Posted on

Cbd oil as a treatment for depression

Cannabidiol: A Potential New Alternative for the Treatment of Anxiety, Depression, and Psychotic Disorders

1 Neurosciences Institute, University Miguel Hernández-CSIC, Avda de Ramón y Cajal s/n, San Juan de Alicante, 03550 Alicante, Spain; [email protected] (M.S.G.-G.); [email protected] (F.N.); [email protected] (A.G.); [email protected] (A.A.-O.); [email protected] (F.S.)

2 Subject Area Network of Cooperative Health Research (RETICS), Network for Addiction Disorders, Health Institute Carlos III, MICINN and FEDER, 28029 Madrid, Spain

Francisco Navarrete

1 Neurosciences Institute, University Miguel Hernández-CSIC, Avda de Ramón y Cajal s/n, San Juan de Alicante, 03550 Alicante, Spain; [email protected] (M.S.G.-G.); [email protected] (F.N.); [email protected] (A.G.); [email protected] (A.A.-O.); [email protected] (F.S.)

2 Subject Area Network of Cooperative Health Research (RETICS), Network for Addiction Disorders, Health Institute Carlos III, MICINN and FEDER, 28029 Madrid, Spain

Ani Gasparyan

1 Neurosciences Institute, University Miguel Hernández-CSIC, Avda de Ramón y Cajal s/n, San Juan de Alicante, 03550 Alicante, Spain; [email protected] (M.S.G.-G.); [email protected] (F.N.); [email protected] (A.G.); [email protected] (A.A.-O.); [email protected] (F.S.)

2 Subject Area Network of Cooperative Health Research (RETICS), Network for Addiction Disorders, Health Institute Carlos III, MICINN and FEDER, 28029 Madrid, Spain

Amaya Austrich-Olivares

1 Neurosciences Institute, University Miguel Hernández-CSIC, Avda de Ramón y Cajal s/n, San Juan de Alicante, 03550 Alicante, Spain; [email protected] (M.S.G.-G.); [email protected] (F.N.); [email protected] (A.G.); [email protected] (A.A.-O.); [email protected] (F.S.)

Francisco Sala

1 Neurosciences Institute, University Miguel Hernández-CSIC, Avda de Ramón y Cajal s/n, San Juan de Alicante, 03550 Alicante, Spain; [email protected] (M.S.G.-G.); [email protected] (F.N.); [email protected] (A.G.); [email protected] (A.A.-O.); [email protected] (F.S.)

Jorge Manzanares

1 Neurosciences Institute, University Miguel Hernández-CSIC, Avda de Ramón y Cajal s/n, San Juan de Alicante, 03550 Alicante, Spain; [email protected] (M.S.G.-G.); [email protected] (F.N.); [email protected] (A.G.); [email protected] (A.A.-O.); [email protected] (F.S.)

2 Subject Area Network of Cooperative Health Research (RETICS), Network for Addiction Disorders, Health Institute Carlos III, MICINN and FEDER, 28029 Madrid, Spain

1 Neurosciences Institute, University Miguel Hernández-CSIC, Avda de Ramón y Cajal s/n, San Juan de Alicante, 03550 Alicante, Spain; [email protected] (M.S.G.-G.); [email protected] (F.N.); [email protected] (A.G.); [email protected] (A.A.-O.); [email protected] (F.S.)

2 Subject Area Network of Cooperative Health Research (RETICS), Network for Addiction Disorders, Health Institute Carlos III, MICINN and FEDER, 28029 Madrid, Spain

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (


The potential therapeutic use of some Cannabis sativa plant compounds has been attracting great interest, especially for managing neuropsychiatric disorders due to the relative lack of efficacy of the current treatments. Numerous studies have been carried out using the main phytocannabinoids, tetrahydrocannabinol (THC) and cannabidiol (CBD). CBD displays an interesting pharmacological profile without the potential for becoming a drug of abuse, unlike THC. In this review, we focused on the anxiolytic, antidepressant, and antipsychotic effects of CBD found in animal and human studies. In rodents, results suggest that the effects of CBD depend on the dose, the strain, the administration time course (acute vs. chronic), and the route of administration. In addition, certain key targets have been related with these CBD pharmacological actions, including cannabinoid receptors (CB1r and CB2r), 5-HT1A receptor and neurogenesis factors. Preliminary clinical trials also support the efficacy of CBD as an anxiolytic, antipsychotic, and antidepressant, and more importantly, a positive risk-benefit profile. These promising results support the development of large-scale studies to further evaluate CBD as a potential new drug for the treatment of these psychiatric disorders.

Keywords: cannabidiol, depressive disorders, PTSD, anxiety disorders, schizophrenia, clinical trials, animal studies

1. Introduction

Mental health is currently a major public health challenge worldwide. Approximately one in four people experience some type of mental health problem at least once in their lives. Using disability adjusted life years (DALYs—years lost to ill health and premature death) as the basic measure of impact, mental health problems accounted for 19.5% of the global burden of disease [1]. Depression, alcohol use disorders, and suicide rank in the top 20 causes of DALYs lost due to all diseases at all ages [2]. In many countries, neuropsychiatric disorders account for 35% to 45% of absenteeism at work and are often associated with human rights violations, discrimination and stigma [3].

One major consequence of mental disorders is suicide. Major depressive disorder (MDD), bipolar disorder, schizophrenia (SCZ), and alcohol-use disorders (AUD) are the main risk factors for suicide [4,5,6], which takes approximately 800,000 lives each year. Suicide is the second leading cause of death in people aged 15 to 29 years, and the first in men under 40 years [7].

Limited access to mental health services and to pharmacological and psychotherapeutic treatments, especially in low- and middle-income countries, is a huge problem for these patients. Furthermore, their reluctance to seek help due to fear of being rejected by their family, friends, and community continues to be an obstacle to achieving the highest standard of mental health and well-being.

In contrast to other human diseases, neuropsychiatric disorders are not diagnosed on the basis of objective biological measures, but rather a list of symptoms, according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (DSM-V) or to the International Classification of Diseases, Tenth revision (ICD-10). These procedures result in a high degree of heterogeneity among patients diagnosed with the same psychiatric disease [8]. In part, this is because different psychiatric disorders share common symptoms and display high comorbidity, making it difficult to reach an accurate diagnosis. Together with these problems, current pharmacological and psychotherapeutic treatment options present low efficacy, particularly in medium- to high-severity cases [9,10,11]. The limited knowledge of the neurobiological mechanisms underlying neuropsychiatric diseases makes the pharmacological treatment unspecific, so the same drug groups are used for different mental disorders.

Efforts have been made to characterize the etiopathogenesis of mental disorders and to identify potential biomarkers to guide diagnosis, prognosis and the development of potential new drugs. In this respect, translational research and the advent of new technological approaches, such as neuroimaging and “omics” techniques are driving advances [12].

Thanks to these types of research, it has been possible to identify new neurotransmission systems involved in psychiatric disorders, such as the glutamatergic [13,14,15], GABAergic [16,17,18], and endocannabinoid systems (ECS) [19,20,21,22]. Some of these findings have led to the development and marketing of drugs with new mechanisms of action, such as esketamine, a non-competitive N-methyl- d -aspartate (NMDA) receptor antagonist, approved as therapy for treatment-resistant depression in adults in the USA and Europe [23,24,25]. Another potential drug attracting attention is cannabidiol, one of the major compounds present in the plant Cannabis sativa [26]. Animal models have shown that cannabidiol (CBD) displays anxiolytic, antidepressant, antipsychotic, antiepileptic and neuroprotective properties, suggesting its potential therapeutic use for several psychiatric, neurological and drug-use disorders. CBD was approved in 2018 by the U.S. Food and Drug Administration (FDA) after it was shown to be effective and safe for treating seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients aged two years and older. This has accelerated research into its use for additional disorders. In this review, we summarize the main results provided by animal models and preliminary clinical trials conducted to date on the efficacy of CBD for treating anxiety, depressive disorders, post-traumatic stress disorder (PTSD), and SCZ. The hypothesized mechanisms of action by which CBD potentially produces its effects on these disorders are also explored. Although our results support the efficacy and safety of CBD, large-scale clinical studies are required before its final approval for human clinical use in these psychiatric disorders.

2. Introduction to the Phytocannabinoid Cannabidiol: Chemical Structure, Pharmacokinetics and Pharmacodynamics Profile

Over the last decades, several investigations have focused on characterizing the biological and molecular bases involved in the medical properties of the plant Cannabis sativa. To date, approximately 120 cannabinoids have been identified and classified into 11 groups based on their chemical structure: ∆ 9 -trans-tetrahydrocannabinol (∆ 9 -THC), cannabigerol, cannabicromeno, cannabidiol (CBD), cannabinodiol, cannabielsoin, cannabicyclol, cannabinol, cannabitriol, and a last group in which several cannabinoids with different chemical structure are included [27]. The main compound present in the plant is Δ 9 -THC, characterized by Gaoni and Mechoulam in 1964, responsible for the reinforcing properties of cannabis [28]. CBD is the following majority compound isolated for the first time by Adams and cols. in 1940 [29], although its chemical structure was not fully characterized until 1963 [30].

2.1. Overview of CBD Chemical Structure

CBD has a chemical structure similar to Δ 9 -THC; however, both differ on the spatial conformation, fact that helps to explain the differences observed in relation to their physiopharmacological properties. Δ 9 -THC presents a planar structure that allows binding to the rCB1. In contrast, CBD has a slightly angular structure that produces a steric hindrance that hampers its ability to bind to this receptor [31]. As consequence, CBD displays 100 times less affinity for rCB1 than Δ 9 -THC [32]. This may justify the absence of reinforcing properties of CBD as opposed to Δ 9 -THC [31]. In fact, data achieve to date show that CBD did not induce euphoria or intoxication in healthy volunteers [33,34,35]. Animal studies suggested that CBD may not present reinforcing properties since it did not exhibit drug abuse potential in the conditioned place preference, spontaneous withdrawal and oral self-administration, common animal models used to evaluate the abuse potential of drugs [36,37,38].

2.2. Overview of CBD Pharmacological Profile

During the last years, many researchers studied the potential therapeutic utility of CBD in different diseases pointing out its possible antimicrobial, immunosuppressive, antiemetic, anti-resorptive, spasmolytic, antitumor, antifibrotic, anti-inflammatory, and anticonvulsant efficacy [39,40,41,42]. Some of these properties were further explored leading to its approval for treating spasticity in multiple sclerosis (Sativex) [43] and more recently for treating seizures associated with Lennox-Gastaut or Dravet syndromes in children [44]. Furthermore, other reports suggest that CBD may be useful for treating neurodegenerative [45,46,47,48] and psychiatric disorders [39,49,50,51]. Both animal and clinical studies pointed out that CBD presents anxiolytic, antidepressant, and antipsychotic properties, this will be further explored in detail in the following sections.

2.2.1. Pharmacokinetics

As the majority of phytocannabinoids, CBD presents high liposolubility (Ko/w: 6–7) [52]. The oral administration of CBD presents a poor bioavailability (6–19%) [53] mainly due to its extensive first-pass metabolism. To increase its oral availability, it is recommended to administer CBD together with food. Other routes of administration such as inhalation or intravenous provide better concentrations and more quickly [53,54]. Table 1 summarizes the main pharmacokinetics properties of CBD.

Table 1

Main pharmacokinetics parameters of cannabidiol (CBD).

Parameter Values References
Ko/w 6–7 [52]
Oral bioavailability 6–19% [53]
Cmax 3 ± 3.1 μg/L [55,56,61]
Tmax 2.8 ± 1.3 h [55,56,61]
Vd 32 L/kg [55,56,57]
t1/2 1.4–10.9 h (oromucosal spray)
2–5 h (oral chronic administration)
24 h (intravenously)
31 h (smoked)
Plasma clearance rate 960–1500 mL/min [53,54,55]

Ko/w: octanol water partition coefficient; Cmax: maximum concentration; Tmax: maximum time; Vd: volume of distribution; t1/2: half-life.

CBD presents a high distribution (Vd: 32 L/kg) with great accumulation in brain and adipose tissues, also due to its high liposolubility [55,56,57]. CBD is metabolized in the liver by different mechanisms (including oxidation, β-oxidation, hydroxylation, glucuronide conjugation and epoxidation) [53,56,58,59,60] and eliminated in the urine unmetabolized or as a glucuronide derivative [53,59]. There are different CBD metabolites (around 53), some of them under study to determine its potential involvement in some of its actions.

Finally, evidences about its safety and tolerability are limited to preclinical and clinical studies. No significant side effects have been described [62,63]. Diarrhea, somnolence and decreased appetite are the most commonly side effects reported in the clinical trials performed in children with Lennox-Gastaut syndrome [44].

It is also interesting to highlight that CBD is a potent competitive inhibitor of certain cytochrome P450 isoforms (CYP2C and CYP3A) increasing the risk of drug-interactions when is given together with other drugs metabolized by these enzymes [53,59,60].

2.2.2. Pharmacodynamics

CBD has the peculiarity of acting on more than 65 key targets, including the serotonin 1A receptor (5-HT1A), the cannabinoid-related receptors G protein-coupled receptor 55 (GPR55), transient receptor potential vanilloid 1 (TRPV1), type 1 equilibrative nucleoside transporter (ETN1), fatty acid-binding protein (FABP), nuclear factor erythroid 2-related factor 2 (NRF2), voltage-activated T-type calcium channels, adenosine and glycine receptors, mu and delta opioid receptors, and voltage-dependent anion channel 1 (VDAC1), among others [64].

The first in vitro studies revealed that CBD, at sub-micromolar concentrations, acts as an antagonist of CB1r and as an inverse agonist of CB2r [65]. However, subsequent in vivo studies showed that CBD presents low affinity for both receptors [66,67,68]. CBD seems to act more like a negative allosteric modulator of CB1r, modifying the power and efficiency with which endogenous cannabinoids activate the receptor [69]. In contrast, some studies indicated that CBD inhibits reuptake of anandamide (AEA) and its metabolization by the fatty acid amide hydrolase (FAAH), increasing the endogenous cannabinoid tone, a mechanism suggested by which CBD may indirectly activates CB1r [70].

In the case of CB2r, CBD acts as an inverse agonist but only at very high concentrations [71]. Moreover, CBD also acts as an antagonist of cannabinoid-related receptors as the GPR55 considered one of the main targets by which CBD exerts its properties [72,73,74].

Additional targets, including key elements of the opioidergic, dopaminergic, glutamatergic and serotonergic systems have been associated with the actions of CBD. CBD inhibits the reuptake of dopamine and glutamate in vitro [75,76]. Besides, CBD is an allosteric modulator of mu and delta opioid receptors [77,78] and a partial agonist of dopamine D2 receptors, reinforcing its potential as an antipsychotic [79,80].

Interestingly, additional in vitro and in vivo studies revealed that CBD induces physiological responses trough 5-HT1A receptors [27,81], a serotoninergic key target involved in anxiety and depression.

3. Role of CBD on Anxiety and Depressive Disorders: Animal and Human Studies

3.1. Current Scenario

Today, over 260 million people worldwide suffer from anxiety and mood disorders, affecting an estimated 25% of the European population. Apart from its high incidence, these psychiatric disorders present high rates of prevalence, leading to a substantial reduction in the quality of life and disruptions in work/school performance, family/social life and common daily activities. In fact, anxiety and mood disorders are the main mental health causes for years lived with disability (YLD), standing at 302 YLD and 850 YLD per 100,000 inhabitants in Europe, respectively [82]. Consequently, both psychiatric disorders entail high economic costs, of around EUR 170 billion per year in Europe.

According to the DSM-V, anxiety disorders are classified into generalized anxiety disorder, panic disorder, specific or social phobias and social anxiety disorder (SAD) [83]. All types share common symptoms, including feelings of uneasiness, panic and fear; sleep problems; not being able to stay calm; being cold and/or sweaty; shortness of breath; heart palpitations; dry mouth; nausea; and avoidance of situations. Depressive disorders present high complexity and may be classified into disruptive mood dysregulation disorder (MDD), persistent depressive disorder (dysthymia), premenstrual dysphoric disorder, substance/medication-induced depressive disorder, associated with another medical condition, other specified depressive disorder and unspecified depressive disorder. Patients suffering from depressive disorders experience emotional, cognitive, physical and behavioral alterations including sadness, anxiety, guilt, irritability, impaired memory, thoughts of death and suicide, loss of motivation, disturbed sleep or appetite, tiredness, neglect of responsibilities, changes in personal appearance, and withdrawal from others [84]. The severity of depressive disorders, assessed by clinician-administered depression assessment scales, such as the Hamilton Depression Rating Scale, varies from one patient to another, with moderate-severe cases presenting worse prognosis [85]. Anxiety and depressive disorders are strongly associated with high rates of comorbidity (around 50%) [86], which can reach 90% in psychiatric patients [87,88]. Comorbidity worsens clinical management and consequently, prognosis; it increases resistance to treatment and recurrence, and it dramatically heightens the risk of suicide.

From a pharmacological point of view, anxiolytics and antidepressants are used in the clinical management of both mental disorders. For instance, benzodiazepines, the most common anxiolytic drug, is useful at the beginning of pharmacological treatment of depressive disorders [89]. Similarly, buspirone (a serotonin 5-HT1A receptor agonist) is an anxiolytic for treating depressive disorders [90]. Antidepressants, especially selective serotonin reuptake inhibitors, are the most commonly used first-line treatment for anxiety disorders [91]. Although neurochemical alterations underlying anxiety and depression still remain to be elucidated, the beneficial effects found during the co-administration of both types of drugs suggest the involvement of shared neurobiological pathways.

Despite the available pharmacological treatment options, efficacy is limited, especially for preventing relapse and recurrence [92]. For example, one in three patients diagnosed with MDD develops resistance to antidepressant drugs. More importantly, current pharmacological treatments do not improve the cognitive dysfunctions associated with this mental disorder, even when combined with psychotherapy [93,94]. Conversely, the side effects of these medications, such as weight gain, loss of sexual desire and others, affect the risk-benefit ratio. Therefore, it is necessary to find new pharmacological alternatives to improve treatment outcomes for such psychiatric disorders without the burden of disabling side effects. In this respect, published animal and clinical studies, whose main results are detailed below, provide information supporting the anxiolytic and antidepressant properties of CBD.

3.2. Results from Animal Studies

The potential anxiolytic and antidepressant properties of CBD have been examined in several animal models since the late 1970s. Although preliminary findings were contradictory [95,96], subsequent dose-response studies showed that CBD induced an anxiolytic-like effect, which followed an inverted U-shaped curve, resulting effective at intermediate doses but not at low or high doses [97,98,99]. CBD also attenuated physiological and behavioral responses to stressful situations, reducing restraint stress along with cardiovascular and anxiogenic-like responses [100] by blocking the activation of the hypothalamus-pituitary-adrenal (HPA) axis [101] and activating the 5-HT1A receptor [100]. Additional results from studies carried out using the Vogel-conflict and the marble-burying tests showed that CBD reduced anxiety- and compulsive-like behaviors, respectively [49,102,103] ( Table 2 ). Curiously, cannabinoid CB1 receptor (CB1r), but not 5-HT1A receptor, appears to mediate such effects [104]. The administration of CBD also abolished anxiety-like behavior, hyperthermia and hyperlocomotion induced by tetrahydrocannabinol (THC), modifying c-Fos expression in brain regions (medial preoptic nucleus and lateral periaqueductal gray) [105]. In contrast, CBD failed to modify anxiety induced by repeated administration of THC [106].

Table 2

Summary of cannabidiol studies on animal models of anxiety and depression.

