- Email: [email protected]
Chapter 26. The Cannabinoids: Therapeutic Potentials
253
Chapter 26. The Cannabinoids: Therapeutic Potentials Robert A. Archer, The Lilly Research Laboratories, Indianapolis, Indiana
This review will survey the literature of the past year with particular reference to those articles which indicate the therapeutic potentials for cannabinoids’. For a comprehensive, up-to-date survey of cannabis chemistry, pharmacology and clinical studies, the reader is referred to a new book’ edited by R. Mechoulam. In regard to marijuana or its active component, AS-THC, the following potential medical applications have been listed3 as areas still t o be explored: analgesia, antihypertensive activity, treatment of migraine, management of dying patients and sexual stimulation. Considering the large number of publications in the marijuana area, few of them examine structure-activity relationships. To date, very little has appeared to show whether the A’-THC molecule can be chemically modified to achieve an enhancement of one particular activity present in A’THC itself. Thus, any therapeutic possibility for the cannabinoids rests mainly on pharmacological and clinical evidence gathered on A’-THC or marijuana itself. New activities were discovered last year. It is still too early to decide which of the following areas represents the best possibility for a useful drug in the cannabinoid area. Anti-Edema, Analgesic, Antipyretic and Anti-Inflammatory Effects - A’-THC inhibits the in v i t r o biosynthesis of staglandin E2 (PGE’) from arachidonic acidfroand the biosynthesis of PGEl from 8,11,14-eicosaH trienic acid’. The inhibition of PGE‘ biosynthesis has been postulated as a mechanism of CH3 . / MH action for such non-steroidal anti-inflammatory agents as aspirin and indomethacin6. Some in CH3 V ~ V Odata’,’ appear to correlate. In the carrageenan-induced rat paw edema, a dose of 10 mg/ A -THC kg AS-THC caused a 40% inhibition of paw swelling. Daily administration of 20 mg/kg A’-THC inhibited the developing adjuvant-induced polyarthritis in rats. In several tests of analgesic activity (acetic acid-induced abdominal constriction, Haffner’s tail pinch, hot plate test and Randall-Selitto test) A’THC showed effectiveness with ED50 of 0.9 to 11.6 mg/kg. At doses up to 20 mg/kg Ag-THC did not affect yeast-induced pyrexis in rats.
fj3 ’
254
Topics in Biology
Wechter, Ed.
In another study’ of the effects of A’-THC on yeast-induced pyrexis, carrageenan-induced edema and yeast-induced rat paw hyperesthesia, the following results were obtained: (1) The oral antipyretic totency of A’THC is approximately 2 times that of phenylbutazone, (2) A -THC was essentially devoid of antinociceptive activity except at elevated doses which produced a marked catatonic-like state, and (3) A’-THC at doses up to and including 100 mg/kg was totally ineffective in reducing or preventing the edematous response. Anti-Fertility Activity - At a dose of 2 mg in rats, A’-THC suppressed the cyclic surge of luteinizing hormone secretion and also su pressed ovulation (a characteristic shared by other CNS-active drugs)”. However , mating and fertility indices were similar for control and all treatment groups in a study of the effect of Ag-THC on reproduction in rats”. At doses of 2 and 3 mg/kg, A9-THC caused a deterioration in the sexual performance of male rats (interpreted as reflecting a decreased motivation to copdate) 2. Anti-Epileptic, Anticonvulsant Action - The anticonvulsant properties of marijuana and Ay-THC have been recognized for several years. Now cannabidiol and cannabinol have also been found to be effective anticonvulsants using a maximal electroshock test in mice13. (EDSO’S: A’-THC, 80 mg/kg: CBD, 105 mg/kg and CBN, 230 mg/kg).
CH3 Cannabidiol (CBD)
Cannabinol (CBN)
Treatment of freely moving cats with A’-THC (0.25-0.5 mg/kg) temporarily reduced seizure activity induced by electrical stimulation of subcortical structures14 One study concluded that THC closely resembles acetazolamide rather than diphenylhydantoin’6 .
.
Antihypertensive , Cardiotonic Effects - A previous review” suggested that “the tetrahydrocannabinols warrant evaluation in the treatment of essential hypertension”. A’-THC has since been found to significantly lower the blood pressure of rats and block the appearance of hypertension in immobilized rats”. At 20 mg/kg s.c., the hy-potensive effect persisted over a 96 hr. period and completely counteracted the pressor effects of repeated immobilization stress. In female rats showing adrenal regeneration hypertension, a dose of 3 mg/kg of As-THC was capable of lowering blood pressure” (this moderate dose for a rat does not produce somatic side effects). One study2’ draws attention to the fact that doses of marijuana
Chap. 26
The Cannabinoids: Therapeutic Potentials
255
Archer
which produce marked psychological alterations in man, do not alter blood pressure in a systematic fashion. The same paper notes that tolerance to the hypotensive effects of A’-THC (5-25 mg/kg/day) develops rapidly in the spontaneously hypertensive rat. The mechanism of these blood pressure and other cardiovascular effects has been the subject for much study. Reduction in blood pressure in anesthesized dogs caused by administration of 2.5 mg/kg i .v. of A’-THC is accompanied by a decrease in cardiac output and an increase in local vascular resistance”. The fractional blood flow to the vital coronary, cerebral and renal beds was unchanged“. The reduction in cardiac output appears to result from the action of A9-THC on the heart rate (bradycardia) as well as venous r e t ~ r n ~ ~ , ~A’maximal . degree of bradycardia is produced only when both sympathetic and parasympathetic innervation of the heart is intactz4. A’-THC appears to be devoid of any ganglionic or 6adrenergic blocking properties“. Interestingly, A9-THC produces a doserelated tachycardia in manz5. While both A’-THC and propanolol delay the onset of ventricular ectopic extrasystoles A’-THC does not delay the onset of ouabain-induced arrhythmias’6 .
