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An anxiolytic (also antipanic or antianxiety agent) is a medication or other intervention that inhibits anxiety.
 

ANXIOLYTIC EFFECT & Cannabis studies completed 

2006 - Study - Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug

2007 - Study ~ Chronologically overlapping occurrences of nicotine-induced anxiety- and depression-related behavioral symptoms: effects of anxiolytic and cannabinoid drugs

2007 - Study ~ Modulation of Fear and Anxiety by the Endogenous Cannabinoid System

2008 - Study ~ Cannabinoid Modulation of Amygdala Reactivity to Social Signals of Threat in Humans

2008 - Study - The association between anxiety and alcohol versus cannabis abuse disorders among adolescents in primary care settings

2009 - Study ~ Endocannabinoids: Stress, Anxiety, and Fear

2009 - Study - Effects of {Delta}9-tetrahydrocannabinol on reward and anxiety in rats exposed to chronic unpredictable stress

2009 - Study - Modulation of effective connectivity during emotional processing by Delta9-tetrahydrocannabinol and cannabidiol

2009 - Study - Opposite Effects of Delta-9-Tetrahydrocannabinol and Cannabidiol on Human Brain Function and Psychopathology

2009 - Study ~ Cannabidiol reverses the reduction in social interaction produced by low dose Delta(9)-tetrahydrocannabinol in rats.

2009 - News ~ Medical Marijuana and Anxiety Disorders

2009 - News ~ Medical Marijuana and Panic Disorder

2010 - Study ~ Brain CB2 Receptors: Implications for Neuropsychiatric Disorders

2010 - Study ~ Preservation of Striatal Cannabinoid CB1 Receptor Function Correlates with the Antianxiety Effects of Fatty Acid Amide Hydrolase Inhibition

2010 - Study ~ Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report.

2010 - Study ~ Cannabinoids and anxiety.

2010 - Study ~ A behavioural comparison of acute and chronic Delta9-tetrahydrocannabinol and cannabidiol in C57BL/6JArc mice.

2010 - Study ~ Intra-dorsal periaqueductal gray administration of cannabidiol blocks panic-like response by activating 5-HT1A receptors.

2010 - Study ~ Pharmacological exploitation of the endocannabinoid system: new perspectives for the treatment of depression and anxiety disorders?

2010 - Study ~ Cannabinoids prevent the development of behavioral and endocrine alterations in a rat model of intense stress.

2011 - Study ~ Cannabinoids prevent the development of behavioral and endocrine alterations in a rat model of intense stress.

2011 - Study ~ Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients.

2011 - Study ~ Effects of intracisternal administration of cannabidiol on the cardiovascular and behavioral responses to acute restraint stress.

2011 - Study ~ Cannabinoids and emotionality: a neuroanatomical perspective.

2011 - Study ~ Effect of cannabidiol on sleep disruption induced by the repeated combination tests consisting of open field and elevated plus-maze in rats.

2011 - Study ~ Anti-Aversive Effects of Cannabidiol on Innate Fear-Induced Behaviors Evoked by an Ethological Model of Panic Attacks Based on a Prey vs the Wild Snake Epicrates cenchria crassus Confrontation Paradigm.

2011 - Study ~ Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report.

2011 - Study ~ Inhibition of endocannabinoid catabolic enzymes elicits anxiolytic-like effects in the marble burying assay.

2011 - News ~ Hemp Seed Oil for Anxiety

2012 - Study ~ Differences in Spontaneously Avoiding or Approaching Mice Reflect Differences in CB1-Mediated Signaling of Dorsal Striatal Transmission.

2012 - Study ~ Cannabidiol, a Cannabis sativa constituent, as an anxiolytic drug.

2012 - Study ~ Opposing Roles for Cannabinoid Receptor Type-1 (CB(1)) and Transient Receptor Potential Vanilloid Type-1 Channel (TRPV1) on the Modulation of Panic-Like Responses in Rats.

2012 - Study ~ Cannabinoid-related Agents in the Treatment of Anxiety Disorders: Current Knowledge and Future Perspectives.

2012 - Study ~ Fear relief-toward a new conceptual frame work and what endocannabinoids gotta do with it.

2012 - Study ~ Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytocannabinoid?

2012 - Study ~ Bimodal Control of Fear-Coping Strategies by CB1 Cannabinoid Receptors.

2012 - Study ~ Antipsychotic Profile of Cannabidiol and Rimonabant in an Animal Model of Emotional Context Processing in Schizophrenia.

2012 - Study ~ Cannabinoid CB1 receptor deficiency increases contextual fear memory under highly aversive conditions and long-term potentiation in vivo.