Strain Doses and Route of Administration Effect and Test Reference
Wistar rats 1 mg/kg; i.p.; acute Anxiolytic/SI [99]
2.5, 5, 10.0 mg/kg; i.p.; acute Anxiolytic/EPM [97]
7–30 mg/kg; i.p.; acute Antidepressant/FST [107]
5 and 15 mg/kg, i.p.; acute No effect/SI [99]
1, 10, 20 mg/kg; i.p.; acute Anxiolytic/restraint stress [100]
10 mg/kg; i.p.; acute
10 mg/kg; i.p.; 28 days
Anxiolytic/THC-induced conditioned emotional responses
20 mg/kg; i.p.; acute No effect/EPM [97]
3–30 mg/kg; i.p.; acute ↓ freezing behavior/CFC [109]
30 mg/kg; p.o.; acute Antidepressant/FST [110]
30 mg/kg; i.p.; acute and chronic Antidepressant/FST [111]
100 mg/kg; i.p.; acute No effect/GSP [95]
30 nmol/μL; dlPAG; acute Anxiolytic/EPM and VCT [112]
30 and 60 nmol/μL; PAG; acute Anxiolytic/ETMPanicolytic/ES dPAG [113]
30 and 60 nmol/μL; BNST; acute Anxiolytic/restraint stress [114]
30 nmol/μL; intracisternal; acute Anxiolytic/restraint stress [115]
30 nmol/μL; PL; acute Anxiolytic/EPM [116]
2 μg/μL; icv and mPFC; acute ↓ freezing behavior/CFC [117]
15 or 30 nmol/μL; IL-PFC; acute ↑ freezing behavior/CFC [118]
30 nmol/μL; PL-PFC; acute ↓ freezing behavior/CFC [118]
0.4 μg; IL-PFC; 3 days Improve extinction/CFC [119]
10–30 pmol; dorsal HIP; acute ↓ Memory consolidation/CFC [120]
10 mg/kg; bilateral intra-PFC ↓ Memory consolidation/CFC [109]
10–60 nmol/side; intra-IL or intra-PL; acute Antidepressant/FST [121]
Sprague-Dawley rats 10 mg/kg; i.p.; 7 days
30 mg/kg; i.p.; 7 days
Antidepressant/FST [122]
Lister-hooded rats 10 mg/kg; i.p.; 14 days ↑ Freezing behavior/CFC [123]
Flinders Sensitive rats 7–30 mg/kg; i.p.; acute
30 mg/kg; p.o.; acute
Antidepressant/FST [107]
Flinders Resistant rats 7–30 mg/kg; i.p.; acute Antidepressant/FST [107]
Wistar Kyoto rats 30 mg/kg; p.o.; acute Antidepressant/FST [110]
30 mg/kg; i.p.; acute Antidepressant/SP and OR [124]
Spontaneously Hypertensive rats 1–60 mg/kg; i.p. No effect/SI [99]
DBT rats 30 mg/kg; i.p.; sub-chronic Antidepressant/FST [125]
NGL rats 0.3 mg/kg; i.p.; acute Antidepressant/FST [125]
C57Bl/6J mice 1 mg/kg; i.p.; acute
1 mg/kg; i.p.; 21 days
No effect/OF and EPM Anxiolytic/LDB [126]
1, 10 and 10 mg/kg; i.p.; acute No effect/CFC [127]
30 mg/kg; i.p.; acute ↓ freezing behavior/CFC [127]
5, 10 or 20 mg/kg; i.p.; acute No effect/EPM [128]
10 mg/kg; i.p.; acute No effect/OF
No effect/THC-induced anxiety
15 mg/kg; i.p. (+ FLX, 3 mg/kg; i.p.); acute Anxiolytic/MBT [103]
20 mg/kg/day; i.p.; 3 weeks Anxiolytic/PTSD model [129]
20 mg/kg; i.p.; 6 weeks
20 mg/kg; i.p.; 3 weeks
No effect/LBD and OF
15, 30 and 60 mg/kg; i.p.; acute Anxiolytic/MBT *
* (even 7 days after its administration)
30 mg/kg; i.p.; chronic
30 mg/kg; i.p.; 14 days
Anxiolytic and antidepressant/CMS
50 mg/kg; i.p.; 21 days Anxiolytic/OF [126]
50 mg/kg; i.p.; acute No effect/OF and EPM [126]
50 mg/kg; i.p.; acute
50 mg/kg; i.p.; 3 days and 10 mg/kg; 11 days
ICR mice
Swiss Albino
0.5, 1, 2.5, 5, 10 and 50 mg/kg; i.p.; acute Anxiolytic/EPM [98]
0.01, 0.1 and 100 mg/kg; i.p.; acute No effect/EPM [98]
3 mg/kg; i.p.; acute Anxiolytic/EPM [133]
10 or 30 mg/kg; i.p.; acute No effect/EPM [133]
3, 10 or 30 mg/kg; i.p.; chronic No effect/EPM [133]
7–30 mg/kg; i.p.; acute Antidepressant/FST [107]
10 mg/kg; i.v.; 21 days
100 mg/kg; p.o.; 21 days
Antidepressant/CMS [134]
0.7 mg/kg; i.p.; (plus 0.1 mg/kg; i.p. 5-AZAD or RG108) Antidepressant/FST [135]
7 mg/kg; i.p. (plus FLX 5 mg/kg; i.p. or DES 2.5 mg/kg; i.p.) Antidepressant/FST [136]
10 mg/kg; i.p.; acute Antidepressant/FST [135]
30 mg/kg; i.p.; acute Antidepressant/FST [137]
Swiss Webster mice 2 and 100 mg/kg; i.p.; acute No effect/FST [138]
200 mg/kg; i.p.; acute Antidepressant/FST [138]
DBA/2 mice 2, 100 and 200 mg/kg; i.p.; acute No effect/TST [138]

BNST: bed nucleus of the stria terminalis; CFC: contextual fear conditioning; CMS: chronic mild stress; DBT: diabetic rats; EPM: elevated plus maze; ES dPAG: electrical stimulation dorsal periaqueductal gray; ETM: elevated T-maze; FLX: fluoxetine; FST: forced swim test; GSP: Geller-Seifter paradigm; HIP: hippocampus; icv: intracerebroventricular; IL: infralimbic; IL-PFC: infralimbic prefrontal cortex; i.p.: intraperitoneal; LDB: light dark-box; MBT: marble-burying test; mPFC: medial prefrontal cortex; NGL: normoglycemic rats; OF: open field; OR: object recognition; PAG: periaqueductal gray; PFC: prefrontal cortex; PL: prelimbic; PL-PFC: prelimbic prefrontal cortex; p.o.: oral administration; PTSD: post-traumatic stress disorder; SI: social interaction; SP: sucrose preference; TST: tail suspension test; VCT: Vogel conflict test; ↓: decrease; ↑: increase.

Complementary results indicated that the strain and pattern of administration (single and repeated) may affect CBD actions. In male C57BL/6 mice and spontaneously hypertensive rats, CBD failed to induce any effect [99,105]. Regarding the pattern of administration, chronic treatment with CBD induced an anxiolytic-like effect, whereas acute administration did not [126]. However, another study reported the opposite results [133].

Other authors have evaluated the influence of age and gender in CBD anxiolytic effects. Chronic CBD administration produced an anxiolytic-like effect when given to mice at 5 months, but not at 3 months of age [130]. However, this group of mice significantly reduced its locomotor activity. This may act as a confounding variable when interpreting the results. In contrast, in another study no effects were found in either adolescent or in adult male mice. Moreover, CBD increased anxiety in adult female mice, suggesting sex-dependent effects [128].

Administering CBD also produced interesting findings in specific brain regions. Microinjections into the bed nucleus of stria terminalis [114] and periaqueductal gray [112,113] showed anxiolytic and panicolytic-like effects, respectively. On the other hand, intracisternal or intra-prelimbic medial prefrontal cortex injection of CBD blocked the autonomic activation and anxiogenic-like responses induced by restraint stress [115,139]. These effects appear to be related with 5-HT1A receptors [112,113,139].

In the fear-conditioning model, a type of associative learning task, acute administration of CBD reduced contextual fear- and anxiety-related behaviors [127,140], whereas chronic administration induced just the opposite [123]. Similarly, microinjections/infusions on specific brain regions, such as intracerebroventricular [117] and prelimbic medial prefrontal cortex, reduced freezing and anxiety [118]. However, infralimbic prefrontal cortex infusion showed contradictory results, increasing freezing [118] or facilitating fear extinction [119], depending on the total number of microinjections given. Indeed, CBD seems to disrupt aversive memory consolidation [109,120], involving anandamide, CB1r, CB2r, and peroxisome proliferator-activated receptor gamma (PPARγ) receptors in a time-dependent manner [70,119,120]. CBD also reduced the influence of PFC on corticolimbic circuits, modulating dopamine and immediate gene expression (c-fos and zif-268 proteins) [118,141], and it functionally modified the mesolimbic circuit through the direct activation of 5-HT1A receptors [142,143].

The efficacy of CBD for reducing fear conditioning, together with its anxiolytic properties, stimulated the development of studies focused on evaluating its potential efficacy in animal models of PTSD, a psychiatric disorder currently classified as trauma and a stressor-related disorder. Acute or sub-chronic administration of CBD reduced the long-lasting anxiogenic-like effects induced by predator stress exposure, suggesting the intervention of 5-HT1A receptors in these actions [144,145,146]. Furthermore, a new mice model of PTSD conducted by our research team showed that the administration of CBD alone or in combination with sertraline significantly reduced fear conditioning, anxiety-like behaviors and long-term gene expression alterations in the HPA axis, ECS and serotonin systems. These results support the efficacy of CBD, reducing the intense and long-lasting effects of the PTSD model [129].

Along with its anxiolytic properties, CBD displayed antidepressant efficacy in animal models of depression, inducing an antidepressant-like effect when given alone [137] or in combination with sub-effective doses of the antidepressants fluoxetine or desipramine [136], mainly through the activation of 5HT1A serotonergic receptors [137]. More importantly, CBD showed a rapid and sustained antidepressant effect. A single dose of CBD induced a dose-dependent antidepressant-like effect in Swiss mice, even 7 days after its administration. Similar results were found in Flinders Sensitive and Flinders Resistant Line (FSL/FRL) rats and in Wistar rats [107]. Neuroplasticity changes were also associated, since synaptophysin, postsynaptic density protein 95 (PSD95) and brain-delivered neurotrophic factor were increased on the pre-frontal cortex (PFC) and hippocampus (HIPP) after CBD administration. This effect involves the activation of tropomyosin receptor kinase B/ mammalian target of rapamycin (TrkB/mTOR) signaling [107]. Moreover, treatment with DNA methylation inhibitors (5-AzaD and RG108) and CBD induced an antidepressant-like effect, preventing the alterations induced by stress exposure on DNA methylation and DNA methyltransferase (DNMT) activity in the HIPP and PFC [135]. This study supports the involvement of epigenetic mechanisms on CBD antidepressant properties.

Additional results indicated that the doses and the strain of rodent used may modulate the effects of CBD. In Swiss Webster mice, only the highest dose induced an antidepressant-like effect, whereas no effect was observed in DBA/2 mice [138]. Furthermore, a recent study suggested that the actions of CBD may be gender-specific, since antidepressant-like effects were found in male but not in female FSL rats [110].

Potential differences due to the pattern of CBD administration (acute vs. chronic) were also explored. In C57BL/6J mice submitted to an olfactory bulbectomy, a rodent model of depression, single and chronic administration of CBD induced anxiolytic and antidepressant-like effects. These behavioral alterations were accompanied by increases of serotonin and glutamate levels in the PFC and 5-HT1A receptor function on the dorsal raphe, CA1–CA2 fields of the HIPP, amygdala and medial PFC [132]. The study further supported the involvement of the 5-HT1A receptor rather than CB1r on CBD effects. Similar antidepressant-like effects were observed in Wistar rats [111] and Wistar–Kyoto rats as well as in a genetic model of depression [124] and in animal models displaying depressive-like symptoms such as the diabetic and normoglycemic rats [125]. Moreover, specific brain site microinjections of CBD, e.g., intra-IL or intra-prelimbic, induced antidepressant-like effects in Wistar rats involving 5-HT1A and CB1 receptors [121].

The administration of CBD displayed antidepressant-like effects at different doses in adolescents and adult male Sprague-Dawley rats [122]. The long-lasting effects of CBD were different: 2 days for adolescent and 21 days for adult rats. Therefore, the outcome appears to depend on the age at which the CBD treatment was administered. Taken together, these findings are relevant to further explore efficacy and safety depending on the patient’s age and gender.

The effects of CBD were also evaluated for chronic unpredictable mild stress, an animal model that involved the presentation of repeated mild stressors for several weeks. Following this exposure, rodents exhibited depressive-like behavioral alterations, mainly a persistent reduction of their responsiveness to pleasurable stimuli, such as a palatable sucrose solution [147,148]. In this model, different doses and routes of CBD administration prevented anxiogenic and depressogenic-like behaviors and displayed a neuroprotective effect [116,134,149] through CB1r and CB2r [116,131]. Indeed, culture cell studies showed that CBD induced progenitor proliferation and cell cycle progression, depending on CB1r and CB2r activation and anandamide increase [149]. Overall, these results support the involvement of the endocannabinoid system in the antidepressant-like effects of CBD.

3.3. Results from Clinical Studies

3.3.1. Clinical Studies Focused on Anxiety Disorders

The first clinical trials evaluating the anxiolytic properties of CBD were conducted in 1974 and 1982, suggesting that CBD alleviates THC-induced anxiety in healthy male volunteers [150,151] ( Table 3 ). Subsequently, additional double-blind studies further evaluated the effects of CBD on healthy volunteers. Oral CBD administration decreased anxiety in healthy subjects exposed to the simulated public speaking test [152]. Accordingly, in another double-blind study, CBD significantly reduced subjective anxiety, evaluated by the Visual Analogue Mood Scale (VAMS), and increased mental sedation. These effects were associated with less activity on the medial temporal cluster (left amygdala-hippocampal complex, extending into the hypothalamus), and the left posterior cingulate gyrus, and with high activity on the left parahippocampal gyrus [153].

Table 3

Main outcomes achieved from clinical trials of CBD for anxiety, PTSD and depressive disorders.

Clinical Condition Clinical Trial Design Sample Size and Gender Doses and Route of CBD Administration Outcomes References
Healthy volunteers Double-blind randomized placebo-controlled trial 40 M
(N = 5/group)
15–60 mg dissolved in ethanol and orange juice; p.o.; acute ↓ THC-induced anxiety [150]
Healthy volunteers Double-blind randomized placebo- and diazepam-controlled trial 8
(6 M/2 F)
0.5 mg/kg; dissolved in ethanol and artificial lemon juice; p.o.; acute ↓ THC-induced anxiety [151]
Healthy volunteers Double-blind randomized placebo-controlled trial 40
(18 M/22 F)
300 mg dissolved in corn oil and given in gelatin capsules; p.o.; acute Stimulated public speaking test [152]
Healthy volunteers Double-blind randomized placebo-controlled trial 10 M
(N = 5/group)
400 mg dissolved in corn oil and given in gelatin capsules; p.o.; acute ↓ Subjective anxiety
↑ Mental sedation
Healthy volunteers (Cannabis sativa users) Double-blind, randomized, placebo-controlled trial, repeated-measures within-subject vs. placebo 15 M 600 mg; gelatin capsules; p.o.; 3 separate sessions No behavioral or regional brain activation [154]
Healthy volunteers Double-blind, repeated-measures vs. placebo 16 M 600 mg; opaque capsules; p.o.; 3 consecutive sessions No psychotic symptoms, mental sedation, intellectual impairment or physical sedation [35]
Treatment-naïve SAD patients Double-blind randomized placebo-controlled trial 10 M 400 mg dissolved in corn oil and packed inside gelatin capsules; p.o.; acute ↓ Subjective anxiety
Changes in regional cerebral flow
Treatment-naïve SAD patients Double-blind randomized placebo-controlled trial 12 M 600 mg dissolved in corn oil and packed inside gelatin capsules; p.o.; acute ↓ Subjective anxiety
↓ Cognitive impairment
Psychiatric patients with primary concern of anxiety or poor sleep Large retrospective case series (adjunct to usual treatment) 47 anxiety (28 M/19 F)
25 poor sleep (16 M/9 F)
25 mg/day to 50–75 mg/day; capsule; 1–3 months ↓ Anxiety
Improved sleep disturbances
Non-clinical volunteers with high paranoid traits Double-blind randomized placebo-controlled trial 32 (16 M/16 F)
N = 8/group
600 mg; hard gelatin capsule; p.o.; acute ↑ Anxiety
No effects persecutory ideation
Cannabis use disorder Double-blind randomized placebo-controlled trial 51
CBD N = 27 (18 M/9 F)
Placebo N = 24 (21 M/3 F)
Nabiximols (CBD 2.5 mg plus THC 2.7 mg); 6 days ↓ Anxiety
↓ Craving
↓ Depression
Volunteers selected for high and low frequency of cannabis use and schizotypy (males and females Double-blind, randomized placebo-controlled trial 48
LSS group N = 12 (9 M:3 F)
LHS group N = 12 (7 M:5 F)
HLS group N = 12 (11 M/1 F)
HHS group N = 12 (7 M:5 F)
16 mg, formulated in alcohol solution; vaporization Improved emotional processing [160]
Drug-abstinent patients with heroin user disorder Double-blind randomized placebo-controlled trial 42
CBD 400 mg N = 14 (12 M/2 F)
CBD 800 mg N = 13 (11 M/2 F)
Placebo N = 15 (12 M/3 F)
400 (n = 14) or 800 mg (n = 13); once daily; oral solution Epidiolex; acute (1, 2 or 24 h) and Short-term administration (3 consecutive day) ↓ Anxiety
↓ Craving
↓ Heart rate
↓ Salivary cortisol levels
Healthy volunteers Double-blind, pseudo-randomized, placebo-controlled, repeated-measures, within-subject design 15 M 600 mg; capsules; p.o.; 3 consecutive sessions Altered prefrontal-subcortical connectivity/response to fearful faces [162]
PTSD Open-label 11
(8 F/3 M)
Flexible doses: starting at 25 to 48.64 mg/day; capsule or liquid spray; 8 weeks ↓ PTSD severity [163]
Regular cannabis users Open-label 18
(14 M/4 F)
200 mg/day (99.5% pure crystalline of herbal origin); gelatin-coated capsules; 10 weeks ↓ Depressive
↓ Psychotic symptoms
Regular cannabis users Open-label 20
(16 M/4 F)
200 mg/day (99.5% pure crystalline of herbal origin); gelatin-coated capsules; 10 weeks ↓ Depressive symptoms
↓ Psychotic symptoms
↑ Attentional switching
↑ Verbal learning
↑ Memory

CBD: cannabidiol; F: Female; HHS: heavy high schizotypy; HLS: heavy low schizotypy; LHS: light high schizotypy; LLS: light low schizotypy; M: Male; PTSD: post-traumatic stress disorder; SAD: social anxiety disorder; THC: tetrahydrocannabinol; ↓ reduction of; ↑ increase of.

In a double-blind randomized placebo-controlled trial using a repeated-measures within-subject design in healthy volunteers who had used Cannabis sativa 15 times or less, CBD did not induce any behavioral or regional brain activation in the verbal learning task compared to placebo, in contrast to THC [154]. Similarly, a crossover, double-blind, repeated-measures design in 16 healthy male volunteers revealed that, unlike Δ 9 -THC, CBD did not induce psychotic symptoms, mental sedation, intellectual impairment, or physical sedation compared to placebo [35].

The anxiolytic efficacy of CBD was evaluated in patients diagnosed with anxiety disorders. In treatment-naïve patients with SAD, CBD reduced subjective anxiety, inducing changes in regional cerebral flow [155,156]. A large retrospective case series including psychiatric patients whose primary concern was anxiety or poor sleep suggested that the administration of CBD decreased anxiety rapidly and in a sustained manner. CBD also improved sleep disturbances within the first month of treatment but with fluctuations over the total three-month period evaluated [157]. However, in a clinical trial performed in non-clinical volunteers with high paranoid traits, CBD increased anxiety and had no effects on persecutory ideation in a controlled three-dimensional (3D) virtual-reality scenario [158]. These results suggest, in contrast to those observed in SAD patients, that CBD failed to display an anxiolytic-like effect in healthy volunteers with high paranoid traits.

Additional results supporting the anxiolytic properties of CBD come from clinical trials suggesting that nabiximols, a medication containing THC (2.7 mg) and CBD (2.5 mg) and used to treat spasticity in multiple sclerosis, reduced anxiety, and craving in patients with cannabis use disorder [159]. A previous case report indicated that oral CBD administration reduced cannabis withdrawal, anxiety and dissociative symptoms [166]. Besides, acute CBD vaporization improved emotional processing affect recognition and prevented the impairment of ambiguous face recognition induced by THC [160]. Similarly, in a double-blind, randomized, placebo-controlled trial in heroin users, CBD reduced anxiety and craving after its acute administration, with effects that remained stable even after 7 days [161].

Neuroimaging studies revealed that the administration of CBD altered prefrontal-subcortical connectivity during the response to fearful faces. The connection between anterior cingulate cortex-amygdala was disrupted after the administration of CBD. This finding was associated with a concurrent electrophysiological effect, pointing out both brain regions as potential key targets underlying the anxiolytic actions of CBD [162].

Additional ongoing trials have been identified. An open-label clinical trial ( > NCT02548559) is evaluating the effects of CBD to reduce anxiety in adults (16 participants) [167]. CBD will be given as a sublingual tincture delivered from the whole plant in a total daily dose of 30 mg for 4 weeks. Changes in anxiety behavior will be measured every week by using different scales. Following this phase 1 trial, a double-blind phase 2 clinical trial ( > NCT04286594) will begin following the same procedure in 75 patients diagnosed with anxiety [168].

In addition, a placebo-controlled phase 3 trial ( > NCT03549819) in adults is assessing the efficacy of CBD (oil capsules; flexibly dosed at 200-800 mg per day for 4 weeks) to reduce symptoms in patients diagnosed with generalized anxiety disorder, SAD, panic disorder, or agoraphobia [169]. Similarly, the goal of the pilot trial ( > NCT04267679) is to show the efficacy of CBD (soft gel capsules; up to a total of 100 mg/day; 12 weeks) to decrease anxiety and sleep disturbances in patients diagnosed with anxiety [170].

3.3.2. Clinical Studies Focused on Stress-Related Disorders: PTSD

Today, there is a growing number of clinical trials assessing the efficacy of CBD to modulate the severity of PTSD. In an open-label clinical trial carried out in adults diagnosed with PTSD, CBD plus psychiatric medications and psychotherapy reduced the severity of PTSD symptoms after 8 consecutive weeks of treatment [163]. In addition, a double-blind randomized clinical trial ( > NCT04197102), designed to evaluate the efficacy of CBD (300 mg/day for 8 weeks) to reduce PTSD severity, has been recruiting patients since January 2020. Study completion is expected by May 2024 [171]. Moreover, another clinical trial, expected to finish in August 2021, is assessing the efficacy of CBD (600 mg/day for 6 weeks) for reducing alcohol intake in people with PTSD ( > NCT03248167) [172]. On the other hand, a placebo-controlled clinical trial ( > NCT02759185) is evaluating the efficacy of 4 types of smoked CBD-containing marijuana (up to 1.8 g per day for 3 weeks) for reducing symptoms severity, including anxiety and depression, in 76 military veterans with PTSD [173].

3.3.3. Clinical Studies Focused on Depressive Disorders

Evidence of CBD’s antidepressant actions in humans is still scarce. In a clinical trial carried out in patients with chronic pain, high doses of nabiximols significantly reduced mood state [174]. Interestingly, oral CBD significantly decreased depressive and psychotic symptoms in cannabis users, restoring the harmful effects of cannabis on the subiculum and CA1 sub-regions of the HIPP [164]. Similar results were observed in frequent cannabis users in whom oral CBD reduced depressive- and psychotic-like symptoms and improved attentional switching, verbal learning, and memory [165]. Accordingly, nabiximols, used as an agonist replacement therapy during cannabis withdrawal, significantly reduced depression [159]. More recently, CBD users (n = 2409) reported mood-improving effects in several medical conditions in an online survey. The study did not discriminate between pure CBD and marijuana-derived CBD products with different components in the formulations [175].

An ongoing double-blind, randomized, placebo-controlled clinical trial ( > NCT03310593) is evaluating the effects of CBD (150–300 mg/day for 12 weeks) to reduce anxiety and depression in patients with bipolar disorder (estimated enrollment: 100 participants) [176]. The estimated study completion date is April 2022.

Taken together, these studies provide preliminary evidence supporting the efficacy and safety of CBD on these pathologies, although larger, clinical trials are needed to reach definitive conclusions.

