a careful medical history is warranted, as in any medical and psychiatric consultation, with special attention paid to any hepatic abnormalities and to any other drugs and substances the patient might be using and might interact with CBD. Attention also needs to be paid if we prescribe, alongside CBD, other psychiatric drugs, due to the risk of drug-drug interactions.

The legal status of cannabidiol

It is important to note that – as the purpose of this review was not a careful study of state and country laws regarding CBD, as some of the sources of information regarding the legality of CBD cannot be considered “academic” and as the regulations and laws concerning this domain are bound to rapid change –, the purpose of the following information is purely to paint a general picture of this domain, and we strongly suggest that any CBD prescription and/or use be done only following a review of local laws.

CBD’s legal status in the United States of America is complex, being a Schedule I controlled substance and being considered a drug and not a dietary supplement by the Food and Drug Administration(93). This is complicated even further by state specific legislation. However, CBD can be bought online and at cannabis dispensaries without the need for a prescription(93) with hemp derived CBD being legal as long as it follows certain regulations, and marijuana derived CBD being legal in ten states for recreational use and in 47 states for medicinal use(94).

The recreational use of marijuana and, as such, of CBD has been legalized in Canada, Georgia, Spain and Uruguay, while medicinal use is legal in many more countries including Australia, Canada, Chile, Colombia, Greece, Israel, Italy, the Netherlands, Peru, Poland, the United Kingdom and Germany(95,96). CBD appears to be legal in Austria, Belgium, Bulgaria, Cyprus, Estonia, Finland (with prescription), France, Ireland, Latvia, Lithuania, Luxembourg, Malta (with prescription), Portugal and Slovenia as long as the 9-THC content is under 0.2% (for Austria, it must have no psychotropic properties)(97). CBD is illegal in Slovakia and prohibited in Croatia(97). Topical CBD products are legal in Denmark, while hemp derived CBD needs to have a 9-THC content of below 0.2% and a prescription is required(95). In Sweden, CBD products have not been legalized or illegalized so far(95).

In Romania, it appears that CBD is legal as long as the 9-THC content is under 0.2%(97-99).

Conclusions

CBD as a drug seems to be safe in adults and to have no or a low abuse potential. The current data indicate towards a possible use in different psychiatric disorders such as anxiety disorders, sleep disorders, PTSD, schizophrenia and substance abuse disorders. Regarding anxiety, we consider that if the current findings are confirmed, CBD can be used in much the same way as benzodiazepines are currently used, with the advantage of a significantly lower or no risk of dependence, as well as a different, if not more favorable, side effect profile.

However, it is important to note that bigger randomized controlled trials are required for each specific disease, research that could ultimately lead to meta-analyses which can offer high quality evidence. Legal changes regarding the status of CBD would ideally be made based on these studies.  

Bibliografie

  1. Pisanti S, Bifulco M. Medical Cannabis: A plurimillennial history of an evergreen. J Cell Physiol. 2019; 234(6):8342–51.
  2. Zuardi AW. History of cannabis as a medicine: a review. Rev Bras Psiquiatr. 2006; 28(2):153–7.
  3. FDA approves first drug comprised of an active ingredient derived from marijuana to treat rare, severe forms of epilepsy; 2018 [cited 2019 Jun 25]. Available from: URL: https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-comprised-active-ingredient-derived-marijuana-treat-rare-severe-forms.
  4. Chye Y, Christensen E, Solowij N, Yücel M. The Endocannabinoid System and Cannabidiol’s Promise for the Treatment of Substance Use Disorder. Front Psychiatry. 2019; 10:63.
  5. Chanda D, Neumann D, Glatz JFC. The endocannabinoid system: Overview of an emerging multi-faceted therapeutic target. Prostaglandins Leukot Essent Fatty Acids. 2019; 140:51–6.
  6. McPartland JM, Guy GW, Di Marzo V. Care and feeding of the endocannabinoid system: a systematic review of potential clinical interventions that upregulate the endocannabinoid system. PLoS ONE. 2014; 9(3):e89566.
  7. Pertwee RG. The pharmacology of cannabinoid receptors and their ligands: an overview. Int J Obes (Lond). 2006; 30 Suppl 1:S13-8.