2012 - Study ~ Expression pattern of the cannabinoid receptor genes in the frontal cortex of mood disorder patients and mice selectively bred for high and low fear.

2012 - Study ~ Cannabinoid-related agents in the treatment of anxiety disorders: current knowledge and future perspectives.

2012 - Study ~ Age-related changes of anandamide metabolism in CB1 cannabinoid receptor knockout mice: correlation with behaviour.

2012 - Study ~ Prevalence of Cannabis Use Disorder Diagnoses Among Veterans in 2002, 2008, and 2009.

2012 - Study ~ Cannabinoid facilitation of fear extinction memory recall in humans.

2012 - News ~ Brain altering drug calms fears also

 

 

 

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Single-dose study of nabilone in anxious volunteers



Author(s)Glass RM, Uhlenhuth EH, Hartel FW, Schuster CR, Fischman MW.
Journal, Volume, IssueJ Clin Pharmacol. 1981 Aug-Sep;21(8-9 Suppl):383S-396S.
Major outcome(s)Antianxiety effects in 2 of the 8 subjects
 
IndicationAbstract
Medication

The effects of single oral doses of nabilone, a synthetic cannabinoid, were studied in eight anxious volunteer subjects. Each subject had two exposures to placebo and three dose levels of nabilone at one-week intervals in a single-blind balanced Latin-square design after the nabilone dose range was determined by each subject's response to a test dose. Heart rate and BLOOD PRESSURE were monitored. The Profile of Mood States (POMS), a self-rating adjective checklist, was used as the quantitative measure of subjective effects. Four subjects performed a continuous avoidance procedure. High doses (4 or 5 mg) of nabilone produced orthostatic hypotension in these subjects. Mild dose-related increases in heart rate also occurred. Despite the occurrence of highly significant levels of sedation, there were no significant effects of nabilone on the continuous avoidance procedure. Two of these four subjects experienced an antianxiety effect from low (1 or 2 mg) nabilone doses. Four other subjects received comparatively lower doses of nabilone and performed on three behavioral tasks at intervals before and after drug: a recognition memory procedure, a task requiring spaced responding at a controlled rate, and a reaction time task. In these subjects there were no reliable effects on BLOOD PRESSURE or heart rate, no significant subjective effects on the POMS, and no antianxiety effects. Drug effects were also minimal on the three behavioral tasks.

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Route(s)
Dose(s)
Duration (days)
Participants
Design
Type of publication
Address of author(s)
Full text

Opposite Effects of Delta-9-Tetrahydrocannabinol and Cannabidiol on Human Brain Function and Psychopathology

 

Title

 

Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology.

Author(s)Bhattacharyya S, Morrison PD, Fusar-Poli P, Martin-Santos R, Borgwardt S, Winton-Brown T, Nosarti C, O' Carroll CM, Seal M, Allen P, Mehta MA, Stone JM, Tunstall N, Giampietro V, Kapur S, Murray RM, Zuardi AW, Crippa JA, Atakan Z, McGuire PK 
InstitutionSection of Neuroimaging, Division of Psychological Medicine & Psychiatry, Institute of Psychiatry, King's College London, London, UK. [email protected]
SourceNeuropsychopharmacology 2010 Feb; 35(3):764-74.
Abstract

Delta-9-tetrahydrocannabinol (Delta-9-THC) and Cannabidiol (CBD), the two main ingredients of the Cannabis sativa plant have distinct symptomatic and behavioral effects. We used functional magnetic resonance imaging (fMRI) in healthy volunteers to examine whether Delta-9-THC and CBD had opposite effects on regional brain function.

 

We then assessed whether pretreatment with CBD can prevent the acute psychotic symptoms induced by Delta-9-THC. Fifteen healthy men with minimal earlier exposure to cannabis were scanned while performing a verbal memory task, a response inhibition task, a sensory processing task, and when viewing fearful faces.

 

Subjects were scanned on three occasions, each preceded by oral administration of Delta-9-THC, CBD, or placebo. BOLD responses were measured using fMRI. In a second experiment, six healthy volunteers were administered Delta-9-THC intravenously on two occasions, after placebo or CBD pretreatment to examine whether CBD could block the psychotic symptoms induced by Delta-9-THC. Delta-9-THC and CBD had opposite effects on activation relative to placebo in the striatum during verbal recall, in the hippocampus during the response inhibition task, in the amygdala when subjects viewed fearful faces, in the superior temporal cortex when subjects listened to speech, and in the occipital cortex during visual processing. In the second experiment, pretreatment with CBD prevented the acute induction of psychotic symptoms by Delta-9-tetrahydrocannabinol.