4. Role of CBD on Schizophrenia

4.1. Current Scenario

SCZ is a heterogeneous psychiatric disorder with onset in late adolescence or early adulthood [177]. While heterogeneous, the symptoms are classified into three main categories: positive symptoms (hallucinations, delusions, disorganized thoughts, and senseless speech, bizarre behaviors); negative symptoms (social withdrawal, anhedonia, lack of emotional and facial expression, reduced speech, reduced ability to begin and sustain activities); and cognitive dysfunctions (impaired executive function, working memory and attention) [177,178]. SCZ affects only 1% of the worldwide population; however, it is a subject of intense research due to the limited efficacy of antipsychotic drugs [179]. Current treatments improve only positive symptoms following the first episode of psychosis in just 50% to 70% of patients; they present moderate efficacy for negative symptoms and have no effect on cognitive deficits [180]. At the same time, antipsychotic drugs induce severe side effects, including extrapyramidal symptoms, hyperprolactinemia, and cardiovascular complications or interval QT prolongation (depending on the type of the antipsychotic drug), limiting their chronic use [180]. New antipsychotic drugs have a better risk-benefit balance, but they still show limitations for safety and efficacy. Thus, there is a need to identify new, more effective, safer drugs for the pharmacological management of SCZ [181]. In this respect, CBD has been proposed as a new potential treatment based on findings from several preclinical studies, and more recently in clinical trials, showing its antipsychotic effects [182].

See also  Thc oil benefit for pain vs cbd oil

4.2. Results from Animal Studies

The development of animal models for complex psychiatric disorders, such as SCZ, has been instrumental in increasing our understanding of the neurobiological basis of this disorder and for identifying novel antipsychotic drugs [183]. Different experimental approaches have been used to reproduce the main features of SCZ, mostly in rodents ( Table 4 ). Depending on the type of the manipulation used to induce these alterations, rodent models are classified into developmental models (e.g., maternal immune system’s reactivation); pharmacological models (e.g., amphetamine or ketamine administration); and lesion (e.g., neonatal ventral hippocampal lesion) or genetic (e.g., deficient functioning of the DISC1 gene) manipulation models [183]. Jointly, they enable the reproduction of some behaviors simulating positive and negative symptoms, and to a lesser extent, cognitive impairments.

Table 4

CBD studies on animal models of schizophrenia.

Strain Doses and Route of Administration Effect and Test References
Wistar rats 5, 12 and 30 mg/kg; i.p.; acute No effects on behavioral alterations induced by MK-801 [184]
Sprague Dawley rats 100 ng/0.5 µL, intra-NAcc; acute Improve PPI and hyperlocomotion induced by AMPH [185]
3, 10 and 30 mg/kg, i.p.; acute No effects on behavioral alterations induced by MK-801 [186]
1 and 3 mg/kg; i.p.; acute ↓ anxiety and hyperlocomotion induced by MK-801 [187]
10 mg/kg; i.p.; 11 days Anxiolytic and ↑ recognition and working memory induced by poly I:C given on GD15 [188]
Normalization of CB1r and glutamate decarboxylase alterations in the PFC and HIPP induced by poly I:C given on GD15 [189]
Modulation of muscarinic M1/M4 receptors and choline acetyltransferase levels in PFC and HIPP/poly I:C on GD15 [190]
10 and 30 mg/kg; i.p.; 20 days Normalization of social withdrawal and cognitive impairment induced by MAM on GD17
Normalization of CB1r alterations in PFC induced by MAM given on GD17
C57BL/6J mice 1, 5, 10 and 50 mg/kg; i.p.; chronic CBD (50 mg/kg) attenuated hyperlocomotion induced by DEXAMPH [126]
15, 30 and 60 mg/kg; i.p.; 21 days Dose-dependent attenuation of MK-801-induced disruption in PPI [192]
30 and 60 mg/kg; i.p.; 21 days Improvement of anxiety and cognitive impairment induced by MK-801 [193]
15, 30 and 60 mg/kg; i.p.; 1 week Improvement of anxiety and cognitive impairment induced by MK-801 [194]
1 mg/kg; i.p.; 30 days Attenuation of motor hyperactivity on PND90 induced by poly I:C given on GD9 [195]
Swiss mice 15, 30 and 60 mg/kg; i.p.; acute CBD (30 and 60 mg/kg) blocked AMPH-induced hyperlocomotion
CBD (60 mg/kg) attenuated KET-induced hyperlocomotion
15, 30 & 60 mg/kg; i.p.
60 nmol in 0.2 µL; intra-NAcc; acute
Attenuation of PPI alterations induced by AMPH [197]
15 mg/kg; i.p.; acute Modulation of PPI disruption induced by MK-801 [198]
Nrg1 HET mice 1, 50 and 100 mg/kg; i.p.; 21 days CBD (50 and 100 mg/kg) improved hyperlocomotion and anxiety
No significant improvement in PPI

AMPH: amphetamine; CBD: cannabidiol; DEXAMPH: dexamphetamine; GD: gestational day; HIPP: hippocampus; i.p.: intraperitoneal; KET: ketamine; MAM: methylazoxymethanol acetate; NAcc: nucleus accumbens; NAM: methylazoxymethanol acetate; Nrg1 HET mice: neuregulin 1 heterozygous mutant mice; PFC: prefrontal cortex; PND: postnatal day; PPI: prepulse inhibition. ↓ decrease; ↑ increase.

A large number of these animal models have been used to assess the potential efficacy of CBD for modulating SCZ-related behavioral and neurobiological alterations. One of the most frequent symptoms in people with SCZ is psychomotor agitation, which is pharmacologically reproduced in rodents by administering dopamine receptor agonists such as amphetamine or dexamphetamine. Antipsychotic drugs can modulate this drug-induced motor hyperactivity. In this model, a high dose of CBD reduced amphetamine- and dexamphetamine-induced motor hyperactivity, without causing additional motor effects [126,196]. Similarly, CBD normalized ketamine-motor hyperactivity when given chronically, but not acutely. Interestingly, CBD did not induce catalepsy, showing a similar profile as atypical antipsychotics [196].

Another frequent symptom in schizophrenia is the inability to filter out irrelevant stimuli or make associations for further processing, both effects that are linked to alterations in sensorimotor gating. In animal models, these alterations are measured by the pre-pulse inhibition (PPI) of the startle response, which enables the evaluation of SCZ-like behaviors and the efficacy of new potential antipsychotics. In this model, systemic or intra-nucleus accumbens (NAcc) pre-treatment with CBD attenuated the amphetamine-induced PPI alterations in Swiss mice [197]. In the same study, the authors reported similar results after pre-treatment with the anandamide hydrolysis inhibitor URB597, suggesting that the improvement achieved with CBD may be related with its ability to increase anandamide availability [67,200]. These results are consistent with those found in a clinical study, further explained in the next section of this review, studying the parallels between the improvement of SCZ-related symptoms following administration of CBD and the increase in plasma concentrations of anandamide [201]. Furthermore, similar PPI and locomotor hyperactivity normalization were found in rats pre-treated with CBD. These behavioral alterations may be associated with the regulation of mTOR/p70S6 kinase pathways phosphorylation in the NAcc shell [185].

CBD has displayed interesting effects in other SCZ animal models. Saletti et al. showed that acute CBD administration fully normalized PPI alterations induced by MK-801, a non-competitive antagonist of NMDA receptors, in capuchin monkeys (Sapajus spp.) [202]. Similarly, both acute [198] and chronic [192] administration of CBD modulated the PPI impairment induced by MK-801 in mice, involving, at least in part, TRPV1 receptors [67,198,203]. Chronic administration of CBD also regulated the impairments induced by MK-801 administration in social interaction and novel object recognition tests in mice, behaviors that try to simulate the negative and cognitive symptoms of SCZ. In this study, the high dose of CBD showed the same efficacy as the antipsychotic drug clozapine [193]. Moreover, social interaction and novelty object recognition tests revealed protective effects of CBD when administered after the end of the MK-801 chronic administration, in which 5-HT1A receptors appear to play a relevant role [194]. Despite these promising results, in other rodent studies, CBD slightly modulated the PPI impairment induced by MK-801, without normalizing locomotor hyperactivity or social interaction [184,186]. However, pre-treatment with CBD avoided both alterations [187].

More recently, genetic animal models of SCZ, such as the mutant mice of neuregulin1 (Nrg1 HET), have been used to evaluate the potential antipsychotic-like effects of CBD. Neuregulin1 is a protein involved in neuronal migration, myelination and the regulation of glutamatergic NMDA and GABAergic GABAA receptors expression (for a review, see [204]). Chronic administration of high doses of CBD increased social interaction in mutant mice, with a modest recovery of PPI impairment [199]. Authors identified an increase of GABAA receptor binding in the granular retrosplenial cortex of the mutant mice treated with CBD, suggesting that these GABAergic receptors may be partly responsible for CBD-induced behavioral modulation. In fact, some authors have proposed that CBD may act on GABAergic and glutamatergic systems indirectly, but not exclusively, through its direct action on different targets of the ECS, serotonergic or opioid systems [205]. However, recent in vitro [206] and in vivo [207] studies suggested that CBD modulates the GABAergic system by acting directly on GABAA receptors. Consequently, the effects of CBD on the GABAergic circuits may be the result of both direct and indirect modulation of this system. More studies are needed to further investigate the role of the GABAergic system in the antipsychotic-like effects of CBD.

Epidemiological human studies revealed that exposure to adverse events during pregnancy increases the risk of developing SCZ later on [208]. For this reason, the number of studies attempting to simulate SCZ-like behaviors by exposing pregnant rodents to different disturbances greatly increased in recent years. One of these models is based on the administration of polyinosinic: polycytidylic acid (poly I:C) or the anti-mitotic agent methylazoxymethanol acetate (MAM) on early gestational days (GD) to induce the activation of the maternal immune system. In mice exposed to poly I:C (GD 9 or 15), CBD normalized the increased motor activity [195] and reduced alterations on recognition, working memory, and anxiety [188]. The authors found a normalization of CB1r and glutamate decarboxylase in PFC and HIPP, respectively [189]. Similarly, chronic CBD administration at early ages of development modulated long-term behavioral and neurobiological consequences, including CB1r brain alterations, induced by MAM administration on GD 17 [191]. Previous studies suggested the involvement of CB1r receptors in the antipsychotic-like effects of CBD—one of the first mechanisms described [26,209]. However, the interaction between CBD and CB1r is controversial. On the one hand, CBD appears to activate CB1r by increasing anandamide levels, probably by inhibiting its reuptake and metabolism [201,210]. Conversely, some reports suggested that CBD may act as a negative allosteric modulator of CB1r [65,66,211,212]. Consequently, more studies are needed to further explore the role of CB1r on the antipsychotic actions of CBD. Similarly, the implication of CB2r on CBD antipsychotic-like actions could be evaluated, since this cannabinoid receptor has been related with SCZ in rodents and humans [213,214], and CBD appears to act as an inverse agonist of such receptors [65,67].

Muscarinic M1/M4 receptors and choline acetyltransferase were also associated with the modulating effects of CBD on poly I:C induced-behavioral alterations [190]. In addition, an in vitro study showed that CBD may also act on dopamine D2 receptors, inhibiting dopamine binding in the homogenized striatal tissue of rats [79]. Notably, the modulation of dopaminergic activity by CBD seems to be brain-region specific, since its administration to patients with psychosis and Parkinson’s disease modulated psychotic symptoms without worsening motor activity [215]. Thus, the selective modulation of the dopaminergic system in the striatum enable an antipsychotic effect without extrapyramidal side effects. In addition, both pre-clinical [216] and clinical [201] studies showed that, unlike typical antipsychotics, CBD does not increase plasma prolactin, adding more evidence to support its good safety profile.

Therefore, the existing scientific results suggest that CBD may be useful for modulating SCZ-related features, with a pharmacological profile similar to atypical antipsychotics [182], involving a variety of mechanisms. However, further studies are needed to increase the understanding of CBD efficacy and safety in SCZ.

4.3. Results from Clinical Studies

The promising results found in animal models have encouraged the development of clinical trials to evaluate its therapeutic utility for managing people who have or are at high risk of schizophrenia ( Table 5 ). Two clinical trials evaluated the effects of chronic CBD administration [217,218] in stable antipsychotic-treated patients with SCZ. In the first, CBD did not produce changes in positive or negative symptoms, as assessed on the MATRICS Consensus Cognitive Battery (MCCB) and Positive and Negative Syndrome Scale (PANSS) in comparison with placebo. In addition, CBD failed to produce any improvement in cognitive impairments, evaluated with the MATRICS Consensus Cognitive Battery (MCCB) scale. On the other hand, CBD did not induce movement alterations, clearly a great advantage compared with current antipsychotic drugs [217]. Only sedation was significantly prevalent in the CBD-treated group compared to placebo.

Table 5

Main outcomes achieve from clinical trials in psychosis and schizophrenia.

Clinical Condition Clinical Trial Design Sample Size and Gender Doses and Route of Administration Outcomes Adverse Events References
Chronic schizophrenia Double-blind, randomized, placebo-controlled 36
CBD group N = 18 (12 M/6 F)
Placebo group N = 18 (13 M:5 F)
600 mg/day; p.o.; 6 weeks No improvement in PANSS or MCCB scores No movement alterations [217]
Schizophrenia or a related psychotic disorder Double-blind randomized, placebo-controlled 88
CBD group N = 42 (28 M/14 F)
Placebo group N = 44 (23 M/11 F)
1000 mg/day; oral solution; p.o.; 6 weeks ↓ Positive symptoms (PANSS)
Improve cognitive performances (BACS) and overall functioning (GAF)
No prolactin or metabolic alterations;
No weight gain; No liver alterations
Mild GI events
Acute paranoid schizophrenia Double-blind, randomized CBD vs. amisulpride 39
CBD group N = 20 (15 M/5 F)
Amisulpride group N = 19 (17 M/2 F)
800 mg/day; p.o.; 4 weeks ↓ PANSS scores (no difference compared to amisulpride) Fewer extrapyramidal effects
Less weight gain Lower prolactin increase
Psychosis in the early stages of illness Double-blind, randomized, placebo-controlled 34
Psychosis group N = 15 (10 M:5 F)
Healthy controls N = 19 (11 M:5 F)
600 mg; gelatin capsules; p.o.; acute Attenuation of a dysfunctional activation of mediotemporal and prefrontal cortex, and mediotemporal-striatal functional connectivity during verbal paired associate learning task [219]
Patients at clinical high risk (CHR) of psychosis Double-blind, randomized, placebo-controlled 52
Antipsychotic medication–naive participants at CHR of psychosis N = 33 (CBD group N = 16 (10 M/6 F)
Placebo group N = 17 (7 M/10 F)
Healthy controls N = 19 (11 M/8 F)
600 mg; gelatin capsules; p.o.; acute Improved right caudate, parahippocampal gyrus and midbrain region’s activation during verbal learning task [220]
Patients at CHR of psychosis Double-blind, randomized, placebo-controlled 52
Antipsychotic medication–naive participants at CHR of psychosis N = 33 (CBD group N = 16 (10 M/6 F)
Placebo group N = 17 (7 M/10 F)
Healthy controls N = 19 (11 M/8 F)
600 mg; gelatin capsules; p.o.; acute Attenuated the increased activation in left insula/parietal operculum, and reduced reaction time during monetary incentive delay task [221]
Schizophrenia Double-blind randomized, placebo-controlled 28
CBD 600 mg group N = 9 (5 M/4 F)
CBD 300mg group N = 9 (6 M/3 F)
Placebo group N = 10 (7 M/3 F)
300 or 600 mg; gelatin capsules; p.o.; acute No effects were observed in SCWT and electrodermal responsiveness [222]

BACS: Brief Assessment of Cognition in Schizophrenia; CBD: cannabidiol; GAF: Global Assessment of Functioning; CHR: clinical high risk; GI: gastrointestinal; MCCB: MATRICS Consensus Cognitive Battery; PANSS: MATRICS Consensus Cognitive Battery; p.o.: orally; SCWT: Stroop Color and Word Test. ↓ decrease; ↑ increase.

In the second clinical study, a multicenter randomized controlled trial, CBD significantly improved positive psychotic symptoms (PANSS). There was also a tendency to increase cognitive performance (Brief Assessment of Cognition in Schizophrenia, BACS) and overall functioning (Global Assessment of Functioning, GAF). The administration of CBD did not modify prolactin concentrations in plasma, Simpson Angus Scale rating, weight, waist circumference, liver function, inflammatory markers, or HDL cholesterol levels—common harmful effects of current antipsychotic drugs. The prevalence of adverse events was similar in CBD- and placebo-treated patients, though there was a high proportion of mild gastrointestinal events in the CBD-treated group [218].

Similarly, in a double-blind, randomized clinical trial, CBD led to significant improvements on the PANSS scale, comparable to amisulpride, but with fewer extrapyramidal symptoms, less weight gain and a lower prolactin increase. Furthermore, CBD was well tolerated and did not significantly affect hepatic or cardiac functions. Therefore, the safety profile of CBD was better than the atypical antipsychotic amisulpride. There was also an increase in anandamide plasma concentrations in schizophrenic patients treated with CBD, highlighting this as a potential mechanism of action underlying the effects of CBD [201].

Additional clinical studies using functional magnetic resonance imaging (fMRI) showed that a single dose of CBD attenuated the reduced activity found in the mediotemporal, prefrontal and striatal brain regions of schizophrenic patients while performing verbal paired learning tasks. CBD also attenuated hippocampal-striatal functional connectivity in these patients compared to healthy controls [219]. Neuroimaging studies have also used the fMRI technique in antipsychotic-naïve patients at clinical high risk for psychosis during a verbal learning [220] or a monetary incentive delay task [221]. In the verbal learning task, a single dose of CBD improved the activation in the right caudate and in the parahippocampal gyrus and midbrain during encoding and recall, respectively [220]. In addition, CBD attenuated the hyperactivation of the left insula/parietal operculum and normalized the reaction time in the monetary incentive delay task [221]. However, CBD did not improve selective attention in schizophrenic patients, assessed by the Stroop Color Word Test. Despite these results, authors did not discard a possible beneficial effect after the chronic administration of CBD [222].

Currently, three ongoing clinical trials ( > NCT03883360 [223]; > NCT02926859 [224]; > NCT04411225 [225]) are assessing the efficacy of CBD versus placebo or olanzapine in psychosis and SCZ. The results of these clinical trials should be available in the next few years, providing evidence about the potential usefulness of CBD in psychotic disorders.

In summary, although the clinical studies are heterogeneous, the results found suggest the potential of CBD as monotherapy or as an adjunctive treatment for SCZ. However, more double-blind, placebo-controlled clinical trials are needed to evaluate effectiveness and clarify its profile of side effects.

5. Summary and Conclusions

Our results suggest that CBD may be a potential therapy for treating anxiety, depression, schizophrenia, and related psychotic disorders. Overall, animal models showed that the administration of CBD minimizes anxiety, depression, and stress-related behaviors. Some negative results were also found, suggesting that the anxiolytic and antidepressant properties of CBD depend on the species/strain, age, gender, doses, route of administration and time course (acute vs. chronic). Similarly, in schizophrenia and related psychotic disorders, a variety of animal models show that CBD is effective for modulating hyperactivity and PPI alterations, with a pharmacological profile similar to atypical antipsychotics [154] and the involvement of various mechanisms.

One peculiarity of CBD is its multifactorial molecular profile, acting on more than 65 targets, including the 5-HT1A receptor, the G protein-coupled receptor 55 (GPR55), cannabinoids receptors (CB1r and CB2r), opioid receptors (δ and μ), transient receptor potential vanilloid 1 (TRPV1), and others (for a review, see [39,64,226]). This hampers the identification of the neurobiological mechanisms by which CBD induces its behavioral effects. However, the cumulative data obtained suggest that certain targets appear to play a more relevant role than others in the anxiolytic, antidepressant and antipsychotic effects of CBD, depending on the animal model used. For example, the 5-HT1A receptor plays a significant role in the anxiolytic action of CBD in some studies, but in others, using different experimental conditions, CB1r seems to be the most closely involved target. Despite these discrepancies, there are enough reports to conclude that both receptors, along with additional elements crucial in emotional responses and cognitive processing, such as the HPA axis, anandamide, cannabinoid CB2r, neurogenesis factors and GABAA receptors, are involved, directly or indirectly, on the actions induced by CBD on these diseases ( Figure 1 ). Further studies are needed to fully elucidate the mechanisms of action underlying CBD’s anxiolytic, antidepressant and antipsychotic-like effects, for example, evaluating the role of GPR55, since CBD appears to act as an antagonist of this receptor [72,73], and additional evidence supports its involvement in anxiety [227,228].

Schematic representation of the main hypothesized mechanisms described for the anxiolytic, antidepressant and antipsychotic actions of CBD. AEA: anandamide; 5-HT1A: serotonin receptor 1A; BDNF: brain delivered neurotrophic factor; CB1r: cannabinoid CB1 receptor; CB2r: cannabinoid CB2 receptor; ChAT: choline acetyltransferase; D2: dopamine receptor D2; DNA methyl: DNA methylation; ECS: endocannabinoid system; FAAH: fatty acid amide hydrolase; HPA axis: hypothalamus pituitary-axis; M1/M4r: muscarinic receptor 1 and 4; PPARγ: peroxisome proliferator activated receptor gamma; TRKb/mTOR: tropomyosin-receptor-kinase B/mammalian target of rapamycin; TRPV1: transient receptor potential cation channel subfamily V member 1.

In humans, most studies have evaluated the anxiolytic-like actions of CBD in healthy volunteers or in patients with anxiety secondary to another clinical condition, such as drug use disorders. Few studies have included patients diagnosed with anxiety disorders. Besides, the small number of patients included in these studies precludes definitive conclusions. A similar scenario occurs with PTSD, where preliminary (but small) clinical trials suggest that CBD reduces PSTD severity. In the case of depressive disorders, there is a dearth of studies evaluating the effects of CBD. The efficacy of CBD for reducing depressive symptoms has only been assessed in patients with chronic pain or in cannabis users, with positive results. In the case of SCZ, a larger body of evidence suggests the possible usefulness of CBD as monotherapy or adjunctive treatment. All of the clinical trials carried out indicate that CBD is well tolerated, with no extrapyramidal side effects, less weight gain, and lower prolactin increases than current antipsychotic drugs. Thus, these results suggest that CBD presents an interesting risk-benefit profile that deserves further exploration in large clinical trials, for example, in patients of different ages, in order to ensure its safety in children and the elderly.

