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Cited by 308Cannabis and Cannabinoid ResearchMedicinal Plant Extracts EffectsPsychedelics and Drug Studies

Translational investigation of the therapeutic potential of Cannabidiol (CBD): Toward a new age

Open access
Crippa, José A., Guimarães, Francisco S., Campos, Alline C., Zuardi, Antonio W.·2018·Frontiers in Immunology
DOI 10.3389/fimmu.2018.02009PMC PMC6161644
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Abstract

Background: Among the many cannabinoids in the cannabis plant, cannabidiol (CBD) is a compound that does not produce the typical subjective effects of marijuana. Objectives: The aim of the present review is to describe the main advances in the development of the experimental and clinical use of cannabidiol CBD in neuropsychiatry. Methods: A non-systematic search was performed for studies dealing with therapeutic applications of CBD, especially performed by Brazilian researchers. Results: CBD was shown to have anxiolytic, antipsychotic and neuroprotective properties. In addition, basic and clinical investigations on the effects of CBD have been carried out in the context of many other health conditions, including its potential use in epilepsy, substance abuse and dependence, schizophrenia, social phobia, post-traumatic stress, depression, bipolar disorder, sleep disorders, and Parkinson. Discussion: CBD is an useful and promising molecule that may help patients with a number of clinical conditions. Controlled clinical trials with different neuropsychiatric populations that are currently under investigation should bring important answers in the near future and support the translation of research findings to clinical settings.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review traces Brazilian-led translational research on cannabidiol (CBD) from an “inactive” cannabinoid to a broad-spectrum neuropsychiatric candidate with anxiolytic, antipsychotic, antiepileptic, and neuroprotective properties. It concludes that CBD is promising but that controlled trials with larger neuropsychiatric populations and precise dose ranges are still needed.

Key findings

  • CBD showed anxiolytic effects with an inverted bell-shaped dose-response curve: in 57 healthy male volunteers, CBD 300 mg reduced anxiety in the Simulated Public Speaking Test, but 150 mg and 600 mg did not, with group sizes placebo n = 15, CBD 150 mg n = 15, CBD 300 mg n = 15, and CBD 600 mg n = 12.
  • In social anxiety disorder, 12 patients given CBD 600 mg had lower anxiety, negative self-assessment, and somatic symptoms than 12 placebo patients, and did not differ significantly from 12 healthy controls.
  • Antipsychotic evidence included a 6-week double-blind trial in schizophrenia adding CBD 1,000 mg/day (N = 43) or placebo (N = 45) to existing antipsychotics; the CBD group had lower positive psychotic scores and improved cognitive and general illness symptoms, with equivalent side effects.
  • In Parkinson’s disease with psychosis, an open trial of six outpatients found significant reductions in BPRS and Parkinson Psychosis Questionnaire scores with CBD 150–600 mg/day; in Parkinson’s disease without psychiatric comorbidity, 21 patients randomized to placebo (n = 7), CBD 75 mg/day (n = 7), or CBD 300 mg/day (n = 7) showed significantly lower PDQ-39 scores only in the CBD 300 mg/day group.
  • CBD was ineffective for manic episodes in two bipolar affective disorder patients and did not prevent or reverse D-amphetamine-induced hyperlocomotion in an animal mania model.

Methods

  • Narrative/non-systematic review of experimental and clinical studies on therapeutic applications of CBD in neuropsychiatry, especially work by Brazilian researchers.
  • Searches were performed in PubMed, Web of Science, and SciELO using “cannabidiol” as a keyword.
  • The review summarizes preclinical animal models and human studies, including case reports, open trials, randomized controlled trials, and neuroimaging studies; no systematic review or meta-analytic pooling was performed.

Limitations

  • The paper states that the search was non-systematic and that more controlled clinical trials with different and larger neuropsychiatric populations are needed, along with better definition of safety and precise dose ranges for each disorder.
  • The text makes evident that many included human findings come from small samples, open-label trials, or case reports, and several results are described as preliminary.
  • The conflict-of-interest statement notes that several authors are co-inventors on a fluorinated CBD patent, that the University of São Paulo has licensed the patent and has an agreement to develop synthetic cannabidiol, and that one author has received travel support and serves as a medical advisor to BSPG-Pharm.