  8. Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M. International Union of Pharmacology. XXVII. Classification of Cannabinoid Receptors. International Union of Pharmacology. XXVII. 2002; 54(54):161–202.
  9. Baggelaar MP, Maccarrone M, van der Stelt M. 2-Arachidonoylglycerol: A signaling lipid with manifold actions in the brain. Prog Lipid Res. 2018; 71:1–17.
  10. Sugiura T. Physiological roles of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand. Biofactors. 2009; 35(1):88–97.
  11. Alhouayek M, Masquelier J, Muccioli GG. Controlling 2-arachidonoylglycerol metabolism as an anti-inflammatory strategy. Drug Discov Today. 2014; 19(3):295–304.
  12. Luchicchi A, Pistis M. Anandamide and 2-arachidonoylglycerol: pharmacological properties, functional features, and emerging specificities of the two major endocannabinoids. Mol Neurobiol. 2012; 46(2):374–92.
  13. Habib AM, Okorokov AL, Hill MN, Bras JT, Lee M-C, Li S et al. Microdeletion in a FAAH pseudogene identified in a patient with high anandamide concentrations and pain insensitivity. Br J Anaesth. 2019. Article in press.
  14. Sousa-Valente J, Varga A, Ananthan K, Khajuria A, Nagy I. Anandamide in primary sensory neurons: too much of a good thing? Eur J Neurosci. 2014; 39(3):409–18.
  15. Malek N, Kucharczyk M, Starowicz K. Alterations in the anandamide metabolism in the development of neuropathic pain. Biomed Res Int. 2014; 2014:686908.
  16. Gimenez VMM, Noriega SE, Kassuha DE, Fuentes LB, Manucha W. Anandamide and endocannabinoid system: an attractive therapeutic approach for cardiovascular disease. Ther Adv Cardiovasc Dis. 2018; 12(7):177–90.
  17. Ritter JK LG, Xia M BK. Anandamide and its metabolites: what are their roles in the kidney? Front Biosci (Schol Ed). 2016; (8):264–77.
  18. Gunduz-Cinar O, Hill MN, McEwen BS, Holmes A. Amygdala FAAH and anandamide: mediating protection and recovery from stress. Trends Pharmacol Sci. 2013; 34(11):637–44.
  19. Morena M, Hill MN. Buzzkill: the consequences of depleting anandamide in the hippocampus. Neuropsychopharmacology. 2019 Jul; 44(8):1347-1348.
  20. Fenner A. Sexual dysfunction: Anandamide shows promise for lifelong delayed ejaculation. Nat Rev Urol. 2015; 12(5):244.
  21. Molvarec A, Fügedi G, Szabó E, Stenczer B, Walentin S, Rigó J. Decreased circulating anandamide levels in preeclampsia. Hypertens Res. 2015; 38(6):413–8.
  22. Belitardo de Oliveira A, de Mello MT, Tufik S, Peres MFP. Weight loss and improved mood after aerobic exercise training are linked to lower plasma anandamide in healthy people. Physiol Behav. 2019; 201:191–7.
  23. Scherma M, Masia P, Satta V, Fratta W, Fadda P, Tanda G. Brain activity of anandamide: a rewarding bliss? Acta Pharmacol Sin. 2019; 40(3):309–23.
  24. Potvin S, Lungu OV, Stip E. Anandamide is involved in appetite-related amygdala hyperactivations in schizophrenia patients treated with olanzapine: a functional magnetic resonance imaging study. J Clin Psychopharmacol. 2015; 35(1):82–3.
  25. Martinez-Vargas M, Morales-Gomez J, Gonzalez-Rivera R, Hernandez-Enriquez C, Perez-Arredondo A, Estrada-Rojo F, et al. Does the neuroprotective role of anandamide display diurnal variations? Int J Mol Sci. 2013; 14(12):23341–55.
  26. Radwan MM, ElSohly MA, Slade D, Ahmed SA, Khan IA, Ross SA. Biologically active cannabinoids from high-potency Cannabis sativa. J Nat Prod. 2009; 72(5):906–11.
  27. Mehmedic Z, Chandra S, Slade D, Denham H, Foster S, Patel AS et al. Potency trends of Δ9-THC and other cannabinoids in confiscated cannabis preparations from 1993 to 2008. J Forensic Sci. 2010; 55(5):1209–17.
