Introduction

 

Although delta-9-tetrahydrocannabinol (delta-9-nic) is commonly accepted as the major psychoactive constituent of Cannabis sativa, several reports have demonstrated that other components of the plant influence its pharmacological activity (Carlini et al. 1970; Kubena and Barry 1972). One of these components is cannabidiol (CBD), which may constitute up to 40 percent of marijuana extracts (Grlic 1976) and is devoid of the typical psychological effects of marijuana on humans (Zuardi et al. 1982).

 

Interactive studies between delta-9-mc and CBD have produced apparently contradictory results both in animals (Karniol and Carlini 1973; Borgen and Davis 1974; Fernandes et al. 1974) and humans (Karniol et al. 1974; Hollister and Gillespie 1975; Dalton et al. 1976; Zuardi et a1.1982). Different schemes of drug administration used in these studies may help to explain the contradictions. It seems that when CBD is administered before delta-9-11-Tc, it potentiates the effects of the latter compound, probably by a pharmacokinetic interaction. A potent inhibitor of hepatic drug metabolism, CBD (Paton and Pertwee 1972; Bornhein et al. 1981), increases delta-9-THC concentrations in the brain (Jones and Pertwee 1972). Concomitant use of both compounds, however, suggests that CBD is able to antagonize delta-9-THC effects (Karniol and Carlini 1973; Davis and Borges 1974; Zuardi et al. 1981,1984; Zuardi and Karnio11983).

 

Since high doses of delta-9-THC can induce psychopathological symptoms, including anxiety, panic attacks, and psychotic symptoms (Melges et al. 1974; Tassinari et al. 1976), the evidence that CBD can block some of the psychoactive effects of THC is of interest.

 

To further investigate this point, we tested the simultaneous oral administration of CBD (1 mg/Kg) with a high delta-9-THC dose (0.5 mg/Kg) in healthy volunteers, using a double-blind procedure' (Zuardi et al. 1982). Previous studies had already shown that at this dosage CBD is not able to change delta-9-THC blood levels (Agurell et al. 1981). We observed that delta-9-THC induced significant subjective anxiety and psychotic-like symptoms. Both effects were significantly lessened by simultaneous administration of CBD. This counteraction does not appear to be caused by a general blocking of delta-9-THC effects, since no significant change was detected in other measurements, such as an increase in pulse rate. Moreover, CBD does not bind to the cannabinoid receptor, and hence it is not a competitive antagonist of these receptors (Howlett et al. 1992). In addition, when administered alone, CBD had its own effects, such as induced sleepiness (Zuardi et al. 1982).

 

Several other studies have also shown that CBD has its own effects both in animals and humans. These include sedative (Pickens 1981; Zuardi et al. 1981), hypnotic (Monti 1977; Colasanti et al. 1984; Carlini et al. 1979), anticonvulsant (Carlini et al. 1973; Izquierdo et al. 1973; Cunha et al. 1980) and hormonal effects (Zuardi et al. 1984, 1993). Our results, therefore, led us to suspect that CBD could have anxiolytic and or antipsychotic effects.

 

Possible Anxiolytic Effects of CBD

 

PRECLINICAL STUDIES

 

Early studies produced contradictory results concerning a possible anxiolytic effect of CBD. For example, Zuardi and Karniol (1983) reported that CBD (10 mg/kg) induced a change in the lever-pressing behavior of rats similar to that obtained by typical anxiolytic compounds. However, Silveira Filho and Tufik (1981) did not find any anxiolytic effect of CBD in doses above 100 mg/kg. CBD was ineffective as an anxiolytic in a conflict test and in increasing food intake suppressed by neophobia.

 

There were large differences between doses of CBD used in these two studies. So we decided to investigate the effects of CBD over a wider range of doses in a new animal model that is now largely used to detect anxiolytic effects, the elevated plus maze (a maze that is shaped like a plus sign). This model of anxiety is based on the natural avoidance of the open (not enclosed)

 

'Neither the drug administrators nor the volunteers knew what they were given.

 

and elevated arms of a plus-maze displayed by normal rats or mice (Fellow et al. 1985). We showed that CBD (2.5-10 mg/kg) increases exploration of the open arm, an effect typical of anxiolytic compounds (Guimardes et al. 1990). The curve of the drug effect, however, has an inverted U-shape, and higher doses are no longer effective. Musty et al. (1984), measuring water-licking behavior suppressed by concomitant electric shock in rats, and Onaivi et al. (1990), measuring mice's exploration of an elevated plus maze, reported similar anxiolytic results. More recently, we tested three derivatives of CBD, HU219, HU-252 and HU-291, in the elevated plus maze. All compounds increased exploration of the open arm, although over a limited range of doses (Guimardes et al. 1994). Preclinical studies, therefore, seem to support the presence of anxiolytic properties of CBD.