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Integrity signals

Registry

Crossref · 10.3389/fimmu.2018.02009

Cites

159 of 159 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 158 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Among PD patients with no psychiatric comorbidities or dementia, the group treated with CBD 300 mg/day had significantly lower PDQ-39 scores.

    “The group treated with CBD 300 mg/day presented significantly lower scores in the PDQ-39.”
    Quote in the paperSubstantial claim
  • Findingown data

    CBD was unable to prevent or reverse hyperlocomotion induced by chronic D-AMPH (2 mg/kg) in animal studies.

    “In a series of collaborative animal studies, CBD was unable to prevent or reverse hyperlocomotion induced by the chronic injection of D-AMPH (2 mg/kg).”
    Quote in the paperNot a substantial claim
  • Findingcitation

    CBD reversed iron-induced effects, normalizing hippocampal DNM1L, synaptophysin, and caspase 3 levels in rats.

    “More recently, we found that CBD reversed iron-induced effects, normalizing hippocampal DNM1L, synaptophysin, and caspase 3 levels in rats”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [95] da, 2014, Cannabidiol normalizes caspase 3, synaptophysin, and mitochondrial fission protein DNM1L expression levels in rats with brain iron overload: implications for neuroprotection, Mol Neurobiol. source

      Not checked in the free run.

  • Findingcitation

    CBD increased the levels of brain-derived neurotrophic factor (BDNF).

    “However, we found that CBD seems to have antioxidant and neuroprotective properties, as it increased the levels of brain-derived neurotrophic factor (89, 90).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [89] Valvassori, 2011, Effects of cannabidiol on amphetamine-induced oxidative stress generation in an animal model of mania, J Psychopharmacol. source

      Not checked in the free run.

    • cites [90] Réus, 2011, 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. source

      Not checked in the free run.

  • Findingown data

    In transgenic GFAP/Thymidine kinase mice treated with ganciclovir, CBD was not able to prevent the effects of stress response.

    “However, in transgenic GFAP/Thymidine kinase mice treated with ganciclovir, a model of disrupted adult neurogenesis, CBD was not able to prevent the effects of stress response.”
    Quote in the paperSubstantial claim
  • May combine two claims. 41
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingown data

    In chronically stressed mice, CBD prevents stress-induced decreased hippocampal neurogenesis and stress-induced anxiogenesis.

    “Results from our group suggested that in chronically stressed mice, CBD prevents stress-induced decreased hippocampal neurogenesis and stress-induced anxiogenesis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    In chronically stressed mice, chronic CBD administration promoted dendritic remodeling and increased the expression of Synapsin I/II, PSD95, and p-GSK3β in the hippocampus.

    “In chronically stressed mice, chronic CBD administration also promoted dendritic remodeling and increased the expression of Synapsin I/II, PSD95, and p-GSK3β in the hippocampus of rodents submitted to CUS (112).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [112] Campos, 2017, Plastic and neuroprotective mechanisms involved in the therapeutic effects of cannabidiol in psychiatric disorders, Front Pharmacol source

      Not checked in the free run.

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    Findingcitation

    In a model of mesial temporal lobe epilepsy induced by intrahippocampal pilocarpine, CBD has protective effects on seizure control and against neuronal death.

    “In a recent collaborative animal study, we found that CBD has protective effects not only on seizure control, but also against neuronal death in a model of mesial temporal lobe epilepsy induced by intrahippocampal pilocarpine (135).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [135] Do, 2017, Protective effects of Cannabidiol against seizures and neuronal death in a rat model of mesial temporal lobe epilepsy, Front Pharmacol. source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    When the cannabidiol-enriched extract was replaced by pure pharmaceutical-grade CBD, the intoxication signs disappeared and both patients became seizure-free.