  28. Kogel CC, Lopez-Pelayo H, Balcells-Olivero M, Colom J, Gual A. Psychoactive constituents of cannabis and their clinical implications: a systematic review. Adicciones. 2018; 30(2):140–51.
  29. Ahmed SA, Ross SA, Slade D, Radwan MM, Khan IA, ElSohly MA. Minor oxygenated cannabinoids from high potency Cannabis sativa L. Phytochemistry. 2015; 117:194–9.
  30. Ahmed SA, Ross SA, Slade D, Radwan MM, Zulfiqar F, Matsumoto RR et al. Cannabinoid ester constituents from high-potency Cannabis sativa. J Nat Prod. 2008; 71(4):536–42.
  31. Radwan MM, Ross SA, Slade D, Ahmed SA, Zulfiqar F, ElSohly MA. Isolation and characterization of new Cannabis constituents from a high potency variety. Planta Med. 2008; 74(3):267–72.
  32. ElSohly MA, Slade D. Chemical constituents of marijuana: the complex mixture of natural cannabinoids. Life Sci. 2005; 78(5):539–48.
  33. Devinsky O, Cilio MR, Cross H, Fernandez-Ruiz J, French J, Hill C et al. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia. 2014; 55(6):791–802.
  34. Pisanti S, Malfitano AM, Ciaglia E, Lamberti A, Ranieri R, Cuomo G et al. Cannabidiol: State of the art and new challenges for therapeutic applications. Pharmacol Ther. 2017; 175:133–50.
  35. Welty TE, Luebke A, Gidal BE. Cannabidiol: Promise and Pitfalls. Epilepsy Currents. 2014; 14(5):250–2.
  36. Kershaw S. Cannabidiol (CBD): Expert Committee on Drug Dependence Thirty-ninth Meeting 2017.
  37. Taylor L, Gidal B, Blakey G, Tayo B, Morrison G. A Phase I, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose, Multiple Dose, and Food Effect Trial of the Safety, Tolerability and Pharmacokinetics of Highly Purified Cannabidiol in Healthy Subjects. CNS Drugs 2018; 32(11):1053–67.
  38. White CM. A Review of Human Studies Assessing Cannabidiol’s (CBD) Therapeutic Actions and Potential. J Clin Pharmacol. 2019 Jul; 59(7):923-934.
  39. Highlights of Prescribing Information. Epidiolex; 2018 [cited 2019 May 16]. Available from: URL: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf.
  40. Iffland K, Grotenhermen F. An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies. Cannabis Cannabinoid Res. 2017; 2(1):139–54.
  41. Morrison G, Crockett J, Blakey G, Sommerville K. A Phase 1, Open-Label, Pharmacokinetic Trial to Investigate Possible Drug-Drug Interactions Between Clobazam, Stiripentol, or Valproate and Cannabidiol in Healthy Subjects. Clin Pharmacol Drug Dev. 2019 Feb 21; doi: 10.1002/cpdd.665.
  42. Damkier P, Lassen D, Christensen MMH, Madsen KG, Hellfritzsch M, Pottegård A. Interaction between warfarin and cannabis. Basic Clin Pharmacol Toxicol. 2019; 124(1):28–31.
  43. Premoli M, Aria F, Bonini SA, Maccarinelli G, Gianoncelli A, Della Pina S, et al. Cannabidiol: Recent advances and new insights for neuropsychiatric disorders treatment. Life Sci. 2019; 224:120–7.
  44. McPartland JM, Duncan M, Di Marzo V, Pertwee RG. Are cannabidiol and Δ(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol. 2015; 172(3):737–53.
  45. Zuardi AW, Crippa JAS, Hallak JEC, Bhattacharyya S, Atakan Z, Martin-Santos R, McGuire PK, Guimaraes FS. A Critical Review of the Antipsychotic Effects of Cannabidiol: 30 Years of a Translational Investigation. Current Pharmaceutical Design. 2012; 18(32):5131–40.
  46. Bhattacharyya S, Morrison PD, Fusar-Poli P, Martin-Santos R, Borgwardt S, Winton-Brown T, et al. Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology. 2010; 35(3):764–74.