 

Delta-9-THC and CBD can have opposite effects on regional brain function, which may underlie their different symptomatic and behavioral effects, and CBD's ability to block the psychotogenic effects of Delta-9-THC.

Languageeng
Pub Type(s)Comparative Study
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
PubMed ID

19924114

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Modulation of effective connectivity during emotional processing by Delta9-tetrahydrocannabinol and cannabidiol

In Any Language

Int J Neuropsychopharmacol. 2010 May;13(4):421-32. Epub 2009 Sep 24.

 

Fusar-Poli P, Allen P, Bhattacharyya S, Crippa JA, Mechelli A, Borgwardt S, Martin-Santos R, Seal ML, O'Carrol C, Atakan Z, Zuardi AW, McGuire P.

Neuroimaging Section, Division of Psychological Medicine, Institute of Psychiatry, King's College London, UK. [email protected]

Abstract

Cannabis sativa, the most widely used illicit drug, has profound effects on levels of anxiety in animals and humans. Although recent studies have helped provide a better understanding of the neurofunctional correlates of these effects, indicating the involvement of the amygdala and cingulate cortex, their reciprocal influence is still mostly unknown. In this study dynamic causal modelling (DCM) and Bayesian model selection (BMS) were used to explore the effects of pure compounds of C. sativa [600 mg of cannabidiol (CBD) and 10 mg Delta 9-tetrahydrocannabinol (Delta 9-THC)] on prefrontal-subcortical effective connectivity in 15 healthy subjects who underwent a double-blind randomized, placebo-controlled fMRI paradigm while viewing faces which elicited different levels of anxiety. In the placebo condition, BMS identified a model with driving inputs entering via the anterior cingulate and forward intrinsic connectivity between the amygdala and the anterior cingulate as the best fit. CBD but not Delta 9-THC disrupted forward connectivity between these regions during the neural response to fearful faces. This is the first study to show that the disruption of prefrontal-subocritical connectivity by CBD may represent neurophysiological correlates of its anxiolytic properties.

 

 

 

 

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Effects of {Delta}9-tetrahydrocannabinol on reward and anxiety in rats exposed to chronic

In Any Language

Fokos S, PanagisG 
Effects of {Delta}9-tetrahydrocannabinol on reward and anxiety in rats exposed to chronic unpredictable stress. [JOURNAL ARTICLE]
J Psychopharmacol 2009 Apr 30.

 

Abstract

 

Although cannabis derivatives produce clear subjective motivational responses in humans leading to drug-seeking behaviour, the reinforcing attributes of these subjective effects are difficult to define in experimental animals. The aim of this study was to examine how exposure to chronic unpredictable stress (CUS) will affect reward function and anxiety after acute administration of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) in rats.

 

Male rats were exposed to either 10 days of CUS or no stressor. Alterations in brain reward function were assessed with the intracranial self-stimulation (ICSS) paradigm, and anxiety responses were measured with the elevated plus maze. CUS did not affect baseline brain stimulation reward thresholds. Delta(9)-THC did not exhibit reinforcing actions in the ICSS paradigm neither in nonstressed nor in stressed animals. More importantly, in nonstressed animals, both the low and the high dose of Delta(9)-THC exerted anxiolytic-like effects. In stressed animals, however, only the high dose of THC induced an anxiolytic-like response, whereas the low dose induced anxiogenic effects. The present results provide clear evidence for an anxiolytic effect of Delta(9)-THC both in stressed and in nonstressed animals, and indicate that environmental conditions, such as stressful experiences, do not alter the behavioural effects of Delta(9)-THC in the ICSS paradigm.

 

 

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Modulation of effective connectivity during emotional processing by Delta9-tetrahydrocannabinol and cannabidiol

In Any Language

Int J Neuropsychopharmacol. 2010 May;13(4):421-32. Epub 2009 Sep 24.

Fusar-Poli P, Allen P, Bhattacharyya S, Crippa JA, Mechelli A, Borgwardt S, Martin-Santos R, Seal ML, O'Carrol C, Atakan Z, Zuardi AW, McGuire P.

