[ Pobierz całość w formacie PDF ]
.It seems that anxiety is associ-ated with reduced parahippocampal activity, consistent with the findings thatCBD increases activity in this brain area.Because activity in the CBD condi-tion decreased relative to the placebo, these data fit well since there are a lotof data linking amygdala activation in a large variety of anxiety states.Similarly, the hypothalamus is involved in various anxiety states: imagingstudies in particular have shown increases in hypothalamic activity in anxietyinduced in normal volunteers and panic patients, again consistent with the anx-iolytic effect of CBD.In regard to the posterior cingulate gyrus, increasedbrain activity is associated with viewing anxiety-provoking videos, which pro-voked obsessions in obsessive patients.Patients with obsessive-compulsivedisorder (OCD), if untreated, have increased metabolism in the brain area,which decreases with treatment and symptom remission, although there aresome conflicting data (see [20] for references relating to all of the above dis-cussion).While these data might be considered preliminary, they provide thefirst evidence of brain systems that are affected in humans.There seems to bequite strong convergence between animal research and human research, sug-gesting strongly that CBD is a true anxiolytic.Given the fact that this drug hasno psychoactivity in terms of intoxication and is very safe, it seems importantto pursue the potential of CBD, with further behavioral pharmacological stud-ies, mechanistic studies employing neuropharmacological methods and inclinical studies. 146 R.E.MustyDiscussionThe data discussed in this review show there is converging evidence that theCB1 receptor system is involved in the control of anxiety.Many studies haveshown that both antagonists and agonists of the CB1 receptor can produce anx-iolytic effects both in animals and humans.Particularly strong evidence is thefact that CB1-knockout mice are more anxious than wild-type mice The factthat anandamide hydrolysis inhibitors are anxiolytic and that they lead to anincrease in anandamide levels in the brain is further support for the role of thissystem in the control of anxiety.Finally, the observations that CBD increasesor decreases regional cerebral blood flow in areas of the brain predicted to beinvolved in various anxiety states provide strong supportive evidence that atleast this cannabinoid is active in brain areas known to be involved in anxiety.At present, four cannabininoids are available for clinical trials: SR-141716(Rimonbant), the GW Pharmaceuticals extract (Sativex®; a 1:1 ratio of"9-THC/CBD), "9-THC (Marinol) and Nabilone (Cesamet).It would seemreasonable to consider testing these compounds in specific anxiety states,which are refractory to traditional anxiolytics and related drugs.References1 McMeens RR (1860) Report of the Ohio State Medical Committee on Cannabis indica.Ohio StateMedical Society, White Sulphur Springs, OH, 592 Musty RE (1984) Possible anxiolytic effects of cannabidiol.In: S Agurell, W Dewey, R Willette(eds): The Cannabinoids.Academic Press, New York, 829 8443 Guimaraes FS, Chiaretti TM, Graeff FG, Zuardi AW (1990) Antianxiety effect of cannabidiol inthe elevated plus-maze.Psychopharmacology 100: 558 5594 Petitet F, Jeantaud B, Reibaud M, Imperato A, Dubroeucq MC (1998) Complex pharmacology ofnatural cannabinoids: evidence for partial agonist activity of delta-9-tetrahydrocannabinol andantagonist activity of cannabidiol on rat brain cannabinoid receptors.Life Sci 63: PL1 PL65 Thomas BF, Gilliam AF, Burcj DF, Roche MJ, Seltzman HH (1998) Comparative receptor bind-ing analyses of cannabinoid agonists and antagonists.J Pharmacol Exp Ther 285: 285 2926 Musty RE, Conti LH, Mechoulam R (1985) Anxiolytic properties of cannabidiol.In: D Harvey(ed.): Marihuana 84.IRL Press, Oxford, 713 7197 Rinaldi-Carmona M, Barth F, Heaulme, M, Alonso R, Shire D, Congy C, Soubrie P, Breliere JC,Le Fur G (1995) Biochemical and pharmacological characterisation of SR141716A, the