    “When the extract was replaced by pure pharmaceutical-grade CBD, the intoxication signs disappeared and both patients became seizure-free.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Two children with treatment-resistant epilepsy had full seizure remission but presented symptoms of Δ9-THC intoxication and eventual seizure relapse with the use of a cannabidiol-enriched extract.

    “We have recently investigated two cases of children with treatment-resistant epilepsy who had full seizure remission, but presented symptoms of intoxication by Δ9-THC and eventual seizure relapse with the use of a cannabidiol-enriched extract (136).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [136] Crippa, 2016, Δ9-THC intoxication by cannabidiol-enriched cannabis extract in two children with refractory epilepsy: full remission after switching to purified cannabidiol, Front Pharmacol. source

      Not checked in the free run.

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    Findingcitation

    As a result of the INCT-TM network, the authors contributed further evidence on the actions of CBD as a neuroprotector, an anti-inflammatory, and a drug able to increase sleep periods.

    “As a result of this network, we contributed with further evidence on the actions of CBD as a neuroprotector (147), an anti-inflammatory (148, 149), and a drug able to increase sleep periods (150), among other properties (151–157).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [147] Schönhofen, 2015, Cannabidiol exposure during neuronal differentiation sensitizes cells against redox-active neurotoxins, Mol Neurobiol source

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    • cites [148] Vuolo, 2015, Evaluation of serum cytokines levels and the role of cannabidiol treatment in animal model of asthma, Mediators Inflamm. source

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    • cites [149] Ribeiro, 2012, Cannabidiol, a non-psychotropic plant-derived cannabinoid, decreases inflammation in a murine model of acute lung injury: role for the adenosine A(2A) receptor, Eur J Pharmacol. source

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    Premisecitation

    CBD both blocks and potentiates the effects of Δ9-THC in animal tests, depending on the ratio and dose relationship between the two cannabinoids.

    “Later studies on the interaction between cannabinoids showed that CBD both blocked and potentiated the effects of Δ9-THC in animal tests, depending on the ratio and dose relationship between the two cannabinoids (12, 13).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [12] Zuardi, 1983, Effects on variable-interval performance in rats of delta 9-tetrahydrocannabinol and cannabidiol, separately and in combination, Braz J Med Biol Res.

      Not checked in the free run.

    • cites [13] Zuardi, 1984, Pharmacological interaction of the effects of delta 9-trans-tetrahydrocannabinol and cannabidiol on serum corticosterone levels in rats, Arch Int Pharmacodyn Ther.

      Not checked in the free run.

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    Premisenone given

    Basic and clinical investigations on the effects of CBD have been carried out in the context of many health conditions, including its potential use in epilepsy, substance abuse and dependence, schizophrenia, social phobia, post-traumatic stress, depression, bipolar disorder, sleep disorders, and Parkinson.

    “In addition, basic and clinical investigations on the effects of CBD have been carried out in the context of many other health conditions, including its potential use in epilepsy, substance abuse and dependence, schizophrenia, social phobia, post-traumatic stress, depression, bipolar disorder, sleep disorders, and Parkinson.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    CBD has anxiolytic, antipsychotic and neuroprotective properties.

    “CBD was shown to have anxiolytic, antipsychotic and neuroprotective properties.”
    • Also stated in: § Anxiolytic action · boosted
      “As shown later, these properties have been confirmed in both laboratory animals and humans.”
    Quote in the paperSubstantial claim

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    Premisecitation

    CBD has a clear anti-stress effect after either acute or repeated administration, attenuating the behavioral and autonomic consequences of acute restraint stress and the anxiogenic effects of chronic unpredictable stress.

    “It was also found that CBD has a clear anti-stress effect after either acute or repeated administration, attenuating the behavioral and autonomic consequences of acute restraint stress (31, 32) and the anxiogenic effects of chronic unpredictable stress [CUS—(28)].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [31] Resstel, 2009, 5-HT1A receptors are involved in the cannabidiol-induced attenuation of behavioral and cardiovascular responses to acute restraint stress in rats, Br J Pharmacol. source

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    • cites [32] Granjeiro, 2011, Effects of intracisternal administration of cannabidiol on the cardiovascular and behavioral responses to acute restraint stress, Pharmacol Biochem Behav. source

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    • cites [28] Campos, 2012, Cannabidiol blocks long-lasting behavioral consequences of predator threat stress: possible involvement of 5HT1A receptors, J Psychiatr Res. source

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    Premisecitation

    High oral doses of Δ9-THC provoked anxiety and psychotic symptoms in healthy humans, which were attenuated when CBD was administered together with Δ9-THC.