Neuroimaging Section, Division of Psychological Medicine, Institute of Psychiatry, King's College London, UK. [email protected]

Abstract

Cannabis sativa, the most widely used illicit drug, has profound effects on levels of anxiety in animals and humans. Although recent studies have helped provide a better understanding of the neurofunctional correlates of these effects, indicating the involvement of the amygdala and cingulate cortex, their reciprocal influence is still mostly unknown. In this study dynamic causal modelling (DCM) and Bayesian model selection (BMS) were used to explore the effects of pure compounds of C. sativa [600 mg of cannabidiol (CBD) and 10 mg Delta 9-tetrahydrocannabinol (Delta 9-THC)] on prefrontal-subcortical effective connectivity in 15 healthy subjects who underwent a double-blind randomized, placebo-controlled fMRI paradigm while viewing faces which elicited different levels of anxiety. In the placebo condition, BMS identified a model with driving inputs entering via the anterior cingulate and forward intrinsic connectivity between the amygdala and the anterior cingulate as the best fit. CBD but not Delta 9-THC disrupted forward connectivity between these regions during the neural response to fearful faces. This is the first study to show that the disruption of prefrontal-subocritical connectivity by CBD may represent neurophysiological correlates of its anxiolytic properties

 

 

 

 

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Cannabidiol as an antipsychotic. A double-blind, controlled clinical trial on cannabidiol vs. amisulpride in acute schizophrenia.

Title
Delta-9-tetrahydrocannabinol effects in schizophrenia: implications for cognition, psychosis, and addiction.
Author(s)D'Souza DC, Abi-Saab WM, Madonick S, Forselius-Bielen K, Doersch A, Braley G, Gueorguieva R, Cooper TB, Krystal JH.
Journal, Volume, IssueBiol Psychiatry. 2005 Mar 15;57(6):594-608.
Major outcome(s)THC is associated with transient exacerbation in core psychotic and cognitive deficits in schizophrenia.
 
Indication Abstract
MedicationDelta-9-THC

BACKGROUND: Recent advances in the neurobiology of cannabinoids have renewed interest in the association between cannabis and psychotic disorders. METHODS: In a 3-day, double-blind, randomized, placebo-controlled study, the behavioral, cognitive, motor, and endocrine effects of 0 mg, 2.5 mg, and 5 mg intravenous Delta-9-tetrahydrocannabinol (Delta-9-THC) were characterized in 13 stable, antipsychotic-treated schizophrenia patients. These data were compared with effects in healthy subjects reported elsewhere. RESULTS: Delta-9-tetrahydrocannabinol transiently increased 1) learning and recall deficits; 2) positive, negative, and general schizophrenia symptoms; 3) perceptual alterations; 4) akathisia, rigidity, and dyskinesia; 5) deficits in vigilance; and 6) plasma prolactin and cortisol. Schizophrenia patients were more vulnerable to Delta-9-THC effects on recall relative to control subjects. There were no serious short- or long-term adverse events associated with study participation. CONCLUSIONS: Delta-9-tetrahydrocannabinol is associated with transient exacerbation in core psychotic and cognitive deficits in schizophrenia. These data do not provide a reason to explain why schizophrenia patients use or misuse cannabis. Furthermore, Delta-9-THC might differentially affect schizophrenia patients relative to control subjects. Finally, the enhanced sensitivity to the cognitive effects of Delta-9-THC warrants further study into whether brain cannabinoid receptor dysfunction contributes to the pathophysiology of the cognitive deficits associated with schizophrenia.

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Route(s) 
Dose(s)2.5-5 mg THC
Duration (days)3
Participants13 patients with schizophrenia
DesignControlled study
Type of publicationMedical journal
Address of author(s)Schizophrenia Biological Research Center, VA Connecticut Healthcare System, West Haven, CT 06516, USA. [email protected]
Full text
The association between anxiety and alcohol versus cannabis abuse disorders among adolescents in primary care settings (Oxford Journals)
 
 

Abstract

Background. Both clinical and population-based studies show that anxiety disorders and substance misuse frequently co-occur in adults, whereas among adolescents, less examination of this association has been done. Adolescence is frequently the time of substance use initiation and its subsequent interaction with anxiety disorders has not been fully explored. It is unknown in adolescents whether anxiety is more related to alcohol abuse versus cannabis abuse. In addition, as depression has been implicated in adolescents with both anxiety and substance misuse, its role in the association should also be considered.

Objective. To test the association between current anxiety with alcohol versus cannabis abuse disorders.

Method. Cross-sectional, clinician-administered, structured assessment—using the Primary Care Evaluation of Mental Disorders—to evaluate anxiety, mood and substance abuse disorders among 632 adolescents recruited from primary care settings.

Results. Results show a strong association between current anxiety and alcohol [odds ratio = 3.8; 95% confidence interval (CI) 1.2–11.8], but not cannabis (odds ratio = 1.4; 95% CI 0.4–4.7) abuse.

Conclusion. This association in adolescents reflects the importance for increased awareness of anxiety symptoms and alcohol use patterns in primary care. The lack of association of anxiety with cannabis abuse in this group may reflect differences in cannabis’ anxiolytic properties or that this young group has had less exposure thus far. Given adolescence is a time of especially rapid psychosocial, hormonal and brain development, primary care may provide an opportunity for further investigation and, potentially, early screening and intervention.