 

CLINICAL STUDIES

 

Safety Studies. Cannabidiol was extensively tested in laboratory animals to detect possible side or toxic effects (Cunha et al. 1980). In humans, acute oral intake (15 to 160 mg/day), inhalation (0.15 mg/kg), or intravenous administration (30 mg) of CBD were devoid of any significant side effects (Hollister 1973; Karniol et al. 1974; Dalton et al. 1976). Chronic oral ingestion of doses ranging from 10 to 400 mg daily for two to 30 days did not induce significant changes in neurological, clinical, psychiatric, blood, and urine examinations (Mincis et al. 1973; Cunha et al. 1980), with exception of mild somnolence in a few volunteers at the beginning of the trial. These results have justified the use of CBD in clinical trials. For example, Cunha et al. (1980) treated 15 patients with refractory epilepsy with CBD (200-300 mg/day) for as long as four and one-half months with no signs of toxicity. More recently Consroe et al. (1991) also failed to find toxic effects of the drug (in doses of about 700 mg/day) administered over six weeks to patients with Hunting-ton's disease. Therefore, in addition to animal findings, clinical studies also suggest that CBD is a safe compound when administered to humans over a wide range of doses.

 

EFFECTS OF CBD IN A CLINICAL MODEL OF ANXIETY

 

The preclinical and safety studies reported above prompted us to test CBD in a clinical model of anxiety, the simulated public speaking test. In this test healthy volunteers (university students, both sexes, N = 10/group) performed baseline measures, including self-rating scales to evaluate subjective feelings, before receiving, in a double-blind design, a placebo, CBD (300 mg), or two anxiolytics, diazepam (10 mg) or ipsapirone (5 mg). After one hour and 20 minutes, the subject sat in front of a videocamera and video screen and watched a videotape with instructions about the task he or she would have to perform. Subjects were told that they would have two minutes to prepare a four-minute speech about a topic he or she had learned in a course during the previous year. The speech would be recorded on videotape and analyzed later by a psychologist. The subject then started the speech in front of the videocamera while viewing his or her own image on the screen. Self-rating subjective anxiety measures were taken before, during, and after the speech. The test induced significant increases in subjective anxiety (Figure 1) and in its physiological concomitants. This effect was lessened by CBD and the two anxiolytic compounds. No side effects of CBD were found, suggesting that the drug's effect on anxiety levels cannot be attributed to general sedative effects (Zuardi et al. 1993). The results thus suggest that CBD has anxiolytic properties when administered to healthy volunteers.

 

Possible Antipsychotic Effects of Cannabidiol

 

PRECLINICAL STUDIES

 

Typical antipsychotic drugs, although effective in decreasing psychotic symptoms in schizophrenic patients, may induce significant extrapyramidal, Parkinson-like side effects. These side effects are not produced by drugs such as clozapine, often classified as "atypical antipsychotics." The clinical use of clozapine, however, is limited by potentially fatal hematological adverse effects. Intensive research efforts have been made to develop new compounds with an antipsychotic profile similar to that of clozapine but without adverse hematological effects. Recently, we studied the effects of CBD in animal models often used to investigate antipsychotic properties of new compounds, comparing them to those of haloperidol, a typical antipsychotic drug. Both compounds lessened stereotypy (that is, repetitive movements, such as sniffing or biting, made without a clear objective) induced by a dopaminergic agonist, apomorphine (Zuardi et al. 1991). In contrast to haloperidol, however, the potency of CBD in increasing prolactin levels was very low, and the drug did not induce catalepsy (that is, maintenance of abnormal postural positions) at any dose tested (15-480 mg/kg). The ability of typical antipsychotics to provoke catalepsy in rodents is highly correlated with the appearance of Parkinson-like symptoms in patients treated with these drugs. The profile of CBD effects in these tests, therefore, is similar to that seen with clozapine and suggests that CBD may act as an "atypical" antipsychotic.

Effects of cannabidiol (CBD, 300 mg), ipsapirone (IPs, 5 mg), diazepam (DZ, 10 mg) or placebo (PLAC) on anxiety induced by a simulated public speaking test. Bars are means of 10 healthy volunteers (+ sEm). Subjects were evaluated by the visual analogue mood scale (vAms), anxiety factor, before drug administration (BASELINE), during speech performance (TEST), and 15 min. after speech (POST-TEST). See text for detailed explanation of phases. Asterisks indicate significant differences from placebo.

