Cannabidiol: A Potential New Alternative for the Treatment of Anxiety, Depression, and Psychotic Disorders
Abstract
:1. Introduction
2. Introduction to the Phytocannabinoid Cannabidiol: Chemical Structure, Pharmacokinetics and Pharmacodynamics Profile
2.1. Overview of CBD Chemical Structure
2.2. Overview of CBD Pharmacological Profile
2.2.1. Pharmacokinetics
2.2.2. Pharmacodynamics
3. Role of CBD on Anxiety and Depressive Disorders: Animal and Human Studies
3.1. Current Scenario
3.2. Results from Animal Studies
3.3. Results from Clinical Studies
3.3.1. Clinical Studies Focused on Anxiety Disorders
3.3.2. Clinical Studies Focused on Stress-Related Disorders: PTSD
3.3.3. Clinical Studies Focused on Depressive Disorders
4. Role of CBD on Schizophrenia
4.1. Current Scenario
4.2. Results from Animal Studies
4.3. Results from Clinical Studies
5. Summary and Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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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) | [53,54] |
Plasma clearance rate | 960–1500 mL/min | [53,54,55] |
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 Anxiolytic/VCT Anxiolytic/CFC Antidepressant/CMS | [96,102,108] | |
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] [110] |
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 | [105,106] | |
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 Anxiogenic/EPM | [130] [128] | |
15, 30 and 60 mg/kg; i.p.; acute | Anxiolytic/MBT * * (even 7 days after its administration) | [104] | |
30 mg/kg; i.p.; chronic 30 mg/kg; i.p.; 14 days | Anxiolytic and antidepressant/CMS Antidepressant/CMS | [131] [116] | |
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 | Anxiolytic/OF Antidepressant/SP | [132] | |
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] |
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 | [153] |
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 | [155] |
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 | [156] |
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 | [157] |
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 | [158] |
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 | [159] |
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 | [161] |
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 | [164] |
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 | [165] |
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 | [191] | |
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 | [196] |
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 | [199] |
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 | [218] |
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 | [201] |
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] |
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García-Gutiérrez, M.S.; Navarrete, F.; Gasparyan, A.; Austrich-Olivares, A.; Sala, F.; Manzanares, J. Cannabidiol: A Potential New Alternative for the Treatment of Anxiety, Depression, and Psychotic Disorders. Biomolecules 2020, 10, 1575. https://doi.org/10.3390/biom10111575
García-Gutiérrez MS, Navarrete F, Gasparyan A, Austrich-Olivares A, Sala F, Manzanares J. Cannabidiol: A Potential New Alternative for the Treatment of Anxiety, Depression, and Psychotic Disorders. Biomolecules. 2020; 10(11):1575. https://doi.org/10.3390/biom10111575
Chicago/Turabian StyleGarcía-Gutiérrez, María S., Francisco Navarrete, Ani Gasparyan, Amaya Austrich-Olivares, Francisco Sala, and Jorge Manzanares. 2020. "Cannabidiol: A Potential New Alternative for the Treatment of Anxiety, Depression, and Psychotic Disorders" Biomolecules 10, no. 11: 1575. https://doi.org/10.3390/biom10111575
APA StyleGarcía-Gutiérrez, M. S., Navarrete, F., Gasparyan, A., Austrich-Olivares, A., Sala, F., & Manzanares, J. (2020). Cannabidiol: A Potential New Alternative for the Treatment of Anxiety, Depression, and Psychotic Disorders. Biomolecules, 10(11), 1575. https://doi.org/10.3390/biom10111575