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Articles citing this article

Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug

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A.W. Zuardi, J.A.S. Crippa, J.E.C. Hallak, F.A. Moreira and F.S. Guimarães

Departamento de Farmacologia, Departamento de Neurologia, Psiquiatria e Psicologia Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil

 


Abstract 

A high dose of D9-tetrahydrocannabinol, the main Cannabis sativa (cannabis) component, induces anxiety and psychotic-like symptoms in healthy volunteers. These effects of D9-tetrahydrocannabinol are significantly reduced by cannabidiol (CBD), a cannabis constituent which is devoid of the typical effects of the plant. This observation led us to suspect that CBD could have anxiolytic and/or antipsychotic actions. Studies in animal models and in healthy volunteers clearly suggest an anxiolytic-like effect of CBD. The antipsychotic-like properties of CBD have been investigated in animal models using behavioral and neurochemical techniques which suggested that CBD has a pharmacological profile similar to that of atypical antipsychotic drugs. The results of two studies on healthy volunteers using perception of binocular depth inversion and ketamine-induced psychotic symptoms supported the proposal of the antipsychotic-like properties of CBD. In addition, open case reports of schizophrenic patients treated with CBD and a preliminary report of a controlled clinical trial comparing CBD with an atypical antipsychotic drug have confirmed that this cannabinoid can be a safe and well-tolerated alternative treatment for schizophrenia. Future studies of CBD in other psychotic conditions such as bipolar disorder and comparative studies of its antipsychotic effects with those produced by clozapine in schizophrenic patients are clearly indicated.

Key words: Cannabidiol, D9-Tetrahydrocannabinol, Cannabinoid, Anxiety, Antipsychotic, Schizophrenia


Introduction

The use Cannabis sativa (cannabis) extracts as medicine was described in China and India (1) before the birth of Christ. The therapeutic use of cannabis was introduced in Western medicine in the first half of the 19th century and reached its climax in the last two decades of the same century. At the turn of the century, several pharmaceutical companies were marketing cannabis extracts and tinctures which were prescribed by doctors for many different complaints including pain, whooping cough and asthma, and as a sedative/hypnotic agent (2). However, the use of cannabis as a medicine almost completely disappeared at about the middle of the 20th century. The main reasons for this disappearance were the variable potency of cannabis extracts, the erratic and unpredictable individual responses, the introduction of synthetic and more stable pharmaceutical substitutes such as aspirin, chloral hydrate and barbiturates, the recognition of important adverse effects such as anxiety and cognitive impairment, and the legal restrictions to the use of cannabis-derived medicines (2).

Today this situation has changed considerably. The main active psychotropic constituent of cannabis, D9-tetrahydrocannabinol (D9-THC), was isolated, identified and synthesized in the 1960's. Almost three decades later, cannabinoid receptors in the brain were described and cloned and the endogenous cannabinoids were isolated and identified (3). As a result of these discoveries the interest in cannabis research has remarkably increased. For instance, the number of publications using the key word "brain", compiled by the ISI Web of Knowledge, increased 26 times from 1960-1964 to 2000-2004, while the number of publications about `cannabis' increased 78.5 times during the same period. As a consequence, the research on the use of cannabis as medicine has been renewed.

Although D9-THC is commonly accepted as the main factor responsible for the effects of cannabis, several reports have demonstrated that other components of the plant influence its pharmacological activity (4). One of these components is cannabidiol (CBD), which may constitute up to 40% of cannabis extracts (5) and is devoid of the typical psychological effects of cannabis in humans (6). Studies on the interaction between D9-THC and CBD have produced apparently contradictory results (7). Although potentiation of the effects of D9-THC has been observed (8,9), this phenomenon probably involves pharmacokinetic interactions since CBD is a potent inhibitor of hepatic drug metabolism (10) and increases D9-THC concentrations in the brain (11). Several studies, however, have reported antagonism of the effects of D9-THC when both compounds are administered simultaneously to animals (12,13) or humans (6,14).

CBD (1 mg/kg) co-administered with D9-THC (0.5 mg/kg) significantly reduced the anxiety and the psychotomimetic symptoms induced by the latter drug in healthy volunteers (6). Since the dose of CBD used in that study did not change D9-THC levels in blood (15), it was suggested that CBD blocked the effects of D9-THC by some intrinsic pharmacological properties. Actually, when administered alone CBD produced its own effects, including hypnotic (16), anticonvulsive (17), neuroprotective (18), and hormonal (increased corticosterone and cortisol levels) effects (19,20). These effects led to the hypothesis that CBD could have anxiolytic and/or antipsychotic effects.