 

CLINICAL STUDY

 

Based on the preclinical study reported above and on the antagonism of psychotomimetic effects induced by high doses of delta-9-THC (Zuardi et al. 1982), we decided to test CBD on a schizophrenic patient who had significant hormonal side effects during treatment with typical antipsychotics (Zuardi et al. 1995). The patient, a 19-year-old woman, was referred to the inpatient unit of the Clinical Hospital of Ribeirao Preto because of aggressiveness, self-injury, incoherent thoughts, and auditory hallucinations. After the study protocol was approved by the local Ethical Committee, informed consent was obtained from close relatives of the patient. The study began with four days of hospitalization during which the patient received placebo plus usual support measures. From days 4 to 30 she received CBD in progressively increased dosage, up to 1500 mg/day, in two divided doses. The CBD was then suspended and replaced by a placebo for four days. After that, haloperidol administration was started. Adjustment of the dosage was based on clinical evaluation. Diazepam was also administered in periods of great agitation. The mean daily dose of diazepam decreased after the beginning of CBD treatment from 16.3 to 5.7 mg/day. The patient was evaluated by two psychiatrists and two nurse auxiliaries, and the interviews were videotaped. At the end of the study the videotapes were analyzed blindly and in a random sequence by another psychiatrist. Symptoms decreased after CBD treatment (see Figure 2) and there was a trend for worsening of the symptoms after drug withdrawal.

Scores of the Brief Psychiatric Rating scale (BPRs) and the Interactive Observation Scale for Psychiatric Inpatients (IOm) from a patient treated with cannabidiol (CBD) or haloperidol. The BPRS was rated either by two independent psychiatrists (OPEN BPRS) or blindly by a psychiatrist based on videotaped interviews presented in a random order (BLIND BPRS). The IOSPI was evaluated independently by two nurse auxiliaries after daily observation periods of six hours. W indicates periods without medication.

 

The improvement obtained with CBD was not increased by haloperidol. This improvement was seen in all items of the rating scale employed, including those more closely related to psychotic symptoms, making it improbable that anxiolytic action was solely responsible for the antipsychotic effect. The drug was well tolerated during the study, and no Parkinson-like symptom was reported. The results, therefore, suggest that CBD may indeed possess antipsychotic properties devoid of Parkinson-like side effects. The presence of such properties may explain, as suggested by Rottanburg et al. (1982), the finding that patients admitted to a psychiatric hospital in South Africa show a much higher frequency of acute psychotic episodes associated with the use of Cannabis sativa than in other countries. Cannabidiol is virtually absent from the plant variety in that region. (Turner and Hadley 1973).

 

Concluding Remarks

 

The studies reviewed here suggest that CBD may possess anxiolytic and antipsychotic properties. More research efforts, however, are needed to ascertain a role for CBD in our therapeutic armamentarium. Larger, controlled, and double-blind clinical studies on patients suffering from anxiety and schizophrenia are clearly needed to confirm the anxiolytic and antipsychotic properties suggested by our initial findings. Preclinical studies, on the other hand, should concentrate on the elucidation of possible mechanisms of the actions of CBD. Such knowledge may help to develop new and more potent drugs with potential for clinical use.

 

References

 

Agurell, S., S. Carlsson, J.E. Lindgren, A. Ohlsson, H. Gillespie, and L. Hollister. 1981. Interactions of delta-9-tetrahydrocannabinol with cannabinol and cannabidiol following oral administration in man: Assay of cannabinol and cannabidiol by mass fragmentography. Experientia 37 (10): 1090-1092.

Borgen, L.A., and W.M. Davis. 1974. Cannabidiol interaction with delta-9-tetrahydrocannabi-

nol. Research Commununications in Chemical Patholology and Pharmacology 7 (4): 663-670. Bornhein, L.M., H.K. Borys, and R. Karler. 1981. Effect of cannabidiol on cytochrome P-450

and hexobarbital sleep time. Biochemical Pharmacology 30 (5): 503-507.

Carlini, E.A., J.R. Leite, M. Tannhauser, and A.C. Berardi (1973. Cannabidiol and Cannabis sativa extract protect mice and rats against convulsive agents. Journal of Pharmacy and Pharmacology 25 (8): 664-665.

Carlini, E.A., J. Masur, and C.C.P.B. Magalhaes. 1979. Possivel efeito hipnotico do canabidiol no ser human: Estudo preliminar (Possible hypnotic effect of cannabidiol in man: Preliminary study). Ciencia e Cultura 31: 315-322.