    “Studying the interaction between CBD and Δ9-THC in healthy humans, high oral doses of Δ9-THC provoked anxiety and psychotic symptoms, which were attenuated when CBD was administered together with Δ9-THC (15).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] Zuardi, 1982, Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects, Psychopharmacology source

      Not checked in the free run.

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    Premisecitation

    In SAD patients, CBD 600 mg reduced anxiety levels in the performance and anticipatory phases of the SPST, negative self-assessment scores, and somatic symptoms compared with placebo.

    “The group of SAD patients treated with CBD had lower anxiety levels in the performance and anticipatory phases of the test, lower negative self-assessment scores and fewer somatic symptoms compared with SAD patients who received placebo.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Bergamaschi, 2011, Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients, Neuropsychopharmacology source

      Not checked in the free run.

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    Premisecitation

    CBD (300 mg) and the anxiolytic compounds ipsapirone (5 mg) and diazepam (10 mg) all attenuated anxiety induced by the SPST.

    “The findings demonstrated that CBD and the two other anxiolytic compounds all attenuated anxiety induced by the SPST (53).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [53] Zuardi, 1993, Effects of ipsapirone and cannabidiol on human experimental anxiety, J Psychopharmacol. source

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    Premisecitation

    CBD (400 mg) increased left parahippocampal gyrus activity and decreased left amygdala-hippocampus complex activity, extending to left posterior cingulate cortex and hypothalamus.

    “The SPECT results showed an increase in the left parahippocampal gyrus activity and a decrease in left amigdala-hippocampus complex, extending to the left posterior cingulate cortex and the hypothalamus (Figure 4).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [57] Crippa, 2004, Effects of cannabidiol (CBD) on regional cerebral blood flow, Neuropsychopharmacology source

      Not checked in the free run.

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    Premisecitation

    Acute administration of CBD produced anxiolytic effects with a dose-dependent bell-shaped curve in healthy subjects, with personal anxiety reduced with CBD 300 mg, but not with 100 and 900 mg.

    “Again, the acute administration of CBD produced anxiolytic effects with a dose-dependent bell-shaped curve in healthy subjects, since the personal anxiety quantities were reduced with CBD 300 mg, but not with the other CBD doses of 100 and 900 mg (56).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] Zuardi, 2017, Inverted U-shaped dose-response curve of the anxiolytic effect of cannabidiol during public speaking in real life, Front Pharmacol. source

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    Premisecitation

    In healthy male volunteers, CBD produced an anxiolytic effect with an inverted bell-shaped dose-response curve.

    “The results confirmed the anxiolytic effect of CBD and the expected inverted “bell-shaped” dose-response curve was observed (Figure 3), in agreement with the findings from animal studies described above.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Linares, 2018, Cannabidiol presents an inverted U-shaped dose-response curve in a simulated public speaking test, Eur. Neuropsychopharmacol. source

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  • May combine two claims.

    Premisecitation

    No significant differences were found between SAD patients treated with CBD and healthy controls, unlike SAD patients taking placebo.

    “Furthermore, no significant differences were found between SAD patients treated with CBD and healthy controls, unlike what happened with SAD patients taking placebo.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Bergamaschi, 2011, Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients, Neuropsychopharmacology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CBD decreased stereotypy induced by dopaminergic agonists, an effect similar to that of haloperidol.

    “Using classical animal models to evaluate antipsychotic effects, Zuardi et al. (65) made a pioneering investigation and showed that CBD decreased stereotypy induced by dopaminergic agonists, an effect similar to that of haloperidol.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] Zuardi, 1991, Effects of cannabidiol in animal models predictive of antipsychotic activity, Psychopharmacology source

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    Premisecitation

    CBD decreased hyperlocomotion and PPI impairment caused by the glutamate NMDA receptor non-competitive antagonists ketamine and MK801.