Anxiolytic effect of cannabidiol

The anxiolytic properties of CBD has been demonstrated by several pre-clinical studies that employed different paradigms such as the conditioned emotional response (21), the Vogel conflict test and the elevated plus-maze (23,24). In the later study (24), the effective doses of CBD ranged from 2.5 to 10 mg/kg, and the drug produced an inverted U-shaped dose-response curve, the higher doses being no longer effective in rats. This could explain the negative results obtained with high doses of CBD (above 100 mg/kg) in a previous study employing the Geller-Seifter conflict test (25).

To evaluate a possible anxiolytic effect of CBD in humans, a double-blind study was conducted on healthy volunteers submitted to a simulation of the public speaking test. CBD (300 mg, po) was compared to ipsapirone (5 mg), diazepam (10 mg) or placebo. The results showed that both CBD and the two other anxiolytic compounds attenuated the anxiety induced by the test (26). The anxiolytic-like effect of CBD in healthy volunteers was also observed in a more recent double-blind study that investigated its effects on regional cerebral blood flow by single-photon emission computed tomography. Because the procedure, by itself, can be interpreted as an anxiogenic situation, it permits the evaluation of anxiolytic drugs. CBD induced a clear anxiolytic effect and a pattern of cerebral activity compatible with an anxiolytic activity (27). Therefore, similar to the data obtained in animal models, results from studies on healthy volunteers have strongly suggested an anxiolytic-like effect of CBD.

Antipsychotic effect

Studies employing animal models

Animal models used for screening antipsychotic drugs are based on the neurochemical hypothesis of schizophrenia, involving mainly the neurotransmitters dopamine and glutamate.

Antagonism of dopamine D2 receptors may be a common feature of most clinically effective antipsychotic drugs, especially those active against hallucinations and delusions (29). The dopamine-based models usually employ apomorphine, a direct agonist, or amphetamine, a drug that increases the release of this neurotransmitter and blocks its re-uptake. Another common effect of antipsychotic drugs is hyperprolactinemia that results from the antagonism of D2 receptors on anterior-pituitary mammotrophic cells. These cells are tonically inhibited by dopamine produced in the hypothalamic arcuate nucleus (30). Conventional or typical antipsychotic drugs, especially those with high affinity for D2 receptors (haloperidol being the standard compound), induce motor side effects characterized by a Parkinson-like syndrome. On the contrary, atypical antipsychotic drugs, of which clozapine is the prototype, are therapeutically effective at doses that induce fewer or no Parkinson-like effects (29). The probability of an antipsychotic agent to induce Parkinson-like symptoms may be evaluated in the catalepsy test (31). Atypical antipsychotics inhibit the stereotypies and hyperlocomotion induced by dopamine agonists at lower doses than those that produce catalepsy.

As a first step in the investigation of possible antipsychotic-like properties of CBD, the drug was compared to haloperidol in rats submitted to dopamine-based models (32). However, blocking D2 receptors is not necessarily the only mechanism for the antipsychotic activity. Several lines of evidence suggest that the glutamatergic N-methyl-D-aspartate (NMDA) receptor is involved in the mechanism of action of clozapine (33). The glutamate-based models of schizophrenia employ sub-anesthetic doses of ketamine, a glutamate NMDA receptor antagonist, or its related compound phencyclidine, to induce psychotic symptoms. A more recent study investigated the effects of CBD in both dopamine and glutamate-based models predictive of antipsychotic activity. The study compared the ability of CBD, haloperidol and clozapine to prevent the hyperlocomotion induced by amphetamine or ketamine in mice (34). The results of these two studies are summarized in Table 1.

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Table 1. Summary of two studies employing animal models for the screening of antipsychotic drugs, which compared cannabidiol, haloperidol and clozapine in rats and mice.

[View larger version of this table (87 K JPG file)]


CBD (15-60 mg/kg), like haloperidol (0.25-0.5 mg/kg), reduced the apomorphine-induced stereotyped behavior in rats in a dose-related manner. These drugs also increased the plasma levels of prolactin. However, higher doses of CBD were needed (120 and 240 mg/kg) to obtain such effects. Moreover, in contrast to haloperidol, CBD did not induce catalepsy, even at doses as high as 480 mg/kg. In agreement with the results obtained in rats, CBD (15-60 mg/kg) inhibited the hyperlocomotion induced by amphetamine in mice in a dose-related manner. In addition, the drug also attenuated the hyperlocomotion induced by ketamine, expanding its antipsychotic-like effects to a glutamate-based model. As expected, while both haloperidol (0.15-0.6 mg/kg) and clozapine (1.25-5.0 mg/kg) inhibited hyperlocomotion, only haloperidol induced catalepsy in this dose range. Therefore, similar to clozapine, CBD did not induce catalepsy at doses that inhibited hyperlocomotion in mice. These results support the view that CBD exhibits a profile similar to that of atypical antipsychotic drugs.