  47. Zuardi AW, Shirakawa I, Finkelfarb E, Karniol IG. Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects.psychopathology. Psychopharmacology (Berl). 1982; 76(3):245–50.
  48. Niesink RJM, van Laar MW. Does Cannabidiol Protect Against Adverse Psychological Effects of THC? Front Psychiatry. 2013; 4:130.
  49. Bakas T, van Nieuwenhuijzen PS, Devenish SO, McGregor IS, Arnold JC, Chebib M. The direct actions of cannabidiol and 2-arachidonoyl glycerol at GABAA receptors. Pharmacol Res. 2017; 119:358–70.
  50. Morales P, Hurst DP, Reggio PH. Molecular Targets of the Phytocannabinoids: A Complex Picture. Prog Chem Org Nat Prod. 2017; 103:103–31.
  51. Ibeas Bih C, Chen T, Nunn AVW, Bazelot M, Dallas M, Whalley BJ. Molecular Targets of Cannabidiol in Neurological Disorders. Neurotherapeutics. 2015; 12(4):699–730.
  52. Blessing EM, Steenkamp MM, Manzanares J, Marmar CR. Cannabidiol as a Potential Treatment for Anxiety Disorders. Neurotherapeutics. 2015; 12(4):825–36.
  53. Khoury JM, Neves MdCLd, Roque MAV, Queiroz DAdB, Corrêa de Freitas AA, Fátima  de, et al. Is there a role for cannabidiol in psychiatry? World J Biol Psychiatry. 2019; 20(2):101–16.
  54. Schoedel KA, Szeto I, Setnik B, Sellers EM, Levy-Cooperman N, Mills C, et al. Abuse potential assessment of cannabidiol (CBD) in recreational polydrug users: A randomized, double-blind, controlled trial. Epilepsy Behav. 2018; 88:162–71.
  55. Mandolini GM, Lazzaretti M, Pigoni A, Oldani L, Delvecchio G, Brambilla P. Pharmacological properties of cannabidiol in the treatment of psychiatric disorders: a critical overview. Epidemiol Psychiatr Sci. 2018; 27(4):327–35.
  56. Campos AC, Fogaça MV, Sonego AB, Guimarães FS. Cannabidiol, neuroprotection and neuropsychiatric disorders. Pharmacol Res. 2016; 112:119–27.
  57. Fakhoury M. Could cannabidiol be used as an alternative to antipsychotics? 
  58. J Psychiatr Res. 2016; 80:14–21.
  59. Scherma M, Masia P, Deidda M, Fratta W, Tanda G, Fadda P. New Perspectives on the Use of Cannabis in the Treatment of Psychiatric Disorders. Medicines (Basel). 2018; 5(4).
  60. Schier ARdM, Ribeiro NPdO, e Silva ACdO, Hallak JEC, Crippa JAS, Nardi AE, et al. Cannabidiol, a Cannabis sativa constituent, as an anxiolytic drug. Revista Brasileira de Psiquiatria. 2012; 34(Suppl 1):S104-S117.
  61. Shannon S, Opila-Lehman J. Effectiveness of Cannabidiol Oil for Pediatric Anxiety and Insomnia as Part of Posttraumatic Stress Disorder: A Case Report. Perm J. 2016; 20(4):16-005.
  62. Fuss J, Steinle J, Bindila L, Auer MK, Kirchherr H, Lutz B et al. A runner’s high depends on cannabinoid receptors in mice. Proc Natl Acad Sci USA. 2015; 112(42):13105–8.
  63. Zuardi AW, Rodrigues NP, Silva AL, Bernardo SA, Hallak JEC, Guimarães FS, et al. Inverted U-Shaped Dose-Response Curve of the Anxiolytic Effect of Cannabidiol during Public Speaking in Real Life. Front Pharmacol. 2017; 8:259.
  64. Zuardi AW, Cosme RA, Graeff FG, Guimarães FS. Effects of ipsapirone and cannabidiol on human experimental anxiety. J Psychopharmacol (Oxford). 1993; 7(1 Suppl):82–8.