Carlini, E.A., M. Santos, V. Claussen, D. Bieniek, and F. Korte. 1970. Structure activity relationship of four tetrahydrocannabinols and the pharmacological activity of five semi-purified extracts of Cannabis sativa. Psychopharmacologia (Berl) 18 (1): 82-93.

Colasanti, B.K., R.E. Brown, and C.R. Craig. 1984. Ocular hypotension, ocular toxicity, and neurotoxicity in response to marihuana extract and cannabidiol. General Pharmacology 15: 479-484.

Consroe, R, J. Laguna, J. Allender, S. Snider, L. Stern, R. Sandyk, K. Kennedy, and K. Schram. 1991. Controlled clinical trial of cannabidiol in Huntington's disease. Pharmacology Biochemistry and Behavior 40: 701-708.

Cunha, J., E.A. Carlini, A.E. Pereira, O.L. Ramos, C. Pimentel, R. Gagliardi, W.L. Sanvito, N. Lander, and R. Mechoulam. 1980. Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Pharmacology 21 (3): 175-185.

Dalton, W.S., R. Martz, L. Lemberger, B.E. Rodda, and R.B. Forney. 1976. Influence of cannabidiol on delta-9-tetrahydrocannabinol effects. Clinical Pharmacology and Therapeutics 19 (3): 300-309.

Davis, W.M., and L.A. Borgen. 1974. Effects of cannabidiol and delta-9-tetrahydrocannabinol on operant behavior. Research Communications in Chemical Pathology and Pharmacology 9 (3): 453-462.

Dewey, W.L. 1986. Cannabidiol pharmacology. Pharmacology Review 38: 151-178.

Fernandes, M., A. Schabarek, H. Coper, and R. Hill. 1974. Modification of delta-9-THC actions

by cannabinol and cannabidiol in the rat. Psychopharmacologia (Berl.) 38 (4): 329-338. Grlie, L. 1976. A comparative study on some chemical and biological characteristics of various

samples of cannabis resin. Bulletin on Narcotics 14: 37-46.

Guimaraes, F.S., T.M. Chiaretti, F.G. Graeff, and A.W. Zuardi. 1990. Antianxiety effect of cannabidiol in the elevated plus-maze. Psychopharmacology 100 (4): 558-559.

Guimaraes, F.S., J.C. de Aguiar, R. Mechoulam, and A. Breuer. 1994. Anxiolytic effect of cannabidiol derivatives in the elevated plus-maze. General Pharmacology 25: 161-164.

Hollister, L.E., and H. Gillespie. 1975. Interactions in man of delta-9-tetrahydrocannabinol: II. Cannabinol and cannabidiol. Clinical Pharmacology and Therapeutics 18 (1): 80-83.

Howlett, A.C., D. Evans, and D.B. Houston. 1992. The cannabinoid receptor. In Marijuana/Cannabinoids: Neurobiology and Neurophysiology, ed. L. Murphy and A. Bartke, 35-72. Boca Raton, FL: CRC Press.

Izquierdo, I., O.A. Orsingher, and A.C. Berardi. 1973. Effect of cannabidiol and other Cannabis

sativa compounds on hippocampal seizure discharges. Psychopharmacologia 28 (1): 95-102. Jones, G., and R.G. Pertwee. 1972. A metabolic interaction in vivo between cannabidiol and

delta-l-tetrahydrocannabinol. British Journal of Pharmacology 45 (2): 375-377.

Karniol, I.G., and E.A. Carlini. 1973. Pharmacological interaction between cannabidiol and delta-9-tetrahydrocannabinol. Psychopharmacologia (Berl) 33 (1): 53-70.

Karniol, 1.G., I. Shirakawa, N. Kasinski, A. Pfeferman, and E.A. Carlini. 1974. Cannabidiol interferes with the effects of delta-9-tetrahydrocannabinol in man. European Journal of Pharmacology 28 (1): 172-177.

Kubena, R.K., and H. Barry, 111.1972. Stimulus characteristics of marihuana components. Nature 235 (5338): 397-398.

Melges, ET., J.R. Tinklenberg, C.M. Deardorff', N.H. Davies, R.E. Anderson, and C.A. Owen. 1974. Temporal disorganization and delusional-like ideation. Archives of General Psychiatry 30 (6): 855-861.

Meyer, R.E. 1978. Behavioral pharmacology of marihuana. In Psychopharmacology: A Generation of Progress, ed. M.A. Lipton, A. Dimascio and K.F. Killam, 1634-1652. New York: Raven Press.

Mincis, M., A. Pfeferman, R.X. Guimaraes, O.L. Ramos, E. Zukerman, I.G. Karniol, and E.A. Carlini. 1973. Administracao cornica de cannabidiol em seres humanos (Chronic administration of cannabidiol in human beings). Res. Assoc. Med. Brasil 1.9: 185-190.