All of the presented results show that CBD plays a significant role in the regulation of anxiety- and depressive-related behaviors, cognition, and locomotion. However, it is necessary to develop additional, larger animal and human studies to definitively characterize the usefulness, safety, and efficacy of CBD for these psychiatric disorders. Ongoing double-blind studies, expected to finish in the next few years, will be essential to determine whether CBD is truly an option to improve the pharmacological management of these type of psychiatric patients.


We thank all participants in this study.

Author Contributions

M.S.G.-G. and J.M. conceived the presented idea. M.S.G.-G. took the lead in writing the manuscript. F.N., A.G., A.A.-O. and F.S. contributed in writing the manuscript in consultation with M.S.G.-G. All authors provided critical feedback and helped shape the research, analysis, and manuscript. All authors have read and agreed to the published version of the manuscript.


This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.


Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.


2. Whiteford H., Ferrari A.J., Degenhardt L., Feigin V., Vos T. Chapter 2 Global burden of mental, neurological and substance use disorder: An analysis from the global burden of disease study 2010. In: Patel V., Laxminarayan R., Medina-Mora M.L., Dua T., Chisholm D., editors. Mental, Neurological, and Substance Use Disorders: Disease Control Priorities. 3rd ed. Volume 4 The International Bank for Reconstruction and Development; Washington, DC, USA: 2016. [Google Scholar]

3. World Health Organization . Mental Health Policies and Programmes in the Workplace. World Health Organization; Geneva, Switzerland: 2005. [Google Scholar]

4. Dome P., Rihmer Z., Gonda X. Suicide Risk in Bipolar Disorder: A Brief Review. Medicina. 2019; 55 :403. doi: 10.3390/medicina55080403. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

5. Arsenault-Lapierre G., Kim C., Turecki G. Psychiatric diagnoses in 3275 suicides: A meta-analysis. BMC Psychiatry. 2004; 4 :37. doi: 10.1186/1471-244X-4-37. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

6. Cavanagh J.T., Carson A.J., Sharpe M., Lawrie S.M. Psychological autopsy studies of suicide: A systematic review. Psychol. Med. 2003; 33 :395–405. doi: 10.1017/S0033291702006943. [PubMed] [CrossRef] [Google Scholar]

7. World Health Organization . The WHO Special Initiative for Mental Health (2019–2023): Universal Health Coverage for Mental Health. World Health Organization; Geneva, Switzerland: 2019. [Google Scholar]

8. Newson J.J., Hunter D., Thiagarajan T.C. The Heterogeneity of Mental Health Assessment. Front. Psychiatry. 2020; 11 :76. doi: 10.3389/fpsyt.2020.00076. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

9. Maroney M. An update on current treatment strategies and emerging agents for the management of schizophrenia. Am. J. Manag. Care. 2020; 26 :S55–S61. doi: 10.37765/ajmc.2020.43012. [PubMed] [CrossRef] [Google Scholar]

10. Blumberg M.J., Vaccarino S.R., McInerney S.J. Procognitive Effects of Antidepressants and Other Therapeutic Agents in Major Depressive Disorder: A Systematic Review. J. Clin. Psychiatry. 2020; 81 doi: 10.4088/JCP.19r13200. [PubMed] [CrossRef] [Google Scholar]

11. Chen C., Shan W. Pharmacological and non-pharmacological treatments for major depressive disorder in adults: A systematic review and network meta-analysis. Psychiatry Res. 2019; 281 :112595. doi: 10.1016/j.psychres.2019.112595. [PubMed] [CrossRef] [Google Scholar]

12. Machado-Vieira R. Tracking the impact of translational research in psychiatry: State of the art and perspectives. J. Transl. Med. 2012; 10 :175. doi: 10.1186/1479-5876-10-175. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

13. Li C.T., Yang K.C., Lin W.C. Glutamatergic Dysfunction and Glutamatergic Compounds for Major Psychiatric Disorders: Evidence From Clinical Neuroimaging Studies. Front. Psychiatry. 2018; 9 :767. doi: 10.3389/fpsyt.2018.00767. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

14. Averill L.A., Purohit P., Averill C.L., Boesl M.A., Krystal J.H., Abdallah C.G. Glutamate dysregulation and glutamatergic therapeutics for PTSD: Evidence from human studies. Neurosci. Lett. 2017; 649 :147–155. doi: 10.1016/j.neulet.2016.11.064. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

15. Reus G.Z., de Moura A.B., Silva R.H., Resende W.R., Quevedo J. Resilience Dysregulation in Major Depressive Disorder: Focus on Glutamatergic Imbalance and Microglial Activation. Curr. Neuropharmacol. 2018; 16 :297–307. doi: 10.2174/1570159X15666170630164715. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

16. Fogaca M.V., Duman R.S. Cortical GABAergic Dysfunction in Stress and Depression: New Insights for Therapeutic Interventions. Front. Cell. Neurosci. 2019; 13 :87. doi: 10.3389/fncel.2019.00087. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

17. Luscher B., Shen Q., Sahir N. The GABAergic deficit hypothesis of major depressive disorder. Mol. Psychiatry. 2011; 16 :383–406. doi: 10.1038/mp.2010.120. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

18. de Jonge J.C., Vinkers C.H., Hulshoff Pol H.E., Marsman A. GABAergic Mechanisms in Schizophrenia: Linking Postmortem and In Vivo Studies. Front. Psychiatry. 2017; 8 :118. doi: 10.3389/fpsyt.2017.00118. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

19. Saito A., Ballinger M.D., Pletnikov M.V., Wong D.F., Kamiya A. Endocannabinoid system: Potential novel targets for treatment of schizophrenia. Neurobiol. Dis. 2013; 53 :10–17. doi: 10.1016/j.nbd.2012.11.020. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

20. Navarrete F., Garcia-Gutierrez M.S., Jurado-Barba R., Rubio G., Gasparyan A., Austrich-Olivares A., Manzanares J. Endocannabinoid System Components as Potential Biomarkers in Psychiatry. Front. Psychiatry. 2020; 11 :315. doi: 10.3389/fpsyt.2020.00315. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

21. Sloan M.E., Grant C.W., Gowin J.L., Ramchandani V.A., Le Foll B. Endocannabinoid signaling in psychiatric disorders: A review of positron emission tomography studies. Acta Pharmacol. Sin. 2019; 40 :342–350. doi: 10.1038/s41401-018-0081-z. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

22. Lee T.T., Hill M.N., Lee F.S. Developmental regulation of fear learning and anxiety behavior by endocannabinoids. Genes Brain Behav. 2016; 15 :108–124. doi: 10.1111/gbb.12253. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

23. Daly E.J., Singh J.B., Fedgchin M., Cooper K., Lim P., Shelton R.C., Thase M.E., Winokur A., Van Nueten L., Manji H., et al. Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2018; 75 :139–148. doi: 10.1001/jamapsychiatry.2017.3739. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

24. Fedgchin M., Trivedi M., Daly E.J., Melkote R., Lane R., Lim P., Vitagliano D., Blier P., Fava M., Liebowitz M., et al. Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1) Int. J. Neuropsychopharmacol. Off. Sci. J. Coll. Int. Neuropsychopharmacol. 2019; 22 :616–630. doi: 10.1093/ijnp/pyz039. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

25. Daly E.J., Trivedi M.H., Janik A., Li H., Zhang Y., Li X., Lane R., Lim P., Duca A.R., Hough D., et al. Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2019 doi: 10.1001/jamapsychiatry.2019.1189. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

26. Pertwee R.G. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br. J. Pharmacol. 2008; 153 :199–215. doi: 10.1038/sj.bjp.0707442. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

27. Kinghorn A.D., Falk H., Gibbons S., Kobayashi J. Phytocannbinoids: Unraveling the Complex Chemistry and Pharmacology of Cannabis Sativa. Springer International Publishing; Berlin/Heidelberg, Germany: 2017. [Google Scholar]

28. Gaoni Y., Mechoulam R. Isolation, structure, and partial synthesis of an active constituent of hashish. J. Am. Chem. Soc. 1964; 86 :1646–1647. doi: 10.1021/ja01062a046. [CrossRef] [Google Scholar]

29. Adams R., Hunt M., Clark J.H. Structure of cannabidiol, a product isolated from the Marihuana extract of Minnesota Wild Hemp. I. J. Am. Chem. Soc. 1940; 62 :196–200. doi: 10.1021/ja01858a058. [CrossRef] [Google Scholar]

30. Mechoulam R., Shvo Y., Hashish I. The structure of cannabidiol. Tetrahedron. 1963; 19 :2073–2078. doi: 10.1016/0040-4020(63)85022-X. [PubMed] [CrossRef] [Google Scholar]

31. Burstein S. Cannabidiol (CBD) and its analogs: A review of their effects on inflammation. Bioorg. Med. Chem. 2015; 23 :1377–1385. doi: 10.1016/j.bmc.2015.01.059. [PubMed] [CrossRef] [Google Scholar]

32. Zlebnik N.E., Cheer J.F. Beyond the CB1 Receptor: Is Cannabidiol the Answer for Disorders of Motivation? Annu. Rev. Neurosci. 2016; 39 :1–17. doi: 10.1146/annurev-neuro-070815-014038. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

33. Fusar-Poli P., Crippa J.A., Bhattacharyya S., Borgwardt S.J., Allen P., Martin-Santos R., Seal M., Surguladze S.A., O’Carrol C., Atakan Z., et al. Distinct effects of 9-tetrahydrocannabinol and cannabidiol on neural activation during emotional processing. Arch. Gen. Psychiatry. 2009; 66 :95–105. doi: 10.1001/archgenpsychiatry.2008.519. [PubMed] [CrossRef] [Google Scholar]

34. Winton-Brown T.T., Allen P., Bhattacharyya S., Borgwardt S.J., Fusar-Poli P., Crippa J.A., Seal M.L., Martin-Santos R., Ffytche D., Zuardi A.W., et al. Modulation of auditory and visual processing by delta-9-tetrahydrocannabinol and cannabidiol: An FMRI study. Neuropsychopharmacology. 2011; 36 :1340–1348. doi: 10.1038/npp.2011.17. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

35. Martin-Santos R., Crippa J.A., Batalla A., Bhattacharyya S., Atakan Z., Borgwardt S., Allen P., Seal M., Langohr K., Farre M., et al. Acute effects of a single, oral dose of d9-tetrahydrocannabinol (THC) and cannabidiol (CBD) administration in healthy volunteers. Curr. Pharm. Des. 2012; 18 :4966–4979. doi: 10.2174/138161212802884780. [PubMed] [CrossRef] [Google Scholar]

36. Parker L.A., Burton P., Sorge R.E., Yakiwchuk C., Mechoulam R. Effect of low doses of delta9-tetrahydrocannabinol and cannabidiol on the extinction of cocaine-induced and amphetamine-induced conditioned place preference learning in rats. Psychopharmacology. 2004; 175 :360–366. doi: 10.1007/s00213-004-1825-7. [PubMed] [CrossRef] [Google Scholar]

37. Vann R.E., Gamage T.F., Warner J.A., Marshall E.M., Taylor N.L., Martin B.R., Wiley J.L. Divergent effects of cannabidiol on the discriminative stimulus and place conditioning effects of Delta(9)-tetrahydrocannabinol. Drug Alcohol Depend. 2008; 94 :191–198. doi: 10.1016/j.drugalcdep.2007.11.017. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

38. Viudez-Martinez A., Garcia-Gutierrez M.S., Medrano-Relinque J., Navarron C.M., Navarrete F., Manzanares J. Cannabidiol does not display drug abuse potential in mice behavior. Acta Pharmacol. Sin. 2019; 40 :358–364. doi: 10.1038/s41401-018-0032-8. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

39. Pisanti S., Malfitano A.M., Ciaglia E., Lamberti A., Ranieri R., Cuomo G., Abate M., Faggiana G., Proto M.C., Fiore D., et al. Cannabidiol: State of the art and new challenges for therapeutic applications. Pharmacol. Ther. 2017; 175 :133–150. doi: 10.1016/j.pharmthera.2017.02.041. [PubMed] [CrossRef] [Google Scholar]

40. Aviello G., Romano B., Borrelli F., Capasso R., Gallo L., Piscitelli F., Di Marzo V., Izzo A.A. Chemopreventive effect of the non-psychotropic phytocannabinoid cannabidiol on experimental colon cancer. J. Mol. Med. 2012; 90 :925–934. doi: 10.1007/s00109-011-0856-x. [PubMed] [CrossRef] [Google Scholar]

41. El-Remessy A.B., Al-Shabrawey M., Khalifa Y., Tsai N.T., Caldwell R.B., Liou G.I. Neuroprotective and blood-retinal barrier-preserving effects of cannabidiol in experimental diabetes. Am. J. Pathol. 2006; 168 :235–244. doi: 10.2353/ajpath.2006.050500. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

42. Karmaus P.W., Wagner J.G., Harkema J.R., Kaminski N.E., Kaplan B.L. Cannabidiol (CBD) enhances lipopolysaccharide (LPS)-induced pulmonary inflammation in C57BL/6 mice. J. Immunotoxicol. 2013; 10 :321–328. doi: 10.3109/1547691X.2012.741628. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

43. Syed Y.Y., McKeage K., Scott L.J. Delta-9-tetrahydrocannabinol/cannabidiol (Sativex(R)): A review of its use in patients with moderate to severe spasticity due to multiple sclerosis. Drugs. 2014; 74 :563–578. doi: 10.1007/s40265-014-0197-5. [PubMed] [CrossRef] [Google Scholar]

44. Devinsky O., Patel A.D., Cross J.H., Villanueva V., Wirrell E.C., Privitera M., Greenwood S.M., Roberts C., Checketts D., VanLandingham K.E., et al. Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome. N. Engl. J. Med. 2018; 378 :1888–1897. doi: 10.1056/NEJMoa1714631. [PubMed] [CrossRef] [Google Scholar]

45. Martin-Moreno A.M., Reigada D., Ramirez B.G., Mechoulam R., Innamorato N., Cuadrado A., de Ceballos M.L. Cannabidiol and other cannabinoids reduce microglial activation in vitro and in vivo: Relevance to Alzheimer’s disease. Mol. Pharm. 2011; 79 :964–973. doi: 10.1124/mol.111.071290. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

46. Iuvone T., Esposito G., De Filippis D., Scuderi C., Steardo L. Cannabidiol: A promising drug for neurodegenerative disorders? CNS Neurosci. Ther. 2009; 15 :65–75. doi: 10.1111/j.1755-5949.2008.00065.x. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

47. Kozela E., Lev N., Kaushansky N., Eilam R., Rimmerman N., Levy R., Ben-Nun A., Juknat A., Vogel Z. Cannabidiol inhibits pathogenic T cells, decreases spinal microglial activation and ameliorates multiple sclerosis-like disease in C57BL/6 mice. Br. J. Pharmacol. 2011; 163 :1507–1519. doi: 10.1111/j.1476-5381.2011.01379.x. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

48. Perez M., Benitez S.U., Cartarozzi L.P., Del Bel E., Guimaraes F.S., Oliveira A.L. Neuroprotection and reduction of glial reaction by cannabidiol treatment after sciatic nerve transection in neonatal rats. Eur. J. Neurosci. 2013; 38 :3424–3434. doi: 10.1111/ejn.12341. [PubMed] [CrossRef] [Google Scholar]

49. de Mello Schier A.R., de Oliveira Ribeiro N.P., Coutinho D.S., Machado S., Arias-Carrion O., Crippa J.A., Zuardi A.W., Nardi A.E., Silva A.C. Antidepressant-like and anxiolytic-like effects of cannabidiol: A chemical compound of Cannabis sativa. CNS Neurol. Disord. Drug Targets. 2014; 13 :953–960. doi: 10.2174/1871527313666140612114838. [PubMed] [CrossRef] [Google Scholar]

50. Blessing E.M., Steenkamp M.M., Manzanares J., Marmar C.R. Cannabidiol as a Potential Treatment for Anxiety Disorders. Neurother. J. Am. Soc. Exp. Neurother. 2015; 12 :825–836. doi: 10.1007/s13311-015-0387-1. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

51. Iseger T.A., Bossong M.G. A systematic review of the antipsychotic properties of cannabidiol in humans. Schizophr. Res. 2015; 162 :153–161. doi: 10.1016/j.schres.2015.01.033. [PubMed] [CrossRef] [Google Scholar]

52. Huestis M.A. Pharmacokinetics and metabolism of the plant cannabinoids, delta9-tetrahydrocannabinol, cannabidiol and cannabinol. Handb. Exp. Pharm. 2005 doi: 10.1007/3-540-26573-2_23. [PubMed] [CrossRef] [Google Scholar]

53. Hawksworth G.M.K. Metabolism and Pharmacokinetics of Cannabinoids. Pharmaceutical Press; London, UK: 2004. [Google Scholar]

54. Millar S.A., Stone N.L., Yates A.S., O’Sullivan S.E. A Systematic Review on the Pharmacokinetics of Cannabidiol in Humans. Front. Pharm. 2018; 9 :1365. doi: 10.3389/fphar.2018.01365. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

55. Devinsky O., Cilio M.R., Cross H., Fernandez-Ruiz J., French J., Hill C., Katz R., Di Marzo V., Jutras-Aswad D., Notcutt W.G., et al. Cannabidiol: Pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia. 2014; 55 :791–802. doi: 10.1111/epi.12631. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

56. Reddy D.S. The Utility of Cannabidiol in the Treatment of Refractory Epilepsy. Clin. Pharm. 2017; 101 :182–184. doi: 10.1002/cpt.441. [PubMed] [CrossRef] [Google Scholar]

57. Ohlsson A., Lindgren J.E., Andersson S., Agurell S., Gillespie H., Hollister L.E. Single dose kinetics of cannabidiol in man. Cannabinoids Chem. Pharmacol. Ther. Asp. 1984:219–225. doi: 10.1016/b978-0-12-044620-9.50020-8. [CrossRef] [Google Scholar]

58. Harvey D.J., Samara E., Mechoulam R. Comparative metabolism of cannabidiol in dog, rat and man. Pharm. Biochem. Behav. 1991; 40 :523–532. doi: 10.1016/0091-3057(91)90358-9. [PubMed] [CrossRef] [Google Scholar]

59. Ujvary I., Hanus L. Human Metabolites of Cannabidiol: A Review on Their Formation, Biological Activity, and Relevance in Therapy. Cannabis Cannabinoid Res. 2016; 1 :90–101. doi: 10.1089/can.2015.0012. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

60. Jiang R., Yamaori S., Takeda S., Yamamoto I., Watanabe K. Identification of cytochrome P450 enzymes responsible for metabolism of cannabidiol by human liver microsomes. Life Sci. 2011; 89 :165–170. doi: 10.1016/j.lfs.2011.05.018. [PubMed] [CrossRef] [Google Scholar]

61. Guy G.W., Robson P.J. A Phase I, Open Label, Four-Way Crossover Study to Compare the Pharmacokinetic Profiles of a Single Dose of 20 mg of a Cannabis Based Medicine Extract (CBME) Administered on 3 Different Areas of the Buccal Mucosa and to Investigate the Pharmacokinetics of CBME per Oral in Healthy Male and Female Volunteers (GWPK0112) J. Cannabis Ther. 2004; 3 :79–120. doi: 10.1300/j175v03n04_01. [CrossRef] [Google Scholar]

62. Bergamaschi M.M., Queiroz R.H., Zuardi A.W., Crippa J.A. Safety and side effects of cannabidiol, a Cannabis sativa constituent. Curr. Drug Saf. 2011; 6 :237–249. doi: 10.2174/157488611798280924. [PubMed] [CrossRef] [Google Scholar]

63. Zuardi A.W., Morais S.L., Guimaraes F.S., Mechoulam R. Antipsychotic effect of cannabidiol. J. Clin. Psychiatry. 1995; 56 :485–486. [PubMed] [Google Scholar]

64. Ibeas Bih C., Chen T., Nunn A.V., Bazelot M., Dallas M., Whalley B.J. Molecular Targets of Cannabidiol in Neurological Disorders. Neurother. J. Am. Soc. Exp. Neurother. 2015; 12 :699–730. doi: 10.1007/s13311-015-0377-3. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

65. Thomas A., Baillie G.L., Phillips A.M., Razdan R.K., Ross R.A., Pertwee R.G. Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br. J. Pharmacol. 2007; 150 :613–623. doi: 10.1038/sj.bjp.0707133. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

66. Mechoulam R., Peters M., Murillo-Rodriguez E., Hanus L.O. Cannabidiol—Recent advances. Chem. Biodivers. 2007; 4 :1678–1692. doi: 10.1002/cbdv.200790147. [PubMed] [CrossRef] [Google Scholar]

67. Izzo A.A., Borrelli F., Capasso R., Di Marzo V., Mechoulam R. Non-psychotropic plant cannabinoids: New therapeutic opportunities from an ancient herb. Trends Pharmacol. Sci. 2009; 30 :515–527. doi: 10.1016/ [PubMed] [CrossRef] [Google Scholar]

68. McPartland J.M., Duncan M., Di Marzo V., Pertwee R.G. Are cannabidiol and Delta(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br. J. Pharmacol. 2015; 172 :737–753. doi: 10.1111/bph.12944. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

69. Laprairie R.B., Bagher A.M., Kelly M.E., Denovan-Wright E.M. Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br. J. Pharmacol. 2015; 172 :4790–4805. doi: 10.1111/bph.13250. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

70. Stern C.A.J., da Silva T.R., Raymundi A.M., de Souza C.P., Hiroaki-Sato V.A., Kato L., Guimaraes F.S., Andreatini R., Takahashi R.N., Bertoglio L.J. Cannabidiol disrupts the consolidation of specific and generalized fear memories via dorsal hippocampus CB1 and CB2 receptors. Neuropharmacology. 2017; 125 :220–230. doi: 10.1016/j.neuropharm.2017.07.024. [PubMed] [CrossRef] [Google Scholar]

71. De Petrocellis L., Ligresti A., Moriello A.S., Allara M., Bisogno T., Petrosino S., Stott C.G., Di Marzo V. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br. J. Pharmacol. 2011; 163 :1479–1494. doi: 10.1111/j.1476-5381.2010.01166.x. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

72. Whyte L.S., Ryberg E., Sims N.A., Ridge S.A., Mackie K., Greasley P.J., Ross R.A., Rogers M.J. The putative cannabinoid receptor GPR55 affects osteoclast function in vitro and bone mass in vivo. Proc. Natl. Acad. Sci. USA. 2009; 106 :16511–16516. doi: 10.1073/pnas.0902743106. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