firstpotent and selective brain cannabinoid receptor antagonist.Life Sci 56: 1941 19478 Onaivi ES, Babatunde EA, Chakrabarti A (1998) Cannabinoid (CB1) receptor antaginism inducesanxiolysis.1998 Symposium on the Cannabinoids Burlington,VT: International CannabinoidResearch Society, 589 Rodgers RJ, Haller J, Halasz J, Mikics E (2003) One-trial sensitization to the anxiolytic-likeeffects of cannabinoid receptor antagonist SR141716A in the mouse elevated plus-maze.Eur JNeurosci 17: 1279 128610 Valjent E, Maldonado R (2000) A behavioural model to reveal place preference to delta 9-tetrahy-drocannabinol in mice.Psychopharmacology (Berl) 147: 436 43811 Navarro M, Hernandez E, Munoz RM, del Arco I, Villanua MA, Carrera MR, Rodriguez deFonseca F (1997) Acute administration of the CB1 cannabinoid receptor antagonist SR 141716Ainduces anxiety-like responses in the rat.Neuroreport 20; 8(2): 491 49612 Martin M, Ledent C, Parmentier M, Maldonado R, Valverde O (2002) Psychopharmacology (Berl)159: 379 38713 Rodgers RJ, Haller J, Halasz J, Mikics E (2003) One-trial sensitization to the anxiolytic-like Cannabinoids and anxiety 147effects of cannabinoid receptor antagonist SR141716A in the mouse elevated plus-maze.Eur JNeurosci 17: 1279 128614 Kathuria S, Gaetani S, Fegley D, Valino F, Duranti A, Tontini A, Mor M, Tarzia G, La Rana G,Calignano A et al.(2003) Modulation of anxiety through blockade of anandamide hydrolysis.NatMed 9: 76 8115 Consroe P, Musty RE, Tillery W, Pertwee R (1997) Perceived effects of cannabis smoking inpatients with multiple sclerosis.European Neurology 38: 44 4816 Consroe P, Tillery W, Rein J, Musty RE (1998) Reported marijuana effects in patients with spinalcord injury.1998 Symposium on the Cannabinoids, Burlington, VT: International CannabinoidResearch Society, 6417 Musty RE (1988) Individual differences as predictors of marihuana phenomenology.In: GChesher, P Consroe, RE Musty (eds): Marihuana: An International Research Report [ Pobierz caÅ‚ość w formacie PDF ]
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.It seems that anxiety is associ-ated with reduced parahippocampal activity, consistent with the findings thatCBD increases activity in this brain area.Because activity in the CBD condi-tion decreased relative to the placebo, these data fit well since there are a lotof data linking amygdala activation in a large variety of anxiety states.Similarly, the hypothalamus is involved in various anxiety states: imagingstudies in particular have shown increases in hypothalamic activity in anxietyinduced in normal volunteers and panic patients, again consistent with the anx-iolytic effect of CBD.In regard to the posterior cingulate gyrus, increasedbrain activity is associated with viewing anxiety-provoking videos, which pro-voked obsessions in obsessive patients.Patients with obsessive-compulsivedisorder (OCD), if untreated, have increased metabolism in the brain area,which decreases with treatment and symptom remission, although there aresome conflicting data (see [20] for references relating to all of the above dis-cussion).While these data might be considered preliminary, they provide thefirst evidence of brain systems that are affected in humans.There seems to bequite strong convergence between animal research and human research, sug-gesting strongly that CBD is a true anxiolytic.Given the fact that this drug hasno psychoactivity in terms of intoxication and is very safe, it seems importantto pursue the potential of CBD, with further behavioral pharmacological stud-ies, mechanistic studies employing neuropharmacological methods and inclinical studies. 