Monti, J.M. 1977. Hypnotic-like effects of cannabidiol in the rat. Psychopharmacology 55 (3): 263-265.

Musty, R.E., L.H. Conti, and R. Mechoulam. 1984. Anxiolytic properties of cannabidiol. In Marihuana '84: Proceedings of the Oxford Symposium on Cannabis, ed. D.J. Harvey. 713-719. Oxford: IRL Press.

Onaivi, E.S., M.R. Green, and B.R. Martin. 1990. Pharmacological characterization of cannabinoids in the elevated plus maze. ournal of Pharmacology and Experimental Therapeutics 253: 1002-1009.

Paton; W.D.M., and R.G. Pertwee. 1972. Effect of cannabis and certain of its constituents on pentobarbitone sleeping time and phenazone metabolism. British Journal of Pharmacology 44 (2): 250-261.

Pellow, S., P. Chopin, S.E. File, and M. Briley. 1985. Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. Journal of Neuroscience Methods. 14: 149-167.

Pickens, J.T. 1981. Sedative activity of cannabis in relation to its delta-1-trans-tetrahydro-

cannabinol and cannabidiol content. British Journal of Pharmacology 72 (4): 649-656. Rottanburg, D., A.H. Robins, 0. Ben-Arie, A. Teggin, and R. Elk, 1982. Cannabis-associated

psychosis with hypomanic features. Lancet 2 (8312): 1364-1366.

Silveira Filho, N.G., and S. Tufik. 1981. Comparative effects between cannabidiol and diazepam on neophobia, food intake, and conflict behavior. Research Communications in Psychology, Psychiatry and Behavior 6: 25-26.

Tassinari, C.A., G. Ambrosetto, M.R. Peraita-Adrados, and H. Gestaut. 1976. The neuropsychiatric syndrome of delta-9-tetrahydrocannabinol and cannabis intoxication in naive subjects: A clinical and polygraphic study during wakefulness and sleep. In The Pharmacology of Marihuana, ed. M.C. Braude and S. Szara, 357-375. New York: Raven Press.

Turner, C.E. and K. Hadley. 1973. Constituents of Cannabis sativa L. II. Absence of cannabidiol in an African variant. Journal of Pharmaceutical Sciences 62: 251-255.

Zuardi, A.W., R.A. Cosine, F.G. Graeff, and F.S. Guimaraes. 1993. Effects of ipsapirone and cannabidiol on human experimental anxiety. Journal of Psychopharmacology 7: 82-88.

Zuardi, A.W., E. Finkelfarb, O.F.A. Bueno, R.E. Musty, and I.G. Karniol. 1981. Characteristics of the stimulus produced by the mixture of cannabidiol with delta-9-tetrahydrocannabinol. Archives Internationales de Pharmacodynamie et de Therapie 249 (1): 137-146.

Zuardi, A.W., F.S. Guimaraes, and A.C. Moreira. 1993. Effect of cannabidiol on plasma prolactin, growth hormone, and cortisol in human volunteers. Brazil Journal of Medical Biology Research 26: 213-217.

Zuardi, A.W., and I.G. Karniol. 1983. Changes in the conditioned emotional response of rats induced by delta-9-THC, CBD and mixture of the two cannabinoids. Arquivas de Biologia Tecnologia 26: 391-397.

Zuardi, A.W., and I.G. Karniol. 1983. Effects of variable interval performance in rats of delta9-tetrahydrocannabinol and cannabidiol, separately and in combination. Brazilian Journal of Medical and Biological Research 16: 141-146.

Zuardi, A.W., S.L. Morais, F.S. Guimaraes, and R. Mechoulam. 1995. Antipsychotic effect of cannabidiol. Journal of Clinical Psychiatry 56 (10): 485-486.

Zuardi, A.W., J.A. Rodrigues, and J.M. Cunha. 1991. Effects of cannabidiol in animal models predictive of antipsychotic activity. Psychopharmacology 104: 260-264.

Zuardi, A.W., I. Shirakawa, E. Finkelfarb, and I. Karniol. 1982. Action of cannabidiol on the anxiety and other effects produced by delta-9-THC in normal subjects. Psychopharmacology 76 (3): 245-250.

Zuardi, A.W., N.A. Teixeira, and I.G. Karniol. 1984. Pharmacological interaction of the effects of delta-9-tetrahydrocannabinol and cannabidiol on serum corticosterone levels in rats. Archives Internationales de Pharmacodynamie et de Therapie 269 (1): 12-19.

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