73. Sylantyev S., Jensen T.P., Ross R.A., Rusakov D.A. Cannabinoid- and lysophosphatidylinositol-sensitive receptor GPR55 boosts neurotransmitter release at central synapses. Proc. Natl. Acad. Sci. USA. 2013; 110 :5193–5198. doi: 10.1073/pnas.1211204110. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

74. Sylantyev S.J.T., Ross R.A., Rusakov D.A. The enigmatic receptor GPR55 potentiates neurotransmitter release at central synapses; Proceedings of the Neuroscience Meeting Planner Washington, DC: Society for Neuroscience Online: Program; Washington, DC, USA. 12–16 November 2011; Program 653.01, Poster B28. [Google Scholar]

75. Poddar M.K., Dewey W.L. Effects of cannabinoids on catecholamine uptake and release in hypothalamic and striatal synaptosomes. J. Pharmacol. Exp. Ther. 1980; 214 :63–67. [PubMed] [Google Scholar]

76. Pandolfo P., Silveirinha V., dos Santos-Rodrigues A., Venance L., Ledent C., Takahashi R.N., Cunha R.A., Kofalvi A. Cannabinoids inhibit the synaptic uptake of adenosine and dopamine in the rat and mouse striatum. Eur. J. Pharm. 2011; 655 :38–45. doi: 10.1016/j.ejphar.2011.01.013. [PubMed] [CrossRef] [Google Scholar]

77. Vaysse P.J., Gardner E.L., Zukin R.S. Modulation of rat brain opioid receptors by cannabinoids. J. Pharmacol. Exp. Ther. 1987; 241 :534–539. [PubMed] [Google Scholar]

See also  What's the best carrier oil for cbd

78. Kathmann M., Flau K., Redmer A., Trankle C., Schlicker E. Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors. Naunyn-Schmiedeberg’s Arch. Pharmacol. 2006; 372 :354–361. doi: 10.1007/s00210-006-0033-x. [PubMed] [CrossRef] [Google Scholar]

79. Seeman P. Cannabidiol is a partial agonist at dopamine D2High receptors, predicting its antipsychotic clinical dose. Transl. Psychiatry. 2016; 6 :e920. doi: 10.1038/tp.2016.195. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

80. Rock E.M., Bolognini D., Limebeer C.L., Cascio M.G., Anavi-Goffer S., Fletcher P.J., Mechoulam R., Pertwee R.G., Parker L.A. Cannabidiol, a non-psychotropic component of cannabis, attenuates vomiting and nausea-like behaviour via indirect agonism of 5-HT(1A) somatodendritic autoreceptors in the dorsal raphe nucleus. Br. J. Pharmacol. 2012; 165 :2620–2634. doi: 10.1111/j.1476-5381.2011.01621.x. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

81. Russo E.B., Burnett A., Hall B., Parker K.K. Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem. Res. 2005; 30 :1037–1043. doi: 10.1007/s11064-005-6978-1. [PubMed] [CrossRef] [Google Scholar]

82. World Health Organization . Depression and Other Common Mental Disorders. WHO; Geneva, Switzerland: 2017. [Google Scholar]

83. Heather A., Church A.C., Lucey J.V. Core Psychiatry. 3rd ed. Elsevier; Amsterdam, The Netherlands: 2012. [CrossRef] [Google Scholar]

84. Rantala M.J., Luoto S., Krams I., Karlsson H. Depression subtyping based on evolutionary psychiatry: Proximate mechanisms and ultimate functions. Brain Behav. Immun. 2018; 69 :603–617. doi: 10.1016/j.bbi.2017.10.012. [PubMed] [CrossRef] [Google Scholar]

85. Tolentino J.C., Schmidt S.L. DSM-5 Criteria and Depression Severity: Implications for Clinical Practice. Front. Psychiatry. 2018; 9 :450. doi: 10.3389/fpsyt.2018.00450. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

86. Aragones E., Pinol J.L., Labad A. Comorbidity of major depression with other common mental disorders in primary care patients. Aten Primaria. 2009; 41 :545–551. doi: 10.1016/j.aprim.2008.11.011. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

87. Cole J., McGuffin P., Farmer A.E. The classification of depression: Are we still confused? Br. J. Psychiatry. 2008; 192 :83–85. doi: 10.1192/bjp.bp.107.039826. [PubMed] [CrossRef] [Google Scholar]

88. Tiller J.W. Depression and anxiety. Med. J. Aust. 2013; 199 :S28–S31. doi: 10.5694/mja12.10628. [PubMed] [CrossRef] [Google Scholar]

89. Ogawa Y., Takeshima N., Hayasaka Y., Tajika A., Watanabe N., Streiner D., Furukawa T.A. Antidepressants plus benzodiazepines for adults with major depression. Cochrane Database Syst. Rev. 2019; 6 :CD001026. doi: 10.1002/14651858.CD001026.pub2. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

90. Howland R.H. Buspirone: Back to the Future. J. Psychosoc. Nurs. Ment. Health Serv. 2015; 53 :21–24. doi: 10.3928/02793695-20151022-01. [PubMed] [CrossRef] [Google Scholar]

91. NHS Psychological Therapies Service Generalized Anxiety Disorder in Adults-Treatment. [(accessed on 19 November 2020)]; Available online:

92. Machmutow K., Meister R., Jansen A., Kriston L., Watzke B., Harter M.C., Liebherz S. Comparative effectiveness of continuation and maintenance treatments for persistent depressive disorder in adults. Cochrane Database Syst. Rev. 2019; 5 :CD012855. doi: 10.1002/14651858.CD012855.pub2. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

93. Khan A., Faucett J., Lichtenberg P., Kirsch I., Brown W.A. A systematic review of comparative efficacy of treatments and controls for depression. PLoS ONE. 2012; 7 :e41778. doi: 10.1371/journal.pone.0041778. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

94. Barbato A., D’Avanzo B., Parabiaghi A. Couple therapy for depression. Cochrane Database Syst. Rev. 2018; 6 :CD004188. doi: 10.1002/14651858.CD004188.pub3. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

95. Filho N.G.S., Tufik S. Comparative effects between cannabidiol and diazepam on neophobia, food intake and conflict behavior. Res. Commun. Psychol. Psychiatry Behav. 1981; 6 :251–266. [Google Scholar]

96. Zuardi A.W., Karniol I.G. Effects on variable-interval performance in rats of delta 9-tetrahydrocannabinol and cannabidiol, separately and in combination. Braz. J. Med. Biol. Res. 1983; 16 :141–146. [PubMed] [Google Scholar]

97. Guimaraes F.S., Chiaretti T.M., Graeff F.G., Zuardi A.W. Antianxiety effect of cannabidiol in the elevated plus-maze. Psychopharmacology. 1990; 100 :558–559. doi: 10.1007/BF02244012. [PubMed] [CrossRef] [Google Scholar]

98. Onaivi E.S., Green M.R., Martin B.R. Pharmacological characterization of cannabinoids in the elevated plus maze. J. Pharmacol. Exp. Ther. 1990; 253 :1002–1009. [PubMed] [Google Scholar]

99. Almeida V., Levin R., Peres F.F., Niigaki S.T., Calzavara M.B., Zuardi A.W., Hallak J.E., Crippa J.A., Abilio V.C. Cannabidiol exhibits anxiolytic but not antipsychotic property evaluated in the social interaction test. Prog. Neuro-Psychopharmacol. Biol. Psychiatry. 2013; 41 :30–35. doi: 10.1016/j.pnpbp.2012.10.024. [PubMed] [CrossRef] [Google Scholar]

100. Resstel L.B., Tavares R.F., Lisboa S.F., Joca S.R., Correa F.M., Guimaraes F.S. 5-HT1A receptors are involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats. Br. J. Pharmacol. 2009; 156 :181–188. doi: 10.1111/j.1476-5381.2008.00046.x. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

101. Viudez-Martinez A., Garcia-Gutierrez M.S., Manzanares J. Cannabidiol regulates the expression of hypothalamus-pituitary-adrenal axis-related genes in response to acute restraint stress. J. Psychopharmacol. 2018; 32 :1379–1384. doi: 10.1177/0269881118805495. [PubMed] [CrossRef] [Google Scholar]

102. Moreira F.A., Aguiar D.C., Guimaraes F.S. Anxiolytic-like effect of cannabidiol in the rat Vogel conflict test. Prog. Neuro-Psychopharmacol. Biol. Psychiatry. 2006; 30 :1466–1471. doi: 10.1016/j.pnpbp.2006.06.004. [PubMed] [CrossRef] [Google Scholar]

103. Nardo M., Casarotto P.C., Gomes F.V., Guimaraes F.S. Cannabidiol reverses the mCPP-induced increase in marble-burying behavior. Fundam. Clin. Pharmacol. 2014; 28 :544–550. doi: 10.1111/fcp.12051. [PubMed] [CrossRef] [Google Scholar]

104. Casarotto P.C., Gomes F.V., Resstel L.B., Guimaraes F.S. Cannabidiol inhibitory effect on marble-burying behaviour: Involvement of CB1 receptors. Behav. Pharm. 2010; 21 :353–358. doi: 10.1097/FBP.0b013e32833b33c5. [PubMed] [CrossRef] [Google Scholar]

105. Todd S.M., Arnold J.C. Neural correlates of interactions between cannabidiol and Delta(9) -tetrahydrocannabinol in mice: Implications for medical cannabis. Br. J. Pharmacol. 2016; 173 :53–65. doi: 10.1111/bph.13333. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

106. Todd S.M., Zhou C., Clarke D.J., Chohan T.W., Bahceci D., Arnold J.C. Interactions between cannabidiol and Delta(9)-THC following acute and repeated dosing: Rebound hyperactivity, sensorimotor gating and epigenetic and neuroadaptive changes in the mesolimbic pathway. Eur. Neuropsychopharmacol. 2017; 27 :132–145. doi: 10.1016/j.euroneuro.2016.12.004. [PubMed] [CrossRef] [Google Scholar]

107. Sales A.J., Fogaca M.V., Sartim A.G., Pereira V.S., Wegener G., Guimaraes F.S., Joca S.R.L. Cannabidiol Induces Rapid and Sustained Antidepressant-Like Effects Through Increased BDNF Signaling and Synaptogenesis in the Prefrontal Cortex. Mol. Neurobiol. 2019; 56 :1070–1081. doi: 10.1007/s12035-018-1143-4. [PubMed] [CrossRef] [Google Scholar]

108. Gall Z., Farkas S., Albert A., Ferencz E., Vancea S., Urkon M., Kolcsar M. Effects of Chronic Cannabidiol Treatment in the Rat Chronic Unpredictable Mild Stress Model of Depression. Biomolecules. 2020; 10 :801. doi: 10.3390/biom10050801. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

109. Stern C.A., Gazarini L., Takahashi R.N., Guimaraes F.S., Bertoglio L.J. On disruption of fear memory by reconsolidation blockade: Evidence from cannabidiol treatment. Neuropsychopharmacology. 2012; 37 :2132–2142. doi: 10.1038/npp.2012.63. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

110. Shbiro L., Hen-Shoval D., Hazut N., Rapps K., Dar S., Zalsman G., Mechoulam R., Weller A., Shoval G. Effects of cannabidiol in males and females in two different rat models of depression. Physiol. Behav. 2019; 201 :59–63. doi: 10.1016/j.physbeh.2018.12.019. [PubMed] [CrossRef] [Google Scholar]

111. Reus G.Z., Stringari R.B., Ribeiro K.F., Luft T., Abelaira H.M., Fries G.R., Aguiar B.W., Kapczinski F., Hallak J.E., Zuardi A.W., et al. Administration of cannabidiol and imipramine induces antidepressant-like effects in the forced swimming test and increases brain-derived neurotrophic factor levels in the rat amygdala. Acta Neuropsychiatr. 2011; 23 :241–248. doi: 10.1111/j.1601-5215.2011.00579.x. [PubMed] [CrossRef] [Google Scholar]

112. Campos A.C., Guimaraes F.S. Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats. Psychopharmacology. 2008; 199 :223–230. doi: 10.1007/s00213-008-1168-x. [PubMed] [CrossRef] [Google Scholar]

113. de Paula Soares V., Campos A.C., Bortoli V.C., Zangrossi H., Jr., Guimaraes F.S., Zuardi A.W. Intra-dorsal periaqueductal gray administration of cannabidiol blocks panic-like response by activating 5-HT1A receptors. Behav. Brain Res. 2010; 213 :225–229. doi: 10.1016/j.bbr.2010.05.004. [PubMed] [CrossRef] [Google Scholar]

114. Gomes F.V., Alves F.H., Guimaraes F.S., Correa F.M., Resstel L.B., Crestani C.C. Cannabidiol administration into the bed nucleus of the stria terminalis alters cardiovascular responses induced by acute restraint stress through 5-HT(1)A receptor. Eur. Neuropsychopharmacol. 2013; 23 :1096–1104. doi: 10.1016/j.euroneuro.2012.09.007. [PubMed] [CrossRef] [Google Scholar]

115. Granjeiro E.M., Gomes F.V., Guimaraes F.S., Correa F.M., Resstel L.B. Effects of intracisternal administration of cannabidiol on the cardiovascular and behavioral responses to acute restraint stress. Pharm. Biochem. Behav. 2011; 99 :743–748. doi: 10.1016/j.pbb.2011.06.027. [PubMed] [CrossRef] [Google Scholar]

116. Fogaca M.V., Campos A.C., Coelho L.D., Duman R.S., Guimaraes F.S. The anxiolytic effects of cannabidiol in chronically stressed mice are mediated by the endocannabinoid system: Role of neurogenesis and dendritic remodeling. Neuropharmacology. 2018; 135 :22–33. doi: 10.1016/j.neuropharm.2018.03.001. [PubMed] [CrossRef] [Google Scholar]

117. Bitencourt R.M., Pamplona F.A., Takahashi R.N. Facilitation of contextual fear memory extinction and anti-anxiogenic effects of AM404 and cannabidiol in conditioned rats. Eur. Neuropsychopharmacol. 2008; 18 :849–859. doi: 10.1016/j.euroneuro.2008.07.001. [PubMed] [CrossRef] [Google Scholar]

118. Lemos J.I., Resstel L.B., Guimaraes F.S. Involvement of the prelimbic prefrontal cortex on cannabidiol-induced attenuation of contextual conditioned fear in rats. Behav. Brain Res. 2010; 207 :105–111. doi: 10.1016/j.bbr.2009.09.045. [PubMed] [CrossRef] [Google Scholar]

119. Do Monte F.H., Souza R.R., Bitencourt R.M., Kroon J.A., Takahashi R.N. Infusion of cannabidiol into infralimbic cortex facilitates fear extinction via CB1 receptors. Behav. Brain Res. 2013; 250 :23–27. doi: 10.1016/j.bbr.2013.04.045. [PubMed] [CrossRef] [Google Scholar]

120. Raymundi A.M., da Silva T.R., Zampronio A.R., Guimaraes F.S., Bertoglio L.J., Stern C.A.J. A time-dependent contribution of hippocampal CB1, CB2 and PPARgamma receptors to cannabidiol-induced disruption of fear memory consolidation. Br. J. Pharmacol. 2020; 177 :945–957. doi: 10.1111/bph.14895. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

121. Sartim A.G., Guimaraes F.S., Joca S.R. Antidepressant-like effect of cannabidiol injection into the ventral medial prefrontal cortex-Possible involvement of 5-HT1A and CB1 receptors. Behav. Brain Res. 2016; 303 :218–227. doi: 10.1016/j.bbr.2016.01.033. [PubMed] [CrossRef] [Google Scholar]

122. Bis-Humbert C., Garcia-Cabrerizo R., Garcia-Fuster M.J. Decreased sensitivity in adolescent versus adult rats to the antidepressant-like effects of cannabidiol. Psychopharmacology. 2020; 237 :1621–1631. doi: 10.1007/s00213-020-05481-4. [PubMed] [CrossRef] [Google Scholar]

123. ElBatsh M.M., Assareh N., Marsden C.A., Kendall D.A. Anxiogenic-like effects of chronic cannabidiol administration in rats. Psychopharmacology. 2012; 221 :239–247. doi: 10.1007/s00213-011-2566-z. [PubMed] [CrossRef] [Google Scholar]

124. Shoval G., Shbiro L., Hershkovitz L., Hazut N., Zalsman G., Mechoulam R., Weller A. Prohedonic Effect of Cannabidiol in a Rat Model of Depression. Neuropsychobiology. 2016; 73 :123–129. doi: 10.1159/000443890. [PubMed] [CrossRef] [Google Scholar]

125. de Morais H., Chaves Y.C., Waltrick A.P.F., Jesus C.H.A., Genaro K., Crippa J.A., da Cunha J.M., Zanoveli J.M. Sub-chronic treatment with cannabidiol but not with URB597 induced a mild antidepressant-like effect in diabetic rats. Neurosci. Lett. 2018; 682 :62–68. doi: 10.1016/j.neulet.2018.06.006. [PubMed] [CrossRef] [Google Scholar]

126. Long L.E., Chesworth R., Huang X.F., McGregor I.S., Arnold J.C., Karl T. A behavioural comparison of acute and chronic Delta9-tetrahydrocannabinol and cannabidiol in C57BL/6JArc mice. Int. J. Neuropsychopharmacol. Off. Sci. J. Coll. Int. Neuropsychopharmacol. 2010; 13 :861–876. doi: 10.1017/S1461145709990605. [PubMed] [CrossRef] [Google Scholar]

127. Assareh N., Gururajan A., Zhou C., Luo J.L., Kevin R.C., Arnold J.C. Cannabidiol disrupts conditioned fear expression and cannabidiolic acid reduces trauma-induced anxiety-related behaviour in mice. Behav. Pharm. 2020; 31 :591–596. doi: 10.1097/FBP.0000000000000565. [PubMed] [CrossRef] [Google Scholar]

128. Kasten C.R., Zhang Y., Boehm S.L., Jr. Acute Cannabinoids Produce Robust Anxiety-Like and Locomotor Effects in Mice, but Long-Term Consequences Are Age- and Sex-Dependent. Front. Behav. Neurosci. 2019; 13 :32. doi: 10.3389/fnbeh.2019.00032. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

129. Gasparyan A.N.F., Manzanares J. Effects of cannabidiol plus sertraline on behavioural and gene expression alterations in a long-lasting animal model of post-traumatic stress disorder. Authorea. 2020 doi: 10.22541/au.158584231.13745819. [CrossRef] [Google Scholar]

130. Schleicher E.M., Ott F.W., Muller M., Silcher B., Sichler M.E., Low M.J., Wagner J.M., Bouter Y. Prolonged Cannabidiol Treatment Lacks on Detrimental Effects on Memory, Motor Performance and Anxiety in C57BL/6J Mice. Front. Behav. Neurosci. 2019; 13 :94. doi: 10.3389/fnbeh.2019.00094. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

131. Wolf S.A., Bick-Sander A., Fabel K., Leal-Galicia P., Tauber S., Ramirez-Rodriguez G., Muller A., Melnik A., Waltinger T.P., Ullrich O., et al. Cannabinoid receptor CB1 mediates baseline and activity-induced survival of new neurons in adult hippocampal neurogenesis. Cell Commun. Signal. 2010; 8 :12. doi: 10.1186/1478-811X-8-12. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

132. Linge R., Jimenez-Sanchez L., Campa L., Pilar-Cuellar F., Vidal R., Pazos A., Adell A., Diaz A. Cannabidiol induces rapid-acting antidepressant-like effects and enhances cortical 5-HT/glutamate neurotransmission: Role of 5-HT1A receptors. Neuropharmacology. 2016; 103 :16–26. doi: 10.1016/j.neuropharm.2015.12.017. [PubMed] [CrossRef] [Google Scholar]

133. Schiavon A.P., Bonato J.M., Milani H., Guimaraes F.S., Weffort de Oliveira R.M. Influence of single and repeated cannabidiol administration on emotional behavior and markers of cell proliferation and neurogenesis in non-stressed mice. Prog. Neuro-Psychopharmacol. Biol. Psychiatry. 2016; 64 :27–34. doi: 10.1016/j.pnpbp.2015.06.017. [PubMed] [CrossRef] [Google Scholar]

134. Xu C., Chang T., Du Y., Yu C., Tan X., Li X. Pharmacokinetics of oral and intravenous cannabidiol and its antidepressant-like effects in chronic mild stress mouse model. Env. Toxicol. Pharm. 2019; 70 :103202. doi: 10.1016/j.etap.2019.103202. [PubMed] [CrossRef] [Google Scholar]

135. Sales A.J., Guimaraes F.S., Joca S.R.L. CBD modulates DNA methylation in the prefrontal cortex and hippocampus of mice exposed to forced swim. Behav. Brain Res. 2020; 388 :112627. doi: 10.1016/j.bbr.2020.112627. [PubMed] [CrossRef] [Google Scholar]

136. Sales A.J., Crestani C.C., Guimaraes F.S., Joca S.R.L. Antidepressant-like effect induced by Cannabidiol is dependent on brain serotonin levels. Prog. Neuro-Psychopharmacol. Biol. Psychiatry. 2018; 86 :255–261. doi: 10.1016/j.pnpbp.2018.06.002. [PubMed] [CrossRef] [Google Scholar]

137. Zanelati T.V., Biojone C., Moreira F.A., Guimaraes F.S., Joca S.R. Antidepressant-like effects of cannabidiol in mice: Possible involvement of 5-HT1A receptors. Br. J. Pharmacol. 2010; 159 :122–128. doi: 10.1111/j.1476-5381.2009.00521.x. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

138. El-Alfy A.T., Ivey K., Robinson K., Ahmed S., Radwan M., Slade D., Khan I., ElSohly M., Ross S. Antidepressant-like effect of delta9-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L. Pharm. Biochem. Behav. 2010; 95 :434–442. doi: 10.1016/j.pbb.2010.03.004. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

139. Fogaca M.V., Reis F.M., Campos A.C., Guimaraes F.S. Effects of intra-prelimbic prefrontal cortex injection of cannabidiol on anxiety-like behavior: Involvement of 5HT1A receptors and previous stressful experience. Eur. Neuropsychopharmacol. 2014; 24 :410–419. doi: 10.1016/j.euroneuro.2013.10.012. [PubMed] [CrossRef] [Google Scholar]