  65. Corroon J, Phillips JA. A Cross-Sectional Study of Cannabidiol Users. Cannabis Cannabinoid Res. 2018; 3(1):152–61.
  66. Buckner JD, Schmidt NB, Lang AR, Small JW, Schlauch RC, Lewinsohn PM. Specificity of Social Anxiety Disorder as a Risk Factor for Alcohol and Cannabis Dependence. J Psychiatr Res. 2008; 42(3):230–9.
  67. Metrik J, Bassett SS, Aston ER, Jackson KM, Borsari B. Medicinal versus Recreational Cannabis Use among Returning Veterans. Transl Issues Psychol Sci. 2018; 4(1):6–20.
  68. Bergamaschi MM, Queiroz RHC, Chagas MHN, Oliveira DCG de, Martinis BS de, Kapczinski F, et al. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients. Neuropsychopharmacology. 2011; 36(6):1219–26.
  69. Crippa JAS, Derenusson GN, Ferrari TB, Wichert-Ana L, Duran FLS, Martin-Santos R, et al. Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. J Psychopharmacol (Oxford). 2011; 25(1):121–30.
  70. Hundal H, Lister R, Evans N, Antley A, Englund A, Murray RM, et al. The effects of cannabidiol on persecutory ideation and anxiety in a high trait paranoid group. J Psychopharmacol (Oxford). 2018; 32(3):276–82.
  71. Shannon SO-LJ. Cannabidiol Oil for Decreasing Addictive Use of Marijuana: A Case Report. Integrative Medicine. 2015; 14(6):31–5.
  72. Shannon S, Lewis N, Lee H, Hughes S. Cannabidiol in Anxiety and Sleep: A Large Case Series. Perm J. 2019; 23:18–41.
  73. Elms L, Shannon S, Hughes S, Lewis N. Cannabidiol in the Treatment of Post-Traumatic Stress Disorder: A Case Series. J Altern Complement Med. 2019; 25(4):392–7.
  74. Zuardi AW, Morais SL, Huimaraes FS, Mechoulam R. Antipsychotic effect of cannabidiol. The Journal of Clinical Psychiatry. 1995; 56(10):485–6.
  75. Zuardi AW, Hallak JEC, Dursun SM, Morais SL, Sanches RF, Musty RE, et al. Cannabidiol monotherapy for treatment-resistant schizophrenia. 
  76. J Psychopharmacol (Oxford). 2006; 20(5):683–6.
  77. Zuardi AW, Crippa JAS, Hallak JEC, Pinto JP, Chagas MHN, Rodrigues GGR. et al. Cannabidiol for the treatment of psychosis in Parkinson’s disease. 
  78. J Psychopharmacol (Oxford). 2009; 23(8):979–83.
  79. Hallak JEC, Machado-de-Sousa JP, Crippa JA, Sanches RF, Trzesniak C, Chaves C, Bernardo SA, Regalo SC, Zuardi AW. Performance of schizophrenic patients in the Stroop Color Word Test and electrodermal responsiveness after acute administration of cannabidiol (CBD). Revista Brasileira de Psiquiatria. 2010; 32(1):56–61.
  80. Makiol C, Kluge M. Remission of severe, treatment-resistant schizophrenia following adjunctive cannabidiol. Aust NZJ Psychiatry. 2019; 53(3):262.
  81. Leweke FM, Kranaster L, Pahlisch F, Klosterkötter J, Hellmich M, Piomelli D, Koethe D. The efficacy of cannabidiol in the treatment of schizophrenia - a translational approach. Schizophr Bull. 37 2011; 37.
  82. Leweke FM, Piomelli D, Pahlisch F, Muhl D, Gerth CW, Hoyer C, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry. 2012; 2:e94.
  83. Boggs DL, Surti T, Gupta A, Gupta S, Niciu M, Pittman B, et al. The effects of cannabidiol (CBD) on cognition and symptoms in outpatients with chronic schizophrenia a randomized placebo controlled trial. Psychopharmacology (Berl). 2018; 235(7):1923–32.
  84. McGuire P, Robson P, Cubala WJ, Vasile D, Morrison PD, Baron R, TAylor A, Wright S. Cannabidiol (CBD) as an Adjunctive Therapy in Schizophrenia: A Multicenter Randomized Controlled Trial. Am J Psychiatry. 2018; 175(3):225–31.