    “The investigations were expanded to glutamatergic-based animal models of schizophrenia, which showed that CBD decreased hyperlocomotion and PPI impairment caused by the glutamate NMDA receptor non-competitive antagonists ketamine and MK801, respectively (67, 71).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [67] Moreira, 2005, Cannabidiol inhibits the hyperlocomotion induced by psychotomimetic drugs in mice, Eur J Pharmacol. source

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    • cites [71] Gomes, 2015, Decreased glial reactivity could be involved in the antipsychotic-like effect of cannabidiol, Schizophr Res. source

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    Premiseown data

    In treatment-naive SAD patients, CBD reduced subjective measures of anxiety without inducing sedation compared to placebo.

    “We found that, when compared to placebo, CBD was able to reduce subjective measures of anxiety without inducing sedation in treatment-naive SAD patients.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Crippa, 2011, Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report, J Psychopharmacol. source

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    Premisecitation

    CBD produced a pattern of neuronal activation similar to that of clozapine, but distinct from haloperidol.

    “In an early work, we observed that CBD produced a pattern of neuronal activation (measured by the expression of the proto-oncogene cFos) similar to that of clozapine, but distinct from haloperidol.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [68] Guimarães, 2004, Cannabidiol increases Fos expression in the nucleus accumbens but not in the dorsal striatum, Life Sci. source

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    Premisecitation

    In first-episode schizophrenia patients treated for 14 days, CBD significantly decreased psychotic symptoms after 2 weeks compared to baseline, although differences from placebo failed to reach statistical significance.

    “CBD significantly decreased psychotic symptoms after 2 weeks when compared to baseline, although the differences from placebo failed to reach statistical significance.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [78] Leweke, 2011, The efficacy of cannabidiol in the treatment of schizophrenia - a translational approach, Schizophr Bull.

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    Premisecitation

    CBD (up to 800 mg/day) and amisulpride both significantly reduced psychotic symptoms in schizophrenia patients over 4 weeks, with no differences between them; CBD induced fewer side effects.

    “One study compared the effects of CBD (up to 800 mg/day) to amisulpride in 42 schizophrenia patients treated for 4 weeks (77). Both treatments significantly reduced psychotic symptoms, with no differences between them; however, CBD induced fewer side effects compared to amisulpride.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] Leweke, 2012, Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia, Transl Psychiatry source

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    Premisecitation

    CBD prevented and partially reversed catalepsy caused by haloperidol.

    “In fact, CBD prevented and partially reversed catalepsy caused by haloperidol (48).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [48] Gomes, 2013, Cannabidiol attenuates catalepsy induced by distinct pharmacological mechanisms via 5-HT1A receptor activation in mice, Prog Neuropsychopharmacol Biol Psychiatry source

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    Premisecitation

    During CBD treatment, there was a reduction of both psychotic and motor symptoms in PD patients, with no worsening on cognition.

    “Interestingly, we observed a reduction of both psychotic and motor symptoms during CBD treatment, with no worsening on cognition.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] Zuardi, 2009, Cannabidiol for the treatment of psychosis in Parkinson's disease, J Psychopharmacol. source

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    Premisecitation

    In a double-blind trial, schizophrenia patients randomized to receive CBD (1,000 mg/day; N=43) or placebo (N=45) added-on to existing antipsychotics for 6 weeks, the CBD group presented lower positive psychotic scores and improved cognitive and general illness symptoms.

    “After the treatment, the CBD group presented lower positive psychotic scores and improved cognitive and general illness symptoms.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [79] McGuire, 2018, Cannabidiol (CBD) as an adjunctive therapy in schizophrenia: a multicenter randomized controlled trial, Am J Psychiatry source

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  • May combine two claims.

    Interpretationreasoning

    Since the antipsychotic effects of CBD do not appear to depend on dopamine receptor antagonism, CBD may represent a new class of treatment for psychotic disorders in general and schizophrenia in particular.