In addition to being tested on behavioral models, typical and atypical antipsychotics may also be distinguished according to their pattern of neural activation. This may be detected by the expression of the proto-oncogene c-Fos. For example, haloperidol induces Fos immunoreactivity in the dorsal striatum, probably reflecting its motor side effects, while clozapine induces Fos immunoreactivity in the prefrontal cortex but not in the dorsal striatum (35). The Fos immunoreactivity pattern induced by CBD (120 mg/kg) was compared to that of haloperidol (1 mg/kg) and clozapine (20 mg/kg) in rats. Only haloperidol increased Fos immunoreactivity in the dorsal striatum, while both CBD and clozapine, but not haloperidol, induced Fos immunoreactivity in the prefrontal cortex (36,37). These results are consistent with the behavioral data obtained when comparing CBD with these prototype antipsychotics.

In conclusion, animal models employing behavioral as well as neurochemical techniques suggest that CBD has a pharmacological profile similar to that of an atypical antipsychotic drug.

 

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Safety studies

Safety studies of CBD were required before human tests. CBD was extensively investigated in laboratory animals to detect possible side or toxic effects. Acute CBD administration by the oral, inhalatory or intravenous route did not induce any significant toxic effect in humans. In addition, chronic administration of CBD for 30 days to healthy volunteers, at daily doses ranging from 10 to 400 mg, failed to induce any significant alteration in neurological, psychiatric or clinical exams. Finally, in patients suffering from Huntington's disease, daily doses of CBD (700 mg) for 6 weeks did not induce any toxicity. Therefore, confirming results from animal studies, the available clinical data suggest that CBD can be safely administered over a wide dose range.

Clinical use

In 1848 the French psychiatrist Jacques-Joseph Moreau de Tour began to investigate the effects of cannabis. He proposed for the first time the use of the plant as an experimental psychotomimetic (40). Results from a recent study, obtained with more appropriate measurements and scales, agreed with Moreau's observation that D9-THC administration induces subjective, cognitive and behavioral changes that resemble endogenous psychosis, suggesting that D9-THC can, indeed, be used as an experimental psychotomimetic drug.

In 1982, a study investigating a possible interaction between D9-THC and CBD in healthy volunteers demonstrated that the latter drug could inhibit D9-THC-induced subjective changes that resembled symptoms of psychotic diseases (Figure 1). In the same year, it was observed that patients admitted to a psychiatric hospital in South Africa, after the use of a variety of cannabis virtually devoid of CBD, showed much higher frequency of acute psychotic episodes than in other countries. These lines of evidence led to several investigations of a possible antipsychotic effect of CBD.


Figure 1. Percentage of healthy volunteers who exhibited psychotic-like effects after the ingestion of 0.5 mg/kg D9-tetrahydrocannabinol (D9-THC; lozenges) and a combination of 0.5 mg/kg D9-THC + 1 mg/kg cannabidiol (circles).

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In order to evaluate the antipsychotic effects of new drugs in healthy volunteers, a useful model is the perception of binocular depth inversion. When a picture is presented separately to each eye, with a slight difference in the angle, it induces a three-dimensional perception. The inversion of this picture from one eye to the other normally induces a change in convexity. This change may not be perceived if familiar objects (faces, for example) are presented, with the expected image predominating, which is illusory. Schizophrenic patients have difficulty in perceiving this illusory image, reporting a more veridical judgment. During antipsychotic treatment, the inverted faces were seen as more illusionary. This veridical judgment may also be obtained by the administration of psychotomimetic drugs such as nabilone, a D9-THC analogue. In this model, impairment of the perception of the illusory image induced by nabilone was attenuated by CBD, suggesting an antipsychotic-like effect of this compound.

Another important model used to evaluate antipsychotic-like activity in healthy volunteers is the administration of sub-anesthetic doses of ketamine. This glutamate-based model induces a psychotic reaction that mimics both positive and negative symptoms of schizophrenia. A double-blind crossover procedure was performed to study the effect of CBD in this model (46). Nine healthy volunteers were assigned randomly to the placebo or CBD (600 mg) groups in two experimental sessions separated by a 1-week interval. After being submitted to psychiatric assessment scales, the volunteers received placebo orally or the drug and rested for 65 min. An infusion pump was then installed and an intravenous bolus of S-ketamine (0.26 mg/kg) was administered during 1 min followed by a maintenance dose of 0.25 mg/kg for 30 min. A Clinician-Administered Dissociative States Scale (CADSS) was applied at the beginning of the sessions and 90 min after the bolus injection. The volunteers were asked to respond the scale according to the period during which they felt most symptomatic. CBD attenuated the effects of ketamine on the total score of the CADSS and also on each of its factors separately. This effect was significant for the depersonalization factor, further reinforcing the antipsychotic-like properties of CBD (Figure 2).