  85. Bhattacharyya S, Wilson R, Appiah-Kusi E, O’Neill A, Brammer M, Perez J, et al. Effect of Cannabidiol on Medial Temporal, Midbrain, and Striatal Dysfunction in People at Clinical High Risk of Psychosis: A Randomized Clinical Trial. JAMA Psychiatry. 2018; 75(11):1107–17.
  86. Morais H de, Chaves YC, Waltrick APF, Jesus CHA, Genaro K, Crippa JA, et al. Sub-chronic treatment with cannabidiol but not with URB597 induced a mild antidepressant-like effect in diabetic rats. Neurosci Lett. 2018; 682:62–8.
  87. Zuardi A, Crippa J, Dursun S, Morais S, Vilela J, Sanches R, et al. Cannabidiol was ineffective for manic episode of bipolar affective disorder. J Psychopharmacol (Oxford). 2010; 24(1):135–7.
  88. Laux LC, Bebin EM, Checketts D, Chez M, Flamini R, Marsh ED, et al. Long-term safety and efficacy of cannabidiol in children and adults with treatment resistant Lennox-Gastaut syndrome or Dravet syndrome: Expanded access program results. Epilepsy Res. 2019; 154:13–20.
  89. Devinsky O, Nabbout R, Miller I, Laux L, Zolnowska M, Wright S, et al. Long-term cannabidiol treatment in patients with Dravet syndrome: An open-label extension trial. Epilepsia. 2019; 60(2):294–302.
  90. Lattanzi S, Brigo F, Trinka E, Zaccara G, Cagnetti C, Del Giovane C, et al. Efficacy and Safety of Cannabidiol in Epilepsy: A Systematic Review and Meta-Analysis. Drugs. 2018; 78(17):1791–804.
  91. Stockings E, Zagic D, Campbell G, Weier M, Hall WD, Nielsen S, et al. Evidence for cannabis and cannabinoids for epilepsy: a systematic review of controlled and observational evidence. J Neurol Neurosurg Psychiatry. 2018; 89(7):741–53.
  92. Friedman D, French JA, Maccarrone M. Safety, efficacy, and mechanisms of action of cannabinoids in neurological disorders. The Lancet Neurology. 2019; 18(5):504–12.
  93. Manini AF, Yiannoulos G, Bergamaschi MM, Hernandez S, Olmedo R, Barnes AJ, et al. Safety and pharmacokinetics of oral cannabidiol when administered concomitantly with intravenous fentanyl in humans. J Addict Med. 2015; 9(3):204–10.
  94. Arndt DL, Wit H de. Cannabidiol Does Not Dampen Responses to Emotional Stimuli in Healthy Adults. Cannabis Cannabinoid Res. 2017; 2(1):105–13.
  95. Taylor L, Crockett J, Tayo B, Morrison G. A Phase 1, Open-Label, Parallel-Group, Single-Dose Trial of the Pharmacokinetics and Safety of Cannabidiol (CBD) in Subjects With Mild to Severe Hepatic Impairment. J Clin Pharmacol. 2019 Aug; 59(8):1110-1119.
  96. Corroon J, Kight R. Regulatory Status of Cannabidiol in the United States: A Perspective. Cannabis Cannabinoid Res. 2018; 3(1):190–4.
  97. Cadena A. Is CBD Legal? The Legal Status of CBD in 2019; 2019 [cited 2019 May 16]. Available from: URL: https://cbdorigin.com/is-cbd-legal/.
  98. Is CBD Legal In My Country; 2018 [cited 2019 May 16]. Available from: URL: https://nordicoil.eu/wiki/legal-status-cbd-world/.
  99. Moser S. The Legal Situation of Hemp, Marijuana and CBD in the EU in 2019; 2019 [cited 2019 May 16]. Available from: URL: https://straininsider.com/legal-situation-cannabis-europe.
  100. CBD Legality [cited 2019 May 16]. Available from: URL: https://hempnatur.co.uk/legal-status-of-cbd/.
  101. În ce ţări din lume este legal canabidiolul (CBD)?; 2019 [cited 2019 May 16]. Available from: URL: https://www.cbdlife.ro/index.php?route=extension/d_blog_module/post&post_id=18.
  102. Info CBD. Aspecte legale. [cited 2019 May 16]. Available from: URL: http://info-cbd.com/ro/aspecte-legale/.