    “Since the antipsychotic effects of CBD do not appear to depend on dopamine receptor antagonism, this compound may indeed represent a new class of treatment for the psychotic disorders in general and schizophrenia, in particular.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    CBD has antioxidant and neuroprotective properties.

    “However, we found that CBD seems to have antioxidant and neuroprotective properties, as it increased the levels of brain-derived neurotrophic factor (89, 90).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [89] Valvassori, 2011, Effects of cannabidiol on amphetamine-induced oxidative stress generation in an animal model of mania, J Psychopharmacol. source

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    • cites [90] Réus, 2011, 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. source

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  • May combine two claims.

    Interpretationown data

    CBD should be considered as a compound with neuroprotective and memory-rescuing properties.

    “and once again suggesting that CBD should be considered as a compound with neuroprotective and memory-rescuing properties (95).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [95] da, 2014, Cannabidiol normalizes caspase 3, synaptophysin, and mitochondrial fission protein DNM1L expression levels in rats with brain iron overload: implications for neuroprotection, Mol Neurobiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CBD increased mitochondrial complex and creatine kinase activity.

    “In addition, CBD increased mitochondrial complex and creatine kinase activity (91), reversed oxidative stress parameters (TBARS formation and protein carbonyls) (92), and prevented cognitive impairments (92, 93).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [91] Valvassori, 2013, Acute and chronic administration of cannabidiol increases mitochondrial complex and creatine kinase activity in the rat brain, Rev Bras Psiquiatr. source

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    Premisecitation

    In rodents, exposure to chronic stressors induces alterations in dendritic remodeling and decreases adult hippocampal neurogenesis.

    “In rodents, exposure to protocol of chronic stressors, that modeling some features of psychiatric disorders symptoms, induce alterations in dendritic remodeling and decrease adult hippocampal neurogenesis (38, 44, 99).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [38] Campos, 2013, Involvement of serotonin-mediated neurotransmission in the dorsal periaqueductal gray matter on cannabidiol chronic effects in panic-like responses in rats, Psychopharmacology source

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    • cites [44] Campos, 2013, The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system, Int J Neuropsychopharmacol. source

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    • cites [99] Bessa, 2009, The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling, Mol Psychiatry source

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    Premisecitation

    Repeated CBD administration (14 days) decreased phosphorylated forms of Erk1/2 levels in the PFC and improved contextual fear conditioned responses.

    “For example, repeated CBD administration (14 days) decreased phosphorylated forms of Erk1/2 levels in the PFC and improved contextual fear conditioned responses and (111).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [111] ElBatsh, 2012, Anxiogenic-like effects of chronic cannabidiol administration in rats, Psychopharmacology source

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  • May combine two claims.

    Premisecitation

    CBD increases neuritogenesis in PC12 cells, increasing the expression of synaptophysin and synapsin I.

    “Moreover, similar to the neurotrophic factor, nerve growth factor, CBD neuritogenesis in PC12 cells, increasing the expression of synaptophysin and synapsin I (108).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [108] Santos, 2015, The neuroprotection of cannabidiol against MPP?-induced toxicity in PC12 cells involves trkA receptors, upregulation of axonal and synaptic proteins, neuritogenesis, and might be relevant to Parkinson's disease, Toxicol in vitro source

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  • May combine two claims.

    Premisecitation

    CBD improved cognition, motor activity and BDNF levels in mice administered thioacetamide.

    “CBD improved cognition, motor activity and BDNF levels in mice administered with thioacetamide, a drug that induces hepatic encephalopathy (127, 128)).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [127] Magen, 2010, Cannabidiol ameliorates cognitive and motor impairments in bile-duct ligated mice via 5-HT1A receptor activation, Br J Pharmacol. source

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    • cites [128] Avraham, 2011, Cannabidiol improves brain and liver function in a fulminant hepatic failure-induced model of hepatic encephalopathy in mice, Br J Pharmacol. source

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    Premisecitation

    In a middle cerebral artery occlusion model, CBD suppressed the reduction of cerebral blood flow after reperfusion, inhibited MPO activity in neutrophils, and reduced the number of MPO immunopositive cells.