140. Resstel L.B., Joca S.R., Moreira F.A., Correa F.M., Guimaraes F.S. Effects of cannabidiol and diazepam on behavioral and cardiovascular responses induced by contextual conditioned fear in rats. Behav. Brain Res. 2006; 172 :294–298. doi: 10.1016/j.bbr.2006.05.016. [PubMed] [CrossRef] [Google Scholar]

141. Rossignoli M.T., Lopes-Aguiar C., Ruggiero R.N., Do Val da Silva R.A., Bueno-Junior L.S., Kandratavicius L., Peixoto-Santos J.E., Crippa J.A., Cecilio Hallak J.E., Zuardi A.W., et al. Selective post-training time window for memory consolidation interference of cannabidiol into the prefrontal cortex: Reduced dopaminergic modulation and immediate gene expression in limbic circuits. Neuroscience. 2017; 350 :85–93. doi: 10.1016/j.neuroscience.2017.03.019. [PubMed] [CrossRef] [Google Scholar]

142. Norris C., Loureiro M., Kramar C., Zunder J., Renard J., Rushlow W., Laviolette S.R. Cannabidiol Modulates Fear Memory Formation Through Interactions with Serotonergic Transmission in the Mesolimbic System. Neuropsychopharmacology. 2016; 41 :2839–2850. doi: 10.1038/npp.2016.93. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

143. Marinho A.L., Vila-Verde C., Fogaca M.V., Guimaraes F.S. Effects of intra-infralimbic prefrontal cortex injections of cannabidiol in the modulation of emotional behaviors in rats: Contribution of 5HT(1)A receptors and stressful experiences. Behav. Brain Res. 2015; 286 :49–56. doi: 10.1016/j.bbr.2015.02.023. [PubMed] [CrossRef] [Google Scholar]

144. Shallcross J., Hamor P., Bechard A.R., Romano M., Knackstedt L., Schwendt M. The Divergent Effects of CDPPB and Cannabidiol on Fear Extinction and Anxiety in a Predator Scent Stress Model of PTSD in Rats. Front. Behav. Neurosci. 2019; 13 :91. doi: 10.3389/fnbeh.2019.00091. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

145. Campos A.C., Ferreira F.R., Guimaraes F.S. Cannabidiol blocks long-lasting behavioral consequences of predator threat stress: Possible involvement of 5HT1A receptors. J. Psychiatr. Res. 2012; 46 :1501–1510. doi: 10.1016/j.jpsychires.2012.08.012. [PubMed] [CrossRef] [Google Scholar]

146. Twardowschy A., Castiblanco-Urbina M.A., Uribe-Marino A., Biagioni A.F., Salgado-Rohner C.J., Crippa J.A., Coimbra N.C. The role of 5-HT1A receptors in the anti-aversive effects of cannabidiol on panic attack-like behaviors evoked in the presence of the wild snake Epicrates cenchria crassus (Reptilia, Boidae) J. Psychopharmacol. 2013; 27 :1149–1159. doi: 10.1177/0269881113493363. [PubMed] [CrossRef] [Google Scholar]

147. Willner P., Muscat R., Papp M. Chronic mild stress-induced anhedonia: A realistic animal model of depression. Neurosci. Biobehav. Rev. 1992; 16 :525–534. doi: 10.1016/S0149-7634(05)80194-0. [PubMed] [CrossRef] [Google Scholar]

148. Willner P. Validity, reliability and utility of the chronic mild stress model of depression: A 10-year review and evaluation. Psychopharmacology. 1997; 134 :319–329. doi: 10.1007/s002130050456. [PubMed] [CrossRef] [Google Scholar]

149. Campos A.C., Ortega Z., Palazuelos J., Fogaca M.V., Aguiar D.C., Diaz-Alonso J., Ortega-Gutierrez S., Vazquez-Villa H., Moreira F.A., Guzman M., et al. The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: Involvement of the endocannabinoid system. Int. J. Neuropsychopharmacol. Off. Sci. J. Coll. Int. Neuropsychopharmacol. 2013; 16 :1407–1419. doi: 10.1017/S1461145712001502. [PubMed] [CrossRef] [Google Scholar]

150. Karniol I.G., Shirakawa I., Kasinski N., Pfeferman A., Carlini E.A. Cannabidiol interferes with the effects of delta 9 – tetrahydrocannabinol in man. Eur. J. Pharm. 1974; 28 :172–177. doi: 10.1016/0014-2999(74)90129-0. [PubMed] [CrossRef] [Google Scholar]

151. Zuardi A.W., Shirakawa I., Finkelfarb E., Karniol I.G. Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects. Psychopharmacology. 1982; 76 :245–250. doi: 10.1007/BF00432554. [PubMed] [CrossRef] [Google Scholar]

152. Zuardi A.W., Cosme R.A., Graeff F.G., Guimaraes F.S. Effects of ipsapirone and cannabidiol on human experimental anxiety. J. Psychopharmacol. 1993; 7 :82–88. doi: 10.1177/026988119300700112. [PubMed] [CrossRef] [Google Scholar]

153. Crippa J.A., Zuardi A.W., Garrido G.E., Wichert-Ana L., Guarnieri R., Ferrari L., Azevedo-Marques P.M., Hallak J.E., McGuire P.K., Filho Busatto G. Effects of cannabidiol (CBD) on regional cerebral blood flow. Neuropsychopharmacology. 2004; 29 :417–426. doi: 10.1038/sj.npp.1300340. [PubMed] [CrossRef] [Google Scholar]

154. Bhattacharyya S., Fusar-Poli P., Borgwardt S., Martin-Santos R., Nosarti C., O’Carroll C., Allen P., Seal M.L., Fletcher P.C., Crippa J.A., et al. Modulation of mediotemporal and ventrostriatal function in humans by Delta9-tetrahydrocannabinol: A neural basis for the effects of Cannabis sativa on learning and psychosis. Arch. Gen. Psychiatry. 2009; 66 :442–451. doi: 10.1001/archgenpsychiatry.2009.17. [PubMed] [CrossRef] [Google Scholar]

155. Crippa J.A., Derenusson G.N., Ferrari T.B., Wichert-Ana L., Duran F.L., Martin-Santos R., Simoes M.V., Bhattacharyya S., Fusar-Poli P., Atakan Z., et al. Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: A preliminary report. J. Psychopharmacol. 2011; 25 :121–130. doi: 10.1177/0269881110379283. [PubMed] [CrossRef] [Google Scholar]

156. Bergamaschi M.M., Queiroz R.H., Chagas M.H., de Oliveira D.C., De Martinis B.S., Kapczinski F., Quevedo J., Roesler R., Schroder N., Nardi A.E., et al. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naive social phobia patients. Neuropsychopharmacology. 2011; 36 :1219–1226. doi: 10.1038/npp.2011.6. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

157. Shannon S., Lewis N., Lee H., Hughes S. Cannabidiol in Anxiety and Sleep: A Large Case Series. Perm. J. 2019; 23 :18–041. doi: 10.7812/TPP/18-041. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

158. Hundal H., Lister R., Evans N., Antley A., Englund A., Murray R.M., Freeman D., Morrison P.D. The effects of cannabidiol on persecutory ideation and anxiety in a high trait paranoid group. J. Psychopharmacol. 2018; 32 :276–282. doi: 10.1177/0269881117737400. [PubMed] [CrossRef] [Google Scholar]

159. Allsop D.J., Copeland J., Lintzeris N., Dunlop A.J., Montebello M., Sadler C., Rivas G.R., Holland R.M., Muhleisen P., Norberg M.M., et al. Nabiximols as an agonist replacement therapy during cannabis withdrawal: A randomized clinical trial. JAMA Psychiatry. 2014; 71 :281–291. doi: 10.1001/jamapsychiatry.2013.3947. [PubMed] [CrossRef] [Google Scholar]

160. Hindocha C., Freeman T.P., Schafer G., Gardener C., Das R.K., Morgan C.J., Curran H.V. Acute effects of delta-9-tetrahydrocannabinol, cannabidiol and their combination on facial emotion recognition: A randomised, double-blind, placebo-controlled study in cannabis users. Eur. Neuropsychopharmacol. 2015; 25 :325–334. doi: 10.1016/j.euroneuro.2014.11.014. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

161. Hurd Y.L., Spriggs S., Alishayev J., Winkel G., Gurgov K., Kudrich C., Oprescu A.M., Salsitz E. Cannabidiol for the Reduction of Cue-Induced Craving and Anxiety in Drug-Abstinent Individuals With Heroin Use Disorder: A Double-Blind Randomized Placebo-Controlled Trial. Am. J. Psychiatry. 2019; 176 :911–922. doi: 10.1176/appi.ajp.2019.18101191. [PubMed] [CrossRef] [Google Scholar]

162. Fusar-Poli P., Allen P., Bhattacharyya S., Crippa J.A., Mechelli A., Borgwardt S., Martin-Santos R., Seal M.L., O’Carrol C., Atakan Z., et al. Modulation of effective connectivity during emotional processing by Delta 9-tetrahydrocannabinol and cannabidiol. Int. J. Neuropsychopharmacol. Off. Sci. J. Coll. Int. Neuropsychopharmacol. 2010; 13 :421–432. doi: 10.1017/S1461145709990617. [PubMed] [CrossRef] [Google Scholar]

163. 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 :392–397. doi: 10.1089/acm.2018.0437. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

164. Beale C., Broyd S.J., Chye Y., Suo C., Schira M., Galettis P., Martin J.H., Yucel M., Solowij N. Prolonged Cannabidiol Treatment Effects on Hippocampal Subfield Volumes in Current Cannabis Users. Cannabis Cannabinoid Res. 2018; 3 :94–107. doi: 10.1089/can.2017.0047. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

165. Solowij N., Broyd S.J., Beale C., Prick J.A., Greenwood L.M., van Hell H., Suo C., Galettis P., Pai N., Fu S., et al. Therapeutic Effects of Prolonged Cannabidiol Treatment on Psychological Symptoms and Cognitive Function in Regular Cannabis Users: A Pragmatic Open-Label Clinical Trial. Cannabis Cannabinoid Res. 2018; 3 :21–34. doi: 10.1089/can.2017.0043. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

166. Crippa J.A., Hallak J.E., Machado-de-Sousa J.P., Queiroz R.H., Bergamaschi M., Chagas M.H., Zuardi A.W. Cannabidiol for the treatment of cannabis withdrawal syndrome: A case report. J. Clin. Pharm. Ther. 2013; 38 :162–164. doi: 10.1111/jcpt.12018. [PubMed] [CrossRef] [Google Scholar]

167. Gruber S. NCT02548559. Sublingual Cannabidiol for Anxiety. [(accessed on 19 November 2020)]; Available online: > NCT02548559.

168. Gruber S., Mclean Hospital NTC04286594. A Clinical Trial of a Hemp-Derived Cannabidiol Product for Anxiety. [(accessed on 19 November 2020)]; Available online: > NCT04286594.

169. McMaster University NCT03549819. Cannabidiol for the Treatment of Anxiety Disorders: An 8-Week Pilot Study. [(accessed on 19 November 2020)]; Available online: > NCT03549819.

170. CB2 Insights NCT04267679. Cannabidiol for Anxiety. [(accessed on 19 November 2020)]; Available online: > NCT04267679.

171. University of Texas at Austin NCT04197102. Use of CBD Oil in the Treatment of Posttraumatic Stress Disorder. [(accessed on 19 November 2020)]; Available online: > NCT04197102.

172. National Institutes of Health (NIH) NCT03248167. Cannabidiol as a Treatment for AUD Comorbid with PTSD. [(accessed on 19 November 2020)]; Available online: > NCT03248167.

173. Multidisciplinary Association for Psychedelic Studies NCT02759185. Study of Four Different Potencies of Smoked Marijuana in 76 Veterans with PTSD. [(accessed on 19 November 2020)]; Available online: > NCT02759185.

174. Portenoy R.K., Ganae-Motan E.D., Allende S., Yanagihara R., Shaiova L., Weinstein S., McQuade R., Wright S., Fallon M.T. Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: A randomized, placebo-controlled, graded-dose trial. J. Pain Off. J. Am. Pain Soc. 2012; 13 :438–449. doi: 10.1016/j.jpain.2012.01.003. [PubMed] [CrossRef] [Google Scholar]

175. Corroon J., Phillips J.A. A Cross-Sectional Study of Cannabidiol Users. Cannabis Cannabinoid Res. 2018; 3 :152–161. doi: 10.1089/can.2018.0006. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

176. Federal University of Rio Grande do Sul. University of Sao Paulo NCT03310593. Cannabidiol as an Adjunctive Treatment for Bipolar Depression. [(accessed on 19 November 2020)]; Available online: > NCT03310593.

177. APA . Diagnostic and Statistical Manual of Mental Disorders. 5th ed. American Psychiatric Association (APA); Washington, DC, USA: 2013. [Google Scholar]

178. Andreasen N.C. Symptoms, signs, and diagnosis of schizophrenia. Lancet. 1995; 346 :477–481. doi: 10.1016/S0140-6736(95)91325-4. [PubMed] [CrossRef] [Google Scholar]

179. Laursen T.M., Nordentoft M., Mortensen P.B. Excess early mortality in schizophrenia. Annu. Rev. Clin. Psychol. 2014; 10 :425–448. doi: 10.1146/annurev-clinpsy-032813-153657. [PubMed] [CrossRef] [Google Scholar]

180. Kahn R.S., Winter van Rossum I., Leucht S., McGuire P., Lewis S.W., Leboyer M., Arango C., Dazzan P., Drake R., Heres S., et al. Amisulpride and olanzapine followed by open-label treatment with clozapine in first-episode schizophrenia and schizophreniform disorder (OPTiMiSE): A three-phase switching study. Lancet Psychiatry. 2018; 5 :797–807. doi: 10.1016/S2215-0366(18)30252-9. [PubMed] [CrossRef] [Google Scholar]

181. Maric N.P., Jovicic M.J., Mihaljevic M., Miljevic C. Improving Current Treatments for Schizophrenia. Drug Dev. Res. 2016; 77 :357–367. doi: 10.1002/ddr.21337. [PubMed] [CrossRef] [Google Scholar]

182. Zuardi A.W., Crippa J.A., Hallak J.E., Moreira F.A., Guimaraes F.S. Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug. Braz. J. Med. Biol. Res. 2006; 39 :421–429. doi: 10.1590/S0100-879X2006000400001. [PubMed] [CrossRef] [Google Scholar]

183. Jones C.A., Watson D.J., Fone K.C. Animal models of schizophrenia. Br. J. Pharmacol. 2011; 164 :1162–1194. doi: 10.1111/j.1476-5381.2011.01386.x. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

184. Deiana S., Watanabe A., Yamasaki Y., Amada N., Kikuchi T., Stott C., Riedel G. MK-801-induced deficits in social recognition in rats: Reversal by aripiprazole, but not olanzapine, risperidone, or cannabidiol. Behav. Pharm. 2015; 26 :748–765. doi: 10.1097/FBP.0000000000000178. [PubMed] [CrossRef] [Google Scholar]

185. Renard J., Loureiro M., Rosen L.G., Zunder J., de Oliveira C., Schmid S., Rushlow W.J., Laviolette S.R. Cannabidiol Counteracts Amphetamine-Induced Neuronal and Behavioral Sensitization of the Mesolimbic Dopamine Pathway through a Novel mTOR/p70S6 Kinase Signaling Pathway. J. Neurosci. 2016; 36 :5160–5169. doi: 10.1523/JNEUROSCI.3387-15.2016. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

186. Gururajan A., Taylor D.A., Malone D.T. Effect of cannabidiol in a MK-801-rodent model of aspects of schizophrenia. Behav. Brain Res. 2011; 222 :299–308. doi: 10.1016/j.bbr.2011.03.053. [PubMed] [CrossRef] [Google Scholar]

187. Gururajan A., Taylor D.A., Malone D.T. Cannabidiol and clozapine reverse MK-801-induced deficits in social interaction and hyperactivity in Sprague-Dawley rats. J. Psychopharmacol. 2012; 26 :1317–1332. doi: 10.1177/0269881112441865. [PubMed] [CrossRef] [Google Scholar]

188. Osborne A.L., Solowij N., Babic I., Huang X.F., Weston-Green K. Improved Social Interaction, Recognition and Working Memory with Cannabidiol Treatment in a Prenatal Infection (poly I:C) Rat Model. Neuropsychopharmacology. 2017; 42 :1447–1457. doi: 10.1038/npp.2017.40. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

189. Osborne A.L., Solowij N., Babic I., Lum J.S., Newell K.A., Huang X.F., Weston-Green K. Effect of cannabidiol on endocannabinoid, glutamatergic and GABAergic signalling markers in male offspring of a maternal immune activation (poly I:C) model relevant to schizophrenia. Prog. Neuro-Psychopharmacol. Biol. Psychiatry. 2019; 95 :109666. doi: 10.1016/j.pnpbp.2019.109666. [PubMed] [CrossRef] [Google Scholar]

190. Jimenez Naranjo C., Osborne A.L., Weston-Green K. Effect of cannabidiol on muscarinic neurotransmission in the pre-frontal cortex and hippocampus of the poly I:C rat model of schizophrenia. Prog. Neuro-Psychopharmacol. Biol. Psychiatry. 2019; 94 :109640. doi: 10.1016/j.pnpbp.2019.109640. [PubMed] [CrossRef] [Google Scholar]

191. Stark T., Ruda-Kucerova J., Iannotti F.A., D’Addario C., Di Marco R., Pekarik V., Drazanova E., Piscitelli F., Bari M., Babinska Z., et al. Peripubertal cannabidiol treatment rescues behavioral and neurochemical abnormalities in the MAM model of schizophrenia. Neuropharmacology. 2019; 146 :212–221. doi: 10.1016/j.neuropharm.2018.11.035. [PubMed] [CrossRef] [Google Scholar]

192. Gomes F.V., Issy A.C., Ferreira F.R., Viveros M.P., Del Bel E.A., Guimaraes F.S. Cannabidiol Attenuates Sensorimotor Gating Disruption and Molecular Changes Induced by Chronic Antagonism of NMDA receptors in Mice. Int. J. Neuropsychopharmacol. Off. Sci. J. Coll. Int. Neuropsychopharmacol. 2014; 18 doi: 10.1093/ijnp/pyu041. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

193. Gomes F.V., Llorente R., Del Bel E.A., Viveros M.P., Lopez-Gallardo M., Guimaraes F.S. Decreased glial reactivity could be involved in the antipsychotic-like effect of cannabidiol. Schizophr. Res. 2015; 164 :155–163. doi: 10.1016/j.schres.2015.01.015. [PubMed] [CrossRef] [Google Scholar]

194. Rodrigues da Silva N., Gomes F.V., Sonego A.B., Silva N.R.D., Guimaraes F.S. Cannabidiol attenuates behavioral changes in a rodent model of schizophrenia through 5-HT1A, but not CB1 and CB2 receptors. Pharm. Res. 2020; 156 :104749. doi: 10.1016/j.phrs.2020.104749. [PubMed] [CrossRef] [Google Scholar]

195. Peres F.F., Diana M.C., Suiama M.A., Justi V., Almeida V., Bressan R.A., Zuardi A.W., Hallak J.E., Crippa J.A., Abilio V.C. Peripubertal treatment with cannabidiol prevents the emergence of psychosis in an animal model of schizophrenia. Schizophr. Res. 2016; 172 :220–221. doi: 10.1016/j.schres.2016.02.004. [PubMed] [CrossRef] [Google Scholar]

196. Moreira F.A., Guimaraes F.S. Cannabidiol inhibits the hyperlocomotion induced by psychotomimetic drugs in mice. Eur. J. Pharm. 2005; 512 :199–205. doi: 10.1016/j.ejphar.2005.02.040. [PubMed] [CrossRef] [Google Scholar]

197. Pedrazzi J.F., Issy A.C., Gomes F.V., Guimaraes F.S., Del-Bel E.A. Cannabidiol effects in the prepulse inhibition disruption induced by amphetamine. Psychopharmacology. 2015; 232 :3057–3065. doi: 10.1007/s00213-015-3945-7. [PubMed] [CrossRef] [Google Scholar]

198. Long L.E., Malone D.T., Taylor D.A. Cannabidiol reverses MK-801-induced disruption of prepulse inhibition in mice. Neuropsychopharmacology. 2006; 31 :795–803. doi: 10.1038/sj.npp.1300838. [PubMed] [CrossRef] [Google Scholar]

199. Long L.E., Chesworth R., Huang X.F., Wong A., Spiro A., McGregor I.S., Arnold J.C., Karl T. Distinct neurobehavioural effects of cannabidiol in transmembrane domain neuregulin 1 mutant mice. PLoS ONE. 2012; 7 :e34129. doi: 10.1371/journal.pone.0034129. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

200. Ligresti A., Moriello A.S., Starowicz K., Matias I., Pisanti S., De Petrocellis L., Laezza C., Portella G., Bifulco M., Di Marzo V. Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma. J. Pharmacol. Exp. Ther. 2006; 318 :1375–1387. doi: 10.1124/jpet.106.105247. [PubMed] [CrossRef] [Google Scholar]

201. Leweke F.M., Piomelli D., Pahlisch F., Muhl D., Gerth C.W., Hoyer C., Klosterkotter J., Hellmich M., Koethe D. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl. Psychiatry. 2012; 2 :e94. doi: 10.1038/tp.2012.15. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

202. Saletti P.G., Tomaz C. Cannabidiol effects on prepulse inhibition in nonhuman primates. Rev. Neurosci. 2018; 30 :95–105. doi: 10.1515/revneuro-2017-0101. [PubMed] [CrossRef] [Google Scholar]

203. De Petrocellis L., Vellani V., Schiano-Moriello A., Marini P., Magherini P.C., Orlando P., Di Marzo V. Plant-derived cannabinoids modulate the activity of transient receptor potential channels of ankyrin type-1 and melastatin type-8. J. Pharmacol. Exp. Ther. 2008; 325 :1007–1015. doi: 10.1124/jpet.107.134809. [PubMed] [CrossRef] [Google Scholar]

204. Corfas G., Roy K., Buxbaum J.D. Neuregulin 1-erbB signaling and the molecular/cellular basis of schizophrenia. Nat. Neurosci. 2004; 7 :575–580. doi: 10.1038/nn1258. [PubMed] [CrossRef] [Google Scholar]

205. Kano M., Ohno-Shosaku T., Hashimotodani Y., Uchigashima M., Watanabe M. Endocannabinoid-mediated control of synaptic transmission. Physiol. Rev. 2009; 89 :309–380. doi: 10.1152/physrev.00019.2008. [PubMed] [CrossRef] [Google Scholar]