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Figure 2. Depersonalization factor scores of the Clinician-Administered Dissociative States Scale for each healthy volunteer (lines) during intravenous ketamine infusion, after oral placebo or cannabidiol (CBD) (600 mg) administration. Bars indicate the mean ± SEM. *P < 0.05 compared to placebo (paired t-test) for 9 volunteers.

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In view of the safe profile of CBD administration in humans and in laboratory animals, we decided to perform open-label clinical trials in a reduced number of patients. In 1995, CBD was tested in a case study with a 19-year-old schizophrenic female patient who presented serious side effects after treatment with conventional antipsychotics. Following a wash-out period of 4 days this patient received increasing oral doses of CBD dissolved in oil, reaching 1500 mg/day, for 4 weeks. After this period, CBD administration was interrupted and placebo was administered for 4 days. Finally, the treatment was shifted to increasing doses of haloperidol that reached 12.5 mg/day. The psychiatric interviews were video-recorded and the symptoms were assessed by a blinded-psychiatrist using the Brief Psychiatric Rating Scale (BPRS). A significant improvement was observed during CBD treatment, while a worsening was observed when the administration was interrupted. The improvement obtained with CBD was not increased by haloperidol (Figure 3, patient A). Further supporting the safe profile of CBD, no side effects were observed, as assessed by the Ugvalg for Kliniske Undersgelser (UKU) scale.


Figure 3. Brief Psychiatric Rating Scale (BPRS) scores for 4 schizophrenic patients treated with cannabidiol (CBD). Patient A received up to 1500 mg/day CBD and patients B, C, and D received up to 1280 mg/day. Bars indicate BPRS scores for each schizophrenic patient at the end point after the oral administration of placebo, CBD and a control antipsychotic drug (haloperidol for patient A and olanzapine for patients B, C and D). Placebo was administered before and after CBD treatment. Patient A is a woman who presented serious side effects with typical antipsychotics. Patients B, C, and D are men previously treated with typical antipsychotics with no response.

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More recently, CBD was administered to three 22- or 23-year-old male patients with a diagnosis of schizophrenia who had not responded to typical antipsychotic drugs. They received placebo for 5 days in the hospital followed by CBD from the 6th to the 35th day. After this period, they received placebo for an additional 5 days, followed by olanzapine for at least 15 days. The dose of CBD was increased from 40 up to 1280 mg/day. The patients were assessed by two psychiatrists, who were blind to the doses administered, using the BPRS and UKU scales. No side effects were observed during CBD treatment, even at the higher dose of 1280 mg/day. A partial improvement was observed in one patient (Figure 3, patient B) while slight or no improvement was observed in the other two (Figure 3, patients C and D). However, the patients (C and D) were considered to be refractory, since they did not even respond to clozapine, a fact that may explain the lack of CBD effectiveness (48). Figure 3 shows the results obtained with the 4 schizophrenic patients treated so far with CBD. These studies suggest, therefore, that CBD has an antipsychotic-like profile in healthy volunteers and may possess antipsychotic properties in schizophrenic patients, but not in the resistant ones.

Confirming this suggestion, a preliminary report from a 4-week, double-blind controlled clinical trial, using an adequate number of patients and comparing the effects of CBD with amisulpride in acute schizophrenic and schizophreniform psychosis, showed that CBD significantly reduced acute psychotic symptoms after 2 and 4 weeks of treatment when compared to baseline. In this trial CBD did not differ from amisulpride except for a lower incidence of side effects.

In conclusion, results from pre-clinical and clinical studies suggest that CBD is an effective, safe and well-tolerated alternative treatment for schizophrenic patients. Future trials of this cannabinoid in other psychotic conditions such as bipolar disorder (50) and comparative studies of its antipsychotic effects with those produced by clozapine in schizophrenic patients are clearly needed.

 

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Correspondence and Footnotes

Address for correspondence: A.W. Zuardi, Departamento de Neurologia, Psiquiatria e Psicologia Médica, FMRP, USP, Av. Bandeirantes, 3900, 14049-900 Ribeirão Preto, SP, Brasil. E-mail: [email protected]

Several studies reviewed here were supported by FAPESP and CNPq. Received August 9, 2005. Accepted December 14, 2005.

 

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