    “Using the middle cerebral artery occlusion as method to evaluate ischemia-reperfusion injury, CBD suppressed the reduction of cerebral blood flow after reperfusion, inhibited myeloperoxidase (MPO) activity in neutrophils and reduced the number of MPO immunopositive cells (124).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [124] Pazos, 2013, Mechanisms of cannabidiol neuroprotection in hypoxic-ischemic newborn pigs: role of 5HT(1A) and CB2 receptors, Neuropharmacology source

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    Premisecitation

    In mice with bilateral common carotid artery occlusion, CBD stimulated neurogenesis and restored dendritic arbor and BDNF levels in the hippocampus.

    “Recently, Mori et al. (125) demonstrated that in mice that underwent to bilateral common carotid artery occlusion, CBD stimulated neurogenesis and, restores dendritic arbor and BDNF levels in the hippocampus.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [125] Mori, 2017, Cannabidiol reduces neuroinflammation and promotes neuroplasticity and functional recovery after brain ischemia, Prog Neuropsychopharmacol Biol Psychiatry source

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    Premisecitation

    CBD attenuates high-glucose-induced mitochondrial ROS production and the expression of pro-inflammatory molecules.

    “and attenuates high-glucose-induced mitochondrial ROS production and the expression of pro-inflammatory molecules (122).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [122] Rajesh, 2007, Cannabidiol attenuates high glucose-induced endothelial cell inflammatory response and barrier disruption, Am J Physiol Heart Circ Physiol. source

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    Premisecitation

    In cultured hippocampal neurons submitted to oxygen-glucose-deprivation/reperfusion, CBD enhances mitochondrial function and reduces oxidative stress.

    “In cultured hippocampal neurons submitted to oxygen-glucose-deprivation/reperfusion, this phytocannabinoid enhances mitochondrial function and reduces oxidative stress (126)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [126] Sun, 2017, Cannabidiol attenuates OGD/R-induced damage by enhancing mitochondrial bioenergetics and modulating glucose metabolism via pentose-phosphate pathway in hippocampal neurons, Redox Biol. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Acute administration of an anxiolytic dose of CBD is safe and appears to preserve sleep architecture, unlike benzodiazepines and SSRIs.

    “It is particularly important, since different from anxiolytic and antidepressant drugs such as benzodiazepines and SSRIs, acute administration of an anxiolytic dose of CBD is a safe and appear to preserve the sleep architecture.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Linares, 2018, Cannabidiol presents an inverted U-shaped dose-response curve in a simulated public speaking test, Eur. Neuropsychopharmacol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The anticonvulsant effects of CBD were described in animals and in a preliminary clinical trial in the 1970s.

    “Still in the 1970s, the anticonvulsant effects of CBD were one of the first pharmacological properties of the drug described both in animals (132, 133) and in a preliminary clinical trial in patients led by the same Brazilian group (134).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [132] Carlini, 1973, Cannabidiol and Cannabis sativa extract protect mice and rats against convulsive agents, J Pharm Pharmacol. source

      Not checked in the free run.

    • cites [133] Izquierdo, 1973, Effect of cannabidiol and other Cannabis sativa compounds on hippocampal seizures discharges, Psychopharmacologia source

      Not checked in the free run.

    • cites [134] Cunha, 1980, Chronic administration of cannabidiol to healthy volunteers and epileptic patients, Pharmacology source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The experimental and clinical use of CBD has clearly shown anxiolytic, antiepileptic, and antipsychotic properties, among other effects.

    “In conclusion, the experimental and clinical use of CBD, a compound that does not produce the typical subjective effects of marijuana induced by Δ9-THC, has clearly shown anxiolytic, antiepileptic, and antipsychotic properties, among other effects (2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] Zuardi, 2008, Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action, Rev Bras Psiquiatr. source

      Not checked in the free run.

41 of 41

  • The paper relies on this without support.

    No trials to date have assessed neuroprotective treatments with CBD for Parkinson's disease.