206. Bakas T., van Nieuwenhuijzen P.S., Devenish S.O., McGregor I.S., Arnold J.C., Chebib M. The direct actions of cannabidiol and 2-arachidonoyl glycerol at GABAA receptors. Pharm. Res. 2017; 119 :358–370. doi: 10.1016/j.phrs.2017.02.022. [PubMed] [CrossRef] [Google Scholar]

207. Pretzsch C.M., Freyberg J., Voinescu B., Lythgoe D., Horder J., Mendez M.A., Wichers R., Ajram L., Ivin G., Heasman M., et al. Effects of cannabidiol on brain excitation and inhibition systems; a randomised placebo-controlled single dose trial during magnetic resonance spectroscopy in adults with and without autism spectrum disorder. Neuropsychopharmacology. 2019; 44 :1398–1405. doi: 10.1038/s41386-019-0333-8. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

208. Lewis D.A., Levitt P. Schizophrenia as a disorder of neurodevelopment. Annu. Rev. Neurosci. 2002; 25 :409–432. doi: 10.1146/annurev.neuro.25.112701.142754. [PubMed] [CrossRef] [Google Scholar]

209. Bhattacharyya S., Morrison P.D., Fusar-Poli P., Martin-Santos R., Borgwardt S., Winton-Brown T., Nosarti C., CM O.C., Seal M., Allen P., et al. Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology. 2010; 35 :764–774. doi: 10.1038/npp.2009.184. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

210. Devane W.A., Hanus L., Breuer A., Pertwee R.G., Stevenson L.A., Griffin G., Gibson D., Mandelbaum A., Etinger A., Mechoulam R. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992; 258 :1946–1949. doi: 10.1126/science.1470919. [PubMed] [CrossRef] [Google Scholar]

211. Petitet F., Jeantaud B., Reibaud M., Imperato A., Dubroeucq M.C. Complex pharmacology of natural cannabinoids: Evidence for partial agonist activity of delta9-tetrahydrocannabinol and antagonist activity of cannabidiol on rat brain cannabinoid receptors. Life Sci. 1998; 63 :PL1–PL6. doi: 10.1016/S0024-3205(98)00238-0. [PubMed] [CrossRef] [Google Scholar]

212. Boggs D.L., Nguyen J.D., Morgenson D., Taffe M.A., Ranganathan M. Clinical and Preclinical Evidence for Functional Interactions of Cannabidiol and Delta(9)-Tetrahydrocannabinol. Neuropsychopharmacology. 2018; 43 :142–154. doi: 10.1038/npp.2017.209. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

213. Bioque M., Garcia-Bueno B., Macdowell K.S., Meseguer A., Saiz P.A., Parellada M., Gonzalez-Pinto A., Rodriguez-Jimenez R., Lobo A., Leza J.C., et al. Peripheral endocannabinoid system dysregulation in first-episode psychosis. Neuropsychopharmacology. 2013; 38 :2568–2577. doi: 10.1038/npp.2013.165. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

214. De Marchi N., De Petrocellis L., Orlando P., Daniele F., Fezza F., Di Marzo V. Endocannabinoid signalling in the blood of patients with schizophrenia. Lipids Health Dis. 2003; 2 :5. doi: 10.1186/1476-511X-2-5. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

215. Zuardi A.W., Crippa J.A., Hallak J.E., Pinto J.P., Chagas M.H., Rodrigues G.G., Dursun S.M., Tumas V. Cannabidiol for the treatment of psychosis in Parkinson’s disease. J. Psychopharmacol. 2009; 23 :979–983. doi: 10.1177/0269881108096519. [PubMed] [CrossRef] [Google Scholar]

216. Zuardi A.W., Rodrigues J.A., Cunha J.M. Effects of cannabidiol in animal models predictive of antipsychotic activity. Psychopharmacology. 1991; 104 :260–264. doi: 10.1007/BF02244189. [PubMed] [CrossRef] [Google Scholar]

217. Boggs D.L., Surti T., Gupta A., Gupta S., Niciu M., Pittman B., Schnakenberg Martin A.M., Thurnauer H., Davies A., D’Souza D.C., et al. The effects of cannabidiol (CBD) on cognition and symptoms in outpatients with chronic schizophrenia a randomized placebo controlled trial. Psychopharmacology. 2018; 235 :1923–1932. doi: 10.1007/s00213-018-4885-9. [PubMed] [CrossRef] [Google Scholar]

218. McGuire P., Robson P., Cubala W.J., Vasile D., Morrison P.D., Barron R., Taylor A., Wright S. Cannabidiol (CBD) as an Adjunctive Therapy in Schizophrenia: A Multicenter Randomized Controlled Trial. Am. J. Psychiatry. 2018; 175 :225–231. doi: 10.1176/appi.ajp.2017.17030325. [PubMed] [CrossRef] [Google Scholar]

219. O’Neill A., Wilson R., Blest-Hopley G., Annibale L., Colizzi M., Brammer M., Giampietro V., Bhattacharyya S. Normalization of mediotemporal and prefrontal activity, and mediotemporal-striatal connectivity, may underlie antipsychotic effects of cannabidiol in psychosis. Psychol. Med. 2020:1–11. doi: 10.1017/S0033291719003519. [PubMed] [CrossRef] [Google Scholar]

220. Bhattacharyya S., Wilson R., Appiah-Kusi E., O’Neill A., Brammer M., Perez J., Murray R., Allen P., Bossong M.G., McGuire P. 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 :1107–1117. doi: 10.1001/jamapsychiatry.2018.2309. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

221. Wilson R., Bossong M.G., Appiah-Kusi E., Petros N., Brammer M., Perez J., Allen P., McGuire P., Bhattacharyya S. Cannabidiol attenuates insular dysfunction during motivational salience processing in subjects at clinical high risk for psychosis. Transl. Psychiatry. 2019; 9 :203. doi: 10.1038/s41398-019-0534-2. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

222. Hallak J.E., Machado-de-Sousa J.P., Crippa J.A., Sanches R.F., Trzesniak C., Chaves C., Bernardo S.A., Regalo S.C., Zuardi A.W. Performance of schizophrenic patients in the Stroop Color Word Test and electrodermal responsiveness after acute administration of cannabidiol (CBD) Braz. J. Psychiatry. 2010; 32 :56–61. doi: 10.1590/S1516-44462010000100011. [PubMed] [CrossRef] [Google Scholar]

223. Sheppard Pratt Health System. University of California, Los Angeles NTC03883360. Effects of Cannabidiol on Psychiatric Symptons, Cognition, and Cannabis Consumption in Cannabis Users with Recent-Onset Psychosis. [(accessed on 19 November 2020)]; Available online: > NCT03883360.

224. Central Institute of Mental Health, Mannheim NCT02926859. Enhancing Recovery in Early Schizophrenia. [(accessed on 19 November 2020)]; Available online: > NCT02926859.

225. Cadenhead K., University of California, San Diego. NCT04411225. Center for Medicinal Cannabis Research Effects of cannabidiol (CBD) versus Placebo as an Adjunct to Treatment in Early Psychosis. [(accessed on 19 November 2020)]; Available online: > NCT04411225.

226. Elsaid S., Kloiber S., Le Foll B. Effects of cannabidiol (CBD) in neuropsychiatric disorders: A review of pre-clinical and clinical findings. Prog. Mol. Biol. Transl. Sci. 2019; 167 :25–75. doi: 10.1016/bs.pmbts.2019.06.005. [PubMed] [CrossRef] [Google Scholar]

227. Shi Q.X., Yang L.K., Shi W.L., Wang L., Zhou S.M., Guan S.Y., Zhao M.G., Yang Q. The novel cannabinoid receptor GPR55 mediates anxiolytic-like effects in the medial orbital cortex of mice with acute stress. Mol. Brain. 2017; 10 :38. doi: 10.1186/s13041-017-0318-7. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

228. Rahimi A., Moghaddam A.H., Roohbakhsh A. Central administration of GPR55 receptor agonist and antagonist modulates anxiety-related behaviors in rats. Fundam. Clin. Pharm. 2015; 29 :185–190. doi: 10.1111/fcp.12099. [PubMed] [CrossRef] [Google Scholar]

Articles from Biomolecules are provided here courtesy of Multidisciplinary Digital Publishing Institute (MDPI)

11 Best CBD Oil for Anxiety & Depression for 2022 includes affiliate links in some of our stories. If you buy through links on this page, we may receive a commission.

If you suffer from anxiety, panic attacks, or depression, you know that these conditions have more than just a mental and emotional impact. More often than not, mental health disorders also impact physical health, social health, and just overall well-being.

While many mental health disorders are treated with prescription medications and various therapies, there are also all-natural options like CBD which may offer effective relief. While the idea of adding a new supplement to your daily routine may make you unsure or even worried, you can rest assured that CBD oil is a safe option that will allow you to enjoy the world of natural healing.

Mental health issues like anxiety and depression can be much more difficult to manage. Finding the right combination of treatments can feel like an uphill battle, leaving people frustrated and in no better of a mental state.

There is no shortage of medications that are available to those that suffer from anxiety and depression. And though these prescriptions can be effective when taken at the right dose for months and months, they come with a laundry list of potential side effects, some of which are extremely scary!

Treating anxiety or any other mental health issue shouldn’t cause you more anxiety. If you’re interested in an effective treatment that has no adverse side effects on the mind or body, consider giving CBD oil a try.

While most herbal therapies are known to only offer mild effects, CBD has shown to be extremely effective in fighting anxiety, especially when taken at the appropriate dosage consistently. The best part is that there are little to side effects, and any side effects you may experience are extremely mild.

If you’re new to CBD, we’ve got you covered! In this guide we’ll discuss how CBD oil can be used to overcome mental health conditions such as anxiety and depression. We’ll also cover important details such as how much CBD you should take while also providing a list of some of the best CBD oils on the market.

Don’t go another day feeling less than your best! Keep reading to learn everything there is to know about using CBD oil for treating anxiety, depression, and other mental health disorders.

Top 7 CBD Oils for Anxiety And Depression

What to Consider When Choosing CBD Oil for Treating Anxiety

These days, the market is flooded with CBD products. The consumer demand for all-natural products is higher than ever before. And with increased demand comes increased supply. Chances are that you’ve come across a CBD product online or maybe even at a local store.

While it’s nice to have so many options to choose from, it’s important to know that not all CBD products are made with the consumer in mind. There are countless low quality and even potentially dangerous products on the market that exist for brands to make a quick buck.

So before buying CBD oil or any kind of VBD product, here are some of the most important factors that you’ll want to consider. This way you can get the relief you want while also having peace of mind that you’re using a safe, effective product.

Location makes a world of a difference when it comes to hemp plants. Ideally you’ll want to choose a product that contains CBD that’s extracted from U.S. or EU grown hemp. Farmlands in these areas are much more strictly regulated, so you can ensure that the product you’re buying uses CBD that is potent, quality-controlled, contaminant-free, and GMO-free. Hemp plants grown in the U.S. and the EU also tend to contain lower levels of THC.

Low THC levels are important for many reasons. First, THC has psychoactive properties that can make you feel high or euphoric, which isn’t an experience that most CBD users are looking for. Second, in order for a CBD product to be legal in the U.S., it must contain no more than 0.3% THC.

See also  Busted for cbd oil

By choosing a product that’s made with hemp plants grown in the U.S. or EU, there’s a much lower chance of it being low quality or potentially harmful. Having a great experience with CBD starts with a product that’s extracted from safe, mature plants.

Not all CBD is the same! In fact, there are three different types of CBD that can be used to create CBD oil. The three types include isolate, broad-spectrum, and full-spectrum. Understanding the differences between each extract type while helping to guide you in choosing a product that best meets your needs.

As the name implies, CBD isolate is CBD that has been isolated from all of the other naturally occurring plant compounds found in hemp. These products contain strictly CBD and nothing else.

On the opposite side of the spectrum is full spectrum CBD. Full spectrum CBD contains CBD and all other plant compounds, including THC, other cannabinoids, terpenes, flavonoids, fatty acids, and other elements. However, a legal CBD oil that uses full spectrum CBD must still contain no more than 0.3% THC. This is a trace amount that won’t cause any psychoactive effects.

The third kind of CBD is broad spectrum. This kind of CBD contains all of the other plant compounds with the exception of THC. All traces of THC are removed, so you don’t have to worry about any exposure to the cannabinoid.

The potency of CBD oil is measured in milligrams and is determined by the product’s CBD concentration. The more potent a product is, the more efficient it is likely to be. You will find that many brands offer various potencies to choose from. This gives consumers the flexibility to adjust their dose as needed, which is a must for first-time users

Most CBD oil tinctures are available in 30mL bottles. But, there are some CBD brands that offer many sizes, to include 15mL and 60mL. If you’re new to CBD, buy the smallest bottle possible. This way you aren’t spending money on a large bottle of a product that may not work best for you.

It’s safe to say that to most people, CBD oil doesn’t exactly taste good. This is why so many CBD companies offer flavored CBD oil that is designed to stimulate your sense of taste and smell to influence the experience and to improve your overall well-being.

Since everyone has their own preference, it’s nice to have a variety of options to choose from. Most CBD brands offer fruit-based flavors, but you’ll also find some that lean more towards the sweeter side of things, like chocolate and vanilla.

The flavor you choose is ultimately up to you, but for new users, it’s reassuring to know that there are many flavors to pick from.

A high quality CBD oil is made with high quality ingredients. A product’s safety and efficacy is based on the ingredients it uses. When considering CBD oil, you’ll want to ensure that the product you choose uses natural and even organic ingredients. This way you don’t have to worry about potentially unsafe chemicals or other ingredients that could negatively impact your health.

A trusted CBD brand has nothing to hide about its products. A quality CBD oil will have undergone stringent testing at a third-party lab, with these results being readily available on the brand website. Third party labs test for a variety of components, to include a product’s ingredients, potency, safety, and quality.

A company that has a solid reputation is one that is well-liked by its customers. This often means that the products it creates are high quality and offer the expected benefits and overall experience. In the CBD industry, brand reputation is crucial.

Consumers, now more than ever, are interested in transparency. They want to know how CBD brands conduct business and their underlying business practices, to include things like how CBD is grown, manufactured, and extracted. A transparent company is one that welcomes discussion and customer opinions.

These companies are often seen as more reliable and trustworthy by consumers.

Customer service is the first line of direct engagement with customers. It’s important to buy CBD products from a brand that offers customer-focused customer service representatives. This portion of the company should also be transparent and committed to ensuring customers are happy and loyal to the brand.

User-friendly policies are a must when buying from any CBD company. Because the industry is so competitive, a growing number of companies now offer great shipping, return, and refund policies. Other important company policies to consider include reward programs and discounts. You’ll find that many CBD brands offer discounts for military personnel, veterans, and people with financial issues.

The internet is not only where we learn about companies, but how we research products and ultimately complete transactions. When choosing a CBD brand, pay close attention to the website. Look at things like how easy it is to browse through the products, how much information is available, and the presence of customer reviews and testimonials.

Online shopping should be a pleasant experience. The better a website is in regards to user interface and user experience, the more likely it is that customers will make a purchase.

Top 10 CBD Oils For Anxiety & Depression (Full Reviews)

1. Penguin CBD

● Rejuvenates the body and mind

● Made from USA grown hemp

Penguin CBD is another great brand that offers high quality CBD oil and other CBD products. All hemp plants are grown in Oregon following safe farming practices and regulations. Plants are grown without pesticides and other harmful chemicals.

This brand has been named in a variety of sources, including Healthline and Merry Jane. What’s nice about Penguin CBD is that the brand is dedicated to creating safe, trusted, and effective products. All of the customer reviews on the sites offer nothing but positive words, which gives consumers peace of mind that they’re buying a trusted product.

Wondering about the name? Penguin CBD embraces the life of a penguin. These cute creatures are always calm and live life simply. They walk with their friends, work together, and stay cool, even when under pressure. CBD products from this brand are designed to help people embrace a simple, calmer lifestyle.

Product & Brand Highlights

Hemp Source : Oregon, USA

Extract Types : Refined broad spectrum CBD

● Cookies and cream

● Green Scientific Labs

● Infinite Chemicals Analysis

Shipping Policy: Free 2-5 business day shipping through USPS

Return & Refund Policies : Full refunds are available within 30 days of purchase.

Website Experience : Bright and fun website. Very easy to use and navigate. Provides a lot of product information along with photos and customer reviews. There is also a blog that is informational and allows consumers to interact with the brand.

Full spectrum hemp extract loaded with additional cannabinoids (THC, CBG, CBN, CBC, CBDV)

Available in 1500mg strength

25mg of CBD and 2mg of THC

Free shipping on all orders

Tested by independent third-party labs

30-Day Satisfaction Guarantee

Everest is a brand that specializes in all sorts of hemp-derived products, from CBD to Delta 8. While their CBD selection is small at the moment, their offerings are among the very best you can find on the market.

Their CBD oil in particular is a standout. It’s a full spectrum extract with a wide range of cannabinoids. So not only do you get 25mg of CBD with every dose, but also a healthy amount of THC, CBG, CBN, CBC, and other beneficial compounds that work better together. It’s exactly what you need to boost your mood and relieve stress.

Everest’s CBD oil contains 1500mg of CBD per bottle and comes in a blueberry flavor. Every batch is tested by an independent lab, with the results posted directly to their website. They also offer a 30-day return guarantee if you are not satisfied with their product.

Product & Brand Highlights

Hemp Source: American Grown

Extract Types: Full Spectrum Hemp Extract

Organic Medium-Chain Triglyceride (MCT) Oil

Full Spectrum Hemp Extract Natural Flavors

Naturally occurring Cannabinoids: CBD, THC, CBG, CBN, CBC, CBDV, Natural Terpenes

Lab Results: Green Scientific Labs

Shipping Policy: Free shipping in the US on all orders

Return & Refund Policies : 30-day satisfaction guarantee

Website Experience: Simple and easy to navigate. Provides just the right amount of information about Delta 8, their products, and their policies. No difficulty at all in finding the product pages and placing your order.

3. R+R Medicinals: Best Performance

● Full-Spectrum CBD Oil

● CO2 Extracted CBD Oil

● Hundreds of 5-star Google Reviews

R+R Medicinals is quickly becoming one of the most trusted and popular CBD brands by proving one thing – they make the CBD that works. They are employee, minority, and veteran-owned, and truly focus on giving customers the experience they’ve been looking for in CBD.

Using supercritical CO2 extraction on their proprietary Cherry strain of USDA Certified Organic hemp, they yield an unparalleled profile of cannabinoids, terpenes, and other phytonutrients in their products that translate into guaranteed performance. Their 1000mg Fresh Mint Tincture is their best seller and of incredible value for a Full-Spectrum product at $46.99. R+R boasts impressive levels of CBD, CBG, CBC, CBN, CBL, and more in their products so you can truly feel the entourage effect. They also publish third party certificates of analysis on their site for every batch they make.

In addition to being USDA Organic Certified, they are also US Hemp Authority Certified, and they have hundreds of 5-star ratings on Google, so you can take comfort in knowing they do things with the highest standards of safety and quality in mind.

Product & Brand Highlights

Hemp Source: Colorado, US (Outdoor Farm)

Extract Types: Full-Spectrum and Broad Spectrum (THC-Free)

Flavors: Fresh Mint and Unflavored

Ingredients: Organic MCT Oil from Coconut, Organic Industrial Hemp Extract, Organic Natural Mint Flavoring

● Lab Results: SC Labs

Coupon Code: RR15OFF for 15% Off

Shipping Policy : Free Shipping across the US

Return & Refund Policies : 30-Day Guarantee

Website Experience : Easy-to-navigate, very informative, and a professional-looking website

” RRWORKS20 ” for 20% off their first order!


· Made in the USA using organic and sustainable practices

· Vegan, Non-GMO and made with Organic Ingredients

FOCL is a premium CBD brand, based out of Los Angeles and Denver and is ranked by Healthline as one of the best CBD oils on the market for anxiety.

The team at FOCL (short for Focus) is passionate about wellness and obsessed with producing products that actually work. Their product line includes premium CBD oil and gummies, as well as unique wellness formulas designed specifically for Focus, Sleep, Pain Relief and Immunity.

Their ultra pure CBD Drops are ranked among the best in the industry and get rave reviews from loyal customers. Check out their 2000mg for best value .

Product and Brand Highlights

Hemp Source: Grown in the USA using organic and sustainable practices

· True Broad Spectrum CBD (test results show a robust profile of minor cannabinoids)

· Organic MCT Oil

· Organic natural flavors

· Published on website

Shipping Policy: Free shipping for orders $65+ and for all subscriptions

Return & Refund Policy: Full refund available within 60 days of receiving order

5. Colorado Botanicals

● Organically-grown Colorado Hemp

● Uses pharmaceutical separation technique to purify oil

● Natural hemp-derived terpenes

● Named 2021’s #1 CBD Company by Observer

● All-natural, non-GMO, and organic CBD oils

Rated as 2021’s #1 CBD company by Observer, Colorado Botanicals is known for its commitment to quality and transparency and is a leading force of change in the CBD industry.

Colorado Botanicals manufactures its broad-spectrum CBD products through a proprietary extraction and purification process. Instead of using high heat to remove unwanted compounds, the company uses a pharmaceutical separation technique that preserves naturally occurring terpenes while still pulling out THC, fats, waxes, and chlorophyll. This means terpenes don’t need to be added from other plants. When you try a Colorado Botanicals product, you’re getting one of the purest CBD oils on the market.

What we absolutely love about this brand is how open it is about its process. Every batch of CBD is tested in third-party labs, and those results are posted on its website. It’s easy for customers to see which terpenes are in its products as well as how much of each is present. Whether you’re buying the 750mg oil or the gummies or the topicals , you’re getting one of the CBD industry’s best products. Colorado Botanicals holds itself to a high standard, and that’s apparent in the potency and effectiveness of its products.

Product & Brand Highlights

● Organically-grown Colorado Hemp

● Broad Spectrum CBD Extract

● MCT Oil (contains coconut)

● Broad spectrum CBD extract

● Flavoring (if applicable)

● Free 3-5 day shipping over $50, $4-6 for orders under $50

● Priority and overnight options available

Returns & Refund Policy

● 60-day risk-free trial

● Prepaid shipping label provided to send products back (opened and unopened) for a full refund

● Modern and user-friendly with access to a great deal of product information and third-party lab results. Intuitive, engaging, fast, and incredibly helpful in leading customers to the right product.