146 R.E.MustyDiscussionThe data discussed in this review show there is converging evidence that theCB1 receptor system is involved in the control of anxiety.Many studies haveshown that both antagonists and agonists of the CB1 receptor can produce anx-iolytic effects both in animals and humans.Particularly strong evidence is thefact that CB1-knockout mice are more anxious than wild-type mice The factthat anandamide hydrolysis inhibitors are anxiolytic and that they lead to anincrease in anandamide levels in the brain is further support for the role of thissystem in the control of anxiety.Finally, the observations that CBD increasesor decreases regional cerebral blood flow in areas of the brain predicted to beinvolved in various anxiety states provide strong supportive evidence that atleast this cannabinoid is active in brain areas known to be involved in anxiety.At present, four cannabininoids are available for clinical trials: SR-141716(Rimonbant), the GW Pharmaceuticals extract (Sativex®; a 1:1 ratio of"9-THC/CBD), "9-THC (Marinol) and Nabilone (Cesamet).It would seemreasonable to consider testing these compounds in specific anxiety states,which are refractory to traditional anxiolytics and related drugs.References1 McMeens RR (1860) Report of the Ohio State Medical Committee on Cannabis indica.Ohio StateMedical Society, White Sulphur Springs, OH, 592 Musty RE (1984) Possible anxiolytic effects of cannabidiol.In: S Agurell, W Dewey, R Willette(eds): The Cannabinoids.Academic Press, New York, 829 8443 Guimaraes FS, Chiaretti TM, Graeff FG, Zuardi AW (1990) Antianxiety effect of cannabidiol inthe elevated plus-maze.Psychopharmacology 100: 558 5594 Petitet F, Jeantaud B, Reibaud M, Imperato A, Dubroeucq MC (1998) Complex pharmacology ofnatural cannabinoids: evidence for partial agonist activity of delta-9-tetrahydrocannabinol andantagonist activity of cannabidiol on rat brain cannabinoid receptors.Life Sci 63: PL1 PL65 Thomas BF, Gilliam AF, Burcj DF, Roche MJ, Seltzman HH (1998) Comparative receptor bind-ing analyses of cannabinoid agonists and antagonists.J Pharmacol Exp Ther 285: 285 2926 Musty RE, Conti LH, Mechoulam R (1985) Anxiolytic properties of cannabidiol.In: D Harvey(ed.): Marihuana 84.IRL Press, Oxford, 713 7197 Rinaldi-Carmona M, Barth F, Heaulme, M, Alonso R, Shire D, Congy C, Soubrie P, Breliere JC,Le Fur G (1995) Biochemical and pharmacological characterisation of SR141716A, the firstpotent and selective brain cannabinoid receptor antagonist.Life Sci 56: 1941 19478 Onaivi ES, Babatunde EA, Chakrabarti A (1998) Cannabinoid (CB1) receptor antaginism inducesanxiolysis.1998 Symposium on the Cannabinoids Burlington,VT: International CannabinoidResearch Society, 589 Rodgers RJ, Haller J, Halasz J, Mikics E (2003) One-trial sensitization to the anxiolytic-likeeffects of cannabinoid receptor antagonist SR141716A in the mouse elevated plus-maze.Eur JNeurosci 17: 1279 128610 Valjent E, Maldonado R (2000) A behavioural model to reveal place preference to delta 9-tetrahy-drocannabinol in mice.Psychopharmacology (Berl) 147: 436 43811 Navarro M, Hernandez E, Munoz RM, del Arco I, Villanua MA, Carrera MR, Rodriguez deFonseca F (1997) Acute administration of the CB1 cannabinoid receptor antagonist SR 141716Ainduces anxiety-like responses in the rat.Neuroreport 20; 8(2): 491 49612 Martin M, Ledent C, Parmentier M, Maldonado R, Valverde O (2002) Psychopharmacology (Berl)159: 379 38713 Rodgers RJ, Haller J, Halasz J, Mikics E (2003) One-trial sensitization to the anxiolytic-like Cannabinoids and anxiety 147effects of cannabinoid receptor antagonist SR141716A in the mouse elevated plus-maze.Eur JNeurosci 17: 1279 128614 Kathuria S, Gaetani S, Fegley D, Valino F, Duranti A, Tontini A, Mor M, Tarzia G, La Rana G,Calignano A et al.(2003) Modulation of anxiety through blockade of anandamide hydrolysis.NatMed 9: 76 8115 Consroe P, Musty RE, Tillery W, Pertwee R (1997) Perceived effects of cannabis smoking inpatients with multiple sclerosis.European Neurology 38: 44 4816 Consroe P, Tillery W, Rein J, Musty RE (1998) Reported marijuana effects in patients with spinalcord injury.1998 Symposium on the Cannabinoids, Burlington, VT: International CannabinoidResearch Society, 6417 Musty RE (1988) Individual differences as predictors of marihuana phenomenology.In: GChesher, P Consroe, RE Musty (eds): Marihuana: An International Research Report [ Pobierz caÅ‚ość w formacie PDF ]