    “Although the endocannabinoid system has aroused a promising target in the field of neuroprotection, no trials to date have assessed neuroprotective treatments with CBD for PD.”

  • The paper relies on this without support.

    Currently, options for the pharmacological management of REM sleep behavior disorder are limited.

    “Currently, options for the pharmacological management of RBD are limited.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • RBD case series is cited as a Parkinson's trial

    Minor

    The RBD paragraph assigns reference 141 to an open trial involving four patients. Reference 141 is titled as an exploratory double-blind Parkinson's trial, whereas reference 88 is titled as the RBD case series.

  • Figure 3 caption describes brain sites, not the dose-response results

    Minor

    The text points to Figure 3 for a dose-response curve from a public-speaking test, but its caption describes brain sites associated with anxiolytic effects.

  • Figure 2 caption describes the public-speaking results, not brain sites

    Minor

    The text points to Figure 2 for results from injections into brain areas, but the Figure 2 caption describes anxiety scores in healthy volunteers during a public-speaking test.

  • Parkinson's trial is cited as an RBD case series

    Minor

    The paragraph assigns reference 88 to a 21-patient, placebo-controlled Parkinson's trial. Reference 88 is instead titled as a case series on REM sleep behavior disorder; reference 141 is titled as the exploratory double-blind Parkinson's trial.

4 of 4

Cites

Flagged first, then by citations

Research works printed but not linked: 5

  1. Mechoulam, 2014, Fluorinated CBD Compounds, Compositions and Uses Thereof
  2. Takahashi, 1970, Composição química e importância dos diversos constituintes na atividade farmacológica de amostras de Cannabis sativa Brasileiras, Rev Bras Pesqui Med Biol, 10, 379
  3. Zuardi, 1983, Changes in the conditioned emotional response of rats induced by 9-THC, CBD and mixture of the two cannabinoids, Arq Biol TecnoI., 26, 391
  4. Leweke, 2011, The efficacy of cannabidiol in the treatment of schizophrenia - a translational approach, Schizophr Bull., 37, 313
  5. A Double Blind, Randomized Placebo-controlled Trial to Evaluate Efficacy and Safety of Cannabidiol as an add-on Therapy for Treatment in Refractory Epileptic Crisis in Children and Adolescents.

Cited by

Sorted by citations

Related

Authors
Crippa, J. A., Guimarães, F. S., Campos, A. C., & Zuardi, A. W.
Affiliations
Conselho Nacional de Desenvolvimento Científico e Tecnológico (BR)
Corresponding author
Crippa, José A.
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2018-09-21
Volume
9
Pages
2009-2009
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2018.02009
PMC
PMC6161644
OpenAlex
W2890537675
Semantic Scholar
d2c0b77b99bc82b39d91629050b921b540dcfbdd
Cited by
308
References
159
Citations by year
2026: 17 · 2025: 27 · 2024: 40 · 2023: 58 · 2022: 39 · 2021: 47 · 2020: 44 · 2019: 34 · 2018: 2
FWCI
3.71
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq/MS/SCTIE/DECIT No 26/2014—Pesquisas sobre Distúrbios Neuropsiquiátricos; 466805/2014-4)
  • Fundação de Amparo à Pesquisa do Estado de São Paulo
  • Fundação de Apoio ao Ensino, Pesquisa e Assistência do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo
  • Instituto Nacional de Ciência e Tecnologia Translacional em Medicina
Topics
  • Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
  • Health Sciences › Medicine › Complementary and alternative medicine › Medicinal Plant Extracts Effects
  • Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
Keywords
cannabidiol, cannabinoids, neuropsychiatric disorders, anxiolytic effects, antipsychotic effects, neuroprotection, epilepsy, substance abuse, schizophrenia, social anxiety disorder, post-traumatic stress, depression, bipolar disorder, sleep disorders, Parkinson's disease, clinical translation
MeSH terms
Animals, Anxiety, Brazil, Cannabidiol, Cannabis, Clinical Trials as Topic, Epilepsy, Humans, Parkinson Disease, Psychotic Disorders, Neuroprotective Agents, Translational Research, Biomedical

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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