6. Batch CBD

● Vertically integrated company for quality control

● Potent options available

● Best Valued CBD Oil for Anxiety

● Enhanced with natural calming terpenes

● LAB Testing by independent labs

● Vegan, Gluten-Free, and eco friendly

BATCH’s Calm blend was perfectly crafted for anxious people to calm nerves during the day or nighttime. One full dropper will help ease your mind with an enhanced blend of relaxing terpenes (limonene, nerolidol, and myrcene) after a long day. BATCH’s tinctures deliver therapeutic benefits while keeping their ingredient list minimal and vegan so that you can experience CBD in its purest full-spectrum form.

BATCH has gained a reputation in the industry for their radical dedication to transparency, the soil, and their customers. Often unseen in the CBD industry, they are vertically integrated and offer lab tours upon request. Drawing inspiration from Milwaukee’s craft breweries, their CBD is extracted using a proprietary small-batch process . Give the highly-regarded CALM CBD blend a try and get back to feeling like your best self

Product & Brand Highlights

Hemp Source: Wisconsin, US

Extract Types: Full-spectrum cannabinoid blend

● Subtle Mint taste

● Full-spectrum hemp extract

● Organic Peppermint & Blackseed Oil

● Enhanced with calming terpenes (limonene, nerolidol, myrcene)

● Medium-chain triglycerides (fractionated coconut oil — used as a carrier oil)

Lab Results: Desert Valley Testing

Shipping Policy: Free shipping in the US on all orders $15+

Return & Refund Policies: 30-day money-back guarantee

Website Experience: Modern, clean, with ample information to educate shoppers and products arranged in an easy-to-navigate manner. Extremely transparent featuring videos of their proprietary process and farmers.

7. Verma Farms

● Made from U.S. grown hemp plants

● Contains all natural ingredients

● Available in many delicious flavors

● Award winning products

● Pure, powerful, and pesticide-free

Verma Farms is one of the most reputable names in the CBD industry. The company is best known for its Hawaii-inspired CBD gummies, but has also received awards for its CBD oils. In fact, Forbes and Entrepreneur Media ranked Verma Farms’ CBD oil kit as the top product on the market today!

Verma Farms products are made with all natural, high quality ingredients that are used to improve overall well-being. There are a variety of CBD oils to choose from, and each contains a dropper for easy dosing.

What’s great about this brand is the many flavors that are available. You can escape to a tropical paradise with the pineapple or mango flavors, or you can put your mind and body at ease with the sweet mint CBD oil. Whatever you’re craving, Verma Farms is sure to have it.

Product & Brand Highlights

Hemp Source : Various farms throughout the U.S.

Extract Types : Broad spectrum CBD and CBD isolate

● Lemon Lime (Focus)

● CBD isolate (product dependent)

● Broad spectrum CBD (product dependent)

● Coconut oil (product dependent)

● Hemp oil (product dependent)

● Kosher-grade Vegetable Glycerin (product dependent)

Lab Results: Botanacor

Shipping Policy: Free shipping on all U.S. orders

Return & Refund Policies : Unopened products can be returned within 30 days of purchase. Shipping costs are covered if return is due to company error (ie. wrong product sent)

Website Experience : Very easy to use. Tons of product information along with test results and customer reviews. Good balance of text and graphics. The color palette is soothing and makes you feel like you’re at the beach.

8. Sunday Scaries

Stressed Out? Noted as a top remedy for anxiety by Newsweek , Sunday Scaries CBD oil tincture is one of our top picks for daily stress & anxiety management. In addition to using a special broad spectrum blend of CBD oil, Sunday Scaries tincture also incorporates Vitamin D3 (the “sunshine” vitamin), Vitamin B12 and coconut oil into its formulation.

Vitamin D3: According to Healthline , “statistically, people with low vitamin D were at a much greater risk of depression.”

Vitamin B12: According to the MedicalNewsToday , “people who had lower blood levels of vitamin B-12 were more likely to have anxiety.”

What’s more: Sunday Scaries’s mission to promote a “Scarefree”, worry-free life permeates throughout their business. Their 97% customer service rating is always handled in-house, by a member of their team. And since inception, Sunday Scaries has always offered a 100% lifetime money back guarantee, so there’s no buying risk.

Try Sunday Scaries vitamin-boosted, CBD oil tincture today with Discover Magazine’s exclusive 20% off code: NoStress.

Product & Brand Highlights

● USA grown hemp (outside Denver, CO)

Custom Formulated Broad Spectrum CBD

Broad Spectrum CBD Oil

Organic Coconut Oil

ACS Laboratory: Cannabis & Hemp Specialists

Free Shipping on Orders Over $59 & Subscriptions

Return & Refund Policies

100% Lifetime Money Back Guarantee

9. Kiara Naturals

● Full spectrum and THC-free

● Handmade in small batches in Switzerland

● 3rd party Lab certified

Kiara Naturals is always an easy recommendation and are known for their premium Swiss quality unique and strong formulations that often involve other plant extracts that work together with CBD.

They’re a family-owned business that makes everything by hand, in small batches in Appenzellerland, Switzerland under strict GMP standards. Their products are used by natural health practitioners all over Europe due to their high-quality ingredients and certifications.

Their THC-Free PureCBD oils ranges from 1000mg-3000mg and their Brain Boost capsules are formulated with 1200mg of Pure CBD and CBG alongside other strong plants from alternative medicine that addresses anxiety and depression through multiple mechanisms.

Get 15% off using our exclusive code at checkout: discover15

Product & Brand Highlights

Hemp Source : Appenzell, Switzerland

Extract Types : Ultrasonic

● Pure CBD isolate

Shipping Policy: Free shipping through USPS

Return & Refund Policies : 60-day money back guarantee if you’re not happy with the results.

Website Experience : Elegant and modern website. Super easy to to find what you’re looking for. Provides a lot of product information along with photos and customer reviews.

10. TheraOne – Best Premium CBD

USDA Certified Organic full spectrum products

Clean formulas without unnecessary additives

Multiple functional botanical ingredients in each product

Certified good manufacturing practices (GMP)

Backed by Therabody

We love that you always get more than meets the eye with TheraOne, and their Sleep Tincture is a great example. The 1000 mg of CBD from Colorado-grown organic hemp is certainly a sweet spot for potency. But the inclusion of organic valerian root, organic lemon balm oil, and organic chamomile oil really makes this formula special. Add to that, it actually tastes great with no added flavoring (incredibly rare), so you’ll feel encouraged to use it nightly.

Restful sleep is crucial for people who deal with stress daily, and TheraOne Sleep CBD Tincture is the perfect way to promote a sense of calm at bedtime. It’s especially powerful when you combine it with the other things you do (meditation, journaling) to untangle the thoughts in your head and prepare your mind and body for much-needed, restorative sleep.

Product & Brand Highlights

Hemp Source: Colorado, United States (organic)

Flavor: Natural (with subtle hints of clove, chamomile, peppermint

Extract Type: Full Spectrum

Organic Valerian Root

Organic Blood Orange Oil

Organic Lemon Balm Oil

Organic Chamomile Oil

Organic Peppermint Oil

Organic MCT Oil from Coconut

Lab Results: ACS Laboratory (ISO 17025, AHCA and CLIA accredited)

Free shipping in the U.S. ( typically 1-4 days for delivery)

Does not ship to Idaho, military bases, and US Territories.

Return & Refund Policy: 30-day, 100% Satisfaction Guaranteed

Website Experience: Currently, TheraOne CBD products are sold through the Therabody website, which includes a number of non-CBD products such as Theragun (another product we highly recommend). You can navigate to TheraOne products by clicking “Shop” at the top left of any page, selecting “TheraOne” and choosing your product type. When you use the Auto-Ship feature, you get 25% off your first order and 20% off each Auto-Ship order thereafter. Interest-free payment options are available through Affirm.

11. Wild Theory CBD Co.

Created to calm mind and body

Broad Spectrum CBD

Made from organic hemp grown in Wisconsin

Contains 3.7% Terpenes

Wild Theory CBD is another reputable brand that crafts high-quality CBD oils at an affordable price. Their THC-free hemp is grown by organic farmers in Wisconsin without pesticides or herbicides. Customer reviews rave about their friendly service, extraordinary CBD oils, and budget-friendly prices.

But Wild Theory CBD isn’t just another new company trying to capitalize the CBD market. This family-run business also owns a wellness store, so they are experts at holistic living! They know that CBD can relieve symptoms of anxiety and depression, so they specifically crafted Breathe – Broad Spectrum CBD Stress Blend ! It’s created with Cannabichromene (CBC) to enhance your mood, quiet your mind, calm your body, and help you concentrate on the good things in life.

Product & Brand Highlights

Broad Spectrum Hemp Extract

Mild citrus flavor

Pure Broad Spectrum CBD oil from hemp

Cannabichromene (CBC) derived from Broad Spectrum Hemp Extract

Blended with Evening Primrose Oil

Includes 3.7% Terpenes

WI Hemp Scientific

Use WILD25 for 25% discount

Free shipping on all U.S. orders, no minimum purchase amount required

Return & Refund Policies

Full refund of unopened products within 30 days of purchase

Wild Theory account credit of opened products within 90 days of purchase

Helpful website that will advance you along on your wellness journey. Easy to navigate. Specific usage instructions and detailed ingredient list.

How We Decided on the Top 5 CBD Oils

There are several factors that play a role in the overall experience you have when taking CBD oil. Whether you’re a new or experienced user, you’ll not only need to find the dosage that works best for you, it’s also important to take CBD regularly in order to get the full range of benefits.

When using CBD oil for anxiety, there are many variables to consider. Figuring out all of these factors can make you feel overwhelmed and anxious, which isn’t what we want anyone to experience! This is why our team has taken the time to look at dozens upon dozens of different CBD products to find the best ones.

We want all of our readers to have the best experience when taking CBD oil or any other CBD product. This is why we’ve created a list of our top 5 CBD oils, so that readers have a great starting point on their quest to find CBD oil that will help with anxiety, depression, and other mental health issues.

When screening CBD oils for our list, there are five factors that we took into consideration to determine which products are best for our users.

1. Opinions from industry experts

Everyone has their own opinion on certain CBD products, but we thought it was very important to consider what industry experts had to say. This means that we reviewed content from testers, researchers, and consumers that are well-known in the CBD industry.

2. Product reviews

One of the best places to find unbiased information about a product is consumer reviews. In creating this list, we reviewed more than 5,000 consumer testimonials from brand websites and social media, to include blogs and Facebook, along with open forum websites like Reddit. Reviewing product reviews from consumers allowed us to really learn what people think about certain products.

3. The Cannabis Radar (TCR)

We love the experts at The Cannabis Radar and proudly reached out to them for their thoughts and opinions on some of today’s top CBD oil products. TCR conducted a survey that was sent out to more than 8,000 direct subscribers. This enabled TCR to get reactions and opinions from its readers about different CBD oils that are trending today.

4. Website reviews

We took endless hours reviewing brand websites to confirm the authenticity of the information provided by CBD companies. We compared this information with data made available by researchers and scientists on the public domain.

We also looked at each brand’s transparency and reviewed practices such as how hemp plants are farmed, how CBD is extracted and manufactured, and any technology used in any of these processes.

5. Product testing

Of course we had to join in on the fun! We’re glad to report that we physically tested more than 15 different CBD brands. This allowed us to personally determine a product’s efficacy, potency, safety, and value for money.

How CBD Oil Helps In Curbing Different Types of Anxieties

Anxiety is a condition that many Americans face today. It’s important to note that any condition that impacts someone’s mental health also impacts their personal and professional lives. Mental health conditions also impact the lives of family members and friends.

So how can CBD oil help to minimize the effects of anxiety and similar conditions? All vertebrates, which includes humans, have what’s known as an endocannabinoid system (ECS). This system spans throughout the body and is responsible for receiving and sending signals between cannabinoids and endocannabinoid receptors.

The ECS can promote or inhibit certain physiological functions, including sleep, hunger, pain, immune response, and mental balance.

Internally, the ECS is able to produce certain endocannabinoids. But by supplementing with external cannabinoids like CBD, it’s possible to overcome any deficiencies that may be causing or exacerbating health problems, such as pain, sleeplessness, pain, and anxiety.

One of the biggest misconceptions that keeps people from trying CBD oil is the confusion between CBD and THC. However, these two cannabinoids are on complete opposite sides of the spectrum. While THC is known to have psychoactive effects and may cause one to feel euphoric, hallucinogenic, and even anxious, CBD does just the opposite.

How CBD Can Benefit Those with Anxiety

When ingested, CBD calms and relaxes the mind and body. People who have anxiety issues don’t have to worry about any potential psychotropic effects, which can make anxiety worse. CBD is known for its ability to mellow out the mind and body, which can be quite beneficial for those who are overly anxious, worried, or depressed.

CBD oil is taken sublingually, which allows it to be directly absorbed into the bloodstream. Here, CBD is able to research the endocannabinoid system by attaching to specific cannabinoid receptors, including CB1 and CB2. CBD also attaches to non-cannabinoid receptors, including 5-HT1A and serotonin receptors.

By interacting with these receptors, CBD is able to influence the body’s response to pain, inflammation, and stress.

Anxiety disorders are more common than ever before. Some of the most commonly diagnosed conditions include:

● Generalized anxiety disorder (GAD). This condition is marked by random bouts of anxiety pangs that don’t always have an obvious cause. People with GAD tend to be habitual worriers that are in a continuous and constant state of worry and anxiety.

● Social anxiety. Social anxiety is commonly diagnosed in those who have a fear of public speaking, public conversation, and even dining out in the presence of others. Those with social anxiety are anxious due to the idea that others will judge, criticize, or humiliate them.

● Phobias. There are many people who have irrational fears and phobias. Some of the most common include a fear of heights, darkness, closed spaces, and water. But phobias can be something as simple as being afraid of dogs, spiders, or a certain number.

● Panic disorder. Those who have panic disorder experience overwhelming panic attacks, which may be accompanied by nausea, sweating, breathlessness, dizziness, chest pain, and temporary loss of vision. Panic attacks can also be coupled with the feeling of having a heart attack or drowning.

● Obsessive-Compulsive Disorder (OCD). OCD can be triggered or accompanied by anxiety along with an irrational or unfounded fear. People with OCD repeatedly carry out a set of actions (which are often illogical), that allow them to avoid stressful situations.

● Post-Traumatic Stress Disorder (PTSD). PTSD is a condition commonly diagnosed among war veterans and other military members. The condition causes mental instability that derives from stressful life events. Those with PTSD may exhibit irrational and erratic behavior that can sometimes be violent.

Why is CBD Better than Conventional Medications for Treating Anxiety Disorders?

There are many reasons why CBD works better than conventional prescription medications, the biggest being the fact that CBD works very differently.

Anxiety disorders are typically treated with a combination of therapies and prescription medications. For some, therapy isn’t completely effective. Prescription medications are much more effective, but come with the risk of very serious side effects. For those who already suffer from anxiety, the idea of dangerous side effects can cause even more concerned and anxious thoughts.

CBD comes with a much lower risk. Those with anxiety can take CBD and not have to worry about adverse side effects that could be deadly. So why is CBD so different?

● CBD has no addictive compounds or properties

● CBD doesn’t lead to dependence

● CBD doesn’t cause drug tolerance

● CBD isn’t intoxicating and won’t make users “high”

● CBD isn’t psychotropic like THC. This is because CBD doesn’t directly interact with nerve receptors. Instead, it works by indirectly helping to maintain homeostasis, which is the body’s internal chemical balance that keeps everything working as it should.

Scientific Evidence in Using CBD to Treat Anxiety

In looking at CBD oil’s efficacy in treating and managing anxiety disorders, it’s important to point out that we’re specifically referring to CBD, not medical marijuana. This is why we’ve focused on studies that have reviewed CBD’s effects in treating anxiety.

But why are we only specifically looking at CBD?

● Medical marijuana contains higher levels of THC than CBD

● Medical marijuana can make you high due to the high levels of THC

● High THC-content in medical marijuana may worsen depression and anxiety

● Medical marijuana should only be taken under strict medical supervision

A legal, high quality bottle of CBD oil contains no more than 0.3% THC by overall weight. This is the legal limit set forth in the 2018 Farm Bill. This means that CBD oils contain a low level of THC that won’t cause any psychoactive effects.

Here are some of the studies that support claims that CBD can benefit those who suffer from anxiety conditions:

● A 2010 study found that CBD may reduce the symptoms of social anxiety disorder. In this study, subjects’ brain scans showed some changes in blood flow to parts of the brain that have been linked to anxiety. Use of CBD oil was able to calm the participants by impacting blood flow patterns in the brain.

● A 2011 study , published in Neuropsychopharmacology , found evidence that cannabidiol reduced the fear of public speaking in those diagnosed with social anxiety. Each of the 24 subjects involved in the trial were either given 600mg of CBD or a placebo an hour before public speaking. Participants who were given CBD coped better and were more successful at public speaking.

● A 2014 study found similar results on animal subjects. The trial confirmed that CBD curbs anxiety pangs and also worked as an effective antidepressant.

● A generalized review of studies , which was published in 2015, provided a more broad perspective of how effective CBD oil can be in helping those who suffer from various anxiety disorders, including panic disorder, OCBD, generalized anxiety disorder, social anxiety disorder, and PTSD. This review also indicated that CBD may only have short-term benefits for those who experience anxiety issues, so there’s a growing need to learn about the long-term effects of CBD on anxiety.

● A 2016 case study found some good news for those struggling with anxiety issues. It showed positive results when used on a child that experienced anxiety due to a traumatic past. CBD not only calmed the child, it helped her fall into a deep sleep, something that was impossible due to anxiety issues. This case study shows a clear indication that CBD may be able to curb the symptoms of PTSD and its side effects.

How to Use CBD Oil for Anxiety

CBD that’s extracted from hemp plants can be used to create all sorts of products, including edible oils, tinctures, vape liquids, soft gel capsules, crystals, powders, edibles, and even topicals. The form in which CBD is made available is highly dependent on how the product is meant to be administered as well as what other ingredients are added.

For example, someone who is experiencing joint or muscle pain may use a topical salve or lotion to ease aches and pains. For those who want to use CBD for anxiety or other mental health issues, there are many products that can be used, including capsules, edibles, and oils.

For this guide, we’ve specifically focused on CBD oil, which is one of the safest, easiest, and most convenient ways to take CBD. Here are some of the best ways to take CBD oil if you’re using it to treat anxiety.

● Sublingually (tinctures & sprays): The most common way to take CBD oil, such as through a tincture or spray, is sublingually. These products are applied under the tongue, which allows the glands to directly absorb CBD into the bloodstream.

● Orally (capsules & edibles): CBD oil, such as those made with nanotechnology, are easily infused into soft gel capsules as well as edible products like gummies and other delicious candies. These products are taken orally and are impacted by liver enzymes, which substantially reduces bioavailability to around 6%.

● I nhaled or vaped (e-liquids): Raw CBD oil can be taken sublingually as well as in the form of vape liquids. Inhaling CBD increases its bioavailability to (34%-56%), but it’s not the best method for everyone. If you suffer from a lung condition, you’ll want to avoid vaping CBD oil.

How Much CBD Should I Take for Treating Anxiety?

Everyone will have a unique experience when taking CBD. It’s effects differ from person to person, as there are many factors that play a role in how well CBD works within the body. Some of these factors include the severity of the condition as well as one’s internal chemical balance.

Anxiety and depression can be overwhelming to treat, but if left untreated, these conditions can have extremely damaging effects on a person’s life. The good news is that a large dose of CBD doesn’t have to be taken in order to manage the symptoms of these conditions. In fact, most people need very little in order to keep anxiety at bay.

Some of the many variables that play a role in CBD’s effects on those who experience anxiety include:

● The type of anxiety

● Severity of anxiety

● The body’s ability to absorb cannabinoids

● Chemical balance within the endocannabinoid system

● Method of administration

Like most supplements, CBD isn’t FDA-approved. This means that companies cannot provide definitive instructions on how much CBD to take. For new users, it simply takes some trial and error in order to figure out how much CBD oil you need to take.

In general, most users experience the effects of CBD when taking doses that range from 2.85mg to 50mg a day. These levels should provide therapeutic effects that will take the edge off and calm and mind and body.

However, before you jump to the highest dose possible, it’s best to dose low and slow. This way you don’t take too much at once and experience side effects like nausea or dizziness. If you’ve never taken CBD oil before, start with a low dosage, like one or two drops a day. Make note of how you feel each day and up the dosage as needed.

There are also online CBD calculators that you can use that calculate a dosage depending on your age, gender, weight, and other factors.

Most importantly, never use CBD or any other substance without first consulting with your doctor. You also never want to stop taking any prescription medications before getting medical clearance. Ideally you’ll want to discuss taking CBD oil with a medical professional who has experience in using cannabinoids and cannabis medicine for treating anxiety and other mental health conditions.

Final Thoughts: Is CBD Oil Recommended for Treating Anxiety

Anxiety, depression, and other mental conditions are complex and complicated issues that impact almost every aspect of everyday life. Though there are many different medications and therapies that can be used to treat these conditions, it’s rare that they treat the root cause. Other treatments cause unwanted residual effects that can further complication the issues at hand.

While there is still much to learn about CBD, these products are much safer and more effective options for those suffering from anxiety. Though everyone will have a unique experience when taking CBD, anecdotal evidence along with scientific studies support the idea that CBD can help with anxiety, panic disorders, depression, and other issues.

CBD also helps with pain management, which can also benefit those who have certain mental health conditions. Taking CBD oil may even help you sleep better at night! We all know how beneficial a good night’s sleep can be, especially when considering physical and mental health.

After thoroughly analyzing CBD oil and creating a list of the top five CBD oil products, we highly recommend using cannabidiol to treat anxiety. What’s most important is that you start with a low dose, take the product consistently, and are patient with the process.

Lastly, if you are looking to improve your health and energy you need to look at sleep as well. There are lots of way to improve your sleep . According to studies better sleep can lead to better concentration, more energy, faster metabolism and lower inflammation. All in all, good sleep will help you get the most out of the products above and set you up for long-term success on your health journey.

Looking for the best CBD you can find? Check out our awards for the best CBD Gummies , best CBD Oi l, Best CBD Oil For Dogs , and Best CBD Oil for cats .