-
-
Pulmonary Effects Asthma Three groups Yublished last year on the pulmonary effects of marijuana. In one study ‘ Y “ of nine, normal volunteers with previous marijuana smoking experience, airway resistance (measured in a body plethysmograph) fell 38% and specific airway conductance increased 44% at a dose of 84 pg/kg. This effect was accompanied by a 28% increase in heart rate. At a dose of 32 pg/kg, there was no increase in heart rate but there were significant changes in airway dynamics. In another paper‘ thirty-two experienced male marijuana smokers were given A9-THC by smoking or orally (20 mg dose). Again specific airway conductance increased immediately (48% at 1 5 min. after smoking marijuana assayed at 2% A’-THC; 45% at 180 min. after ingestion of 20 mg A’TKC). A study” suggested that these effects operated via a mechanism other than deep breathing or 6-adrenergic stimulation, the dilation being due to, most probably, relaxation of the smooth muscle of the tracheobronchial tree. No data were available on isolated bronchial smooth muscle. These data strongly suggest a therapeutic potential for AS-THC in the treatment of pulmonary congestion; e.g. asthma3’. Nevertheless , one paper32 has pointed out that these pulmonary effects are not reflections of changes in the clinically important peripheral airways (<2 mm diameter). Potentiation of Barbiturates and Anesthetics: - Pretreatment of mice for six successive days at 20 mg/kg of Ay-THC, caused a decrease in the duration of sleeping time after dosing with zoxazolamine and hexobarbital’ . However, under the same experimental conditions, the duration of barbital sleeping time was enhanced. The authors suggest an induction by AS-THC of the hepatic enzyme systems involved in the metabolism of zoxazolamine and hexobarbital, but no metabolism studies are offered in support of this
’
256
Topics in Biology
Wechter, Ed.
possibility. Another paper3‘ from the same laboratory reports that pretreatment of mice with doses of A’-THC (0.625 to 40 mg/kg) caused a significant reduction in the onset to and duration of sleeping time of most of the sedative-hypnotic drugs tested. These studies cast some degree of doubt on the therapeutic potential of A’-THC to potentiate barbiturate sleeping time, unless it is done on an acute dosing basis rather than after chronic treatment. report on the interaction of A’-THC with anestheTwo studies3” tics. The minimum alveolar anesthetic (MAC) requirements for cyclopropane in rats3= and halothane in dogs36 were significantly decreased by pretreatment with A’-THC. Analgesia, sedation and prolonged barbiturate sleeping time after acute A’-THC injection may reflect the potential additive anesthetic-like action of the drug. Alternatively, drugs that deplete norepinephrine in the CNS decrease halothane MAC36. A’-THC and Sleep - A’-THC continues to be studied as a sedative-hypnotic. One study” of the sleep-wakefulness cycle in rabbits was stimulated by the effects of A’-THC on 5HT metabolism in the brain, an effect hypothesized to play an important role in the production of slow wave sleep. No evidence was found that A’-THC in doses of 0.5 and 1.0 mg/kg increased total REM sleep time or prolonged the duration of‘ single episodes3’. In another study3’ in cats, slow wave sleep was significantly decreased.
A clinical study3’ of A’-THC as a hypnotic found that: (1)A’-THC significantly decreases the time it takes to fall asleep in physically healthy insomniacs. ( 2 ) The most significant effect of an oral dose of 30 mg was a “hangover” phenomena or continued ”high” the next day. (3) This “hangover” seemed severe enough to eliminate the 30 mg dose range for clinical use as a hypnotic. A comparison study of A’-THC at doses around 20 mg with a standard hypnotic is in progress. AO-THC when administered to cats at doses of 1-10 mg/kg, i.p. or i.v. , induced sedation and caused a trend toward fewer and lon er REM sleep episodes following initial suppression of paradoxical sleep“. In rats tolerance developed to both the suppression of paradoxical sleep and to behavioral effects (principally excitation)‘l. CH3
CH 3 AO-THC
-
Other CNS Effects: Biogenic Amines With several standard procedures commonly used to detect antidepressant activity, A’-THC was virtually inactive by i.p. administration at doses up to 20 mg/kg42. Clinically, A’-THC (0.3
Chap. 26
The Cannabinoids: Therapeutic Potentials
Archer
257
mg/kg, p.0. twice a day for 7 days) in 8 hospitalized depressed patients failed to produce significant euphoria or antidepressant response43 . The mechanism of the central effects of cannabinoids continues to be investigated. A'-THC, hA-THC and DMHP all increased the amounts of noradrenaline and dopamine accumulated from tyrosine in rat whole brain44. The hypothalmus region was most susceptible to these changes in catecholm i n e biosynthesis. In spite of the observed increase in catecholamine biosynthesis in the brain and adrenals, the endogenous content of NA and DA in the brain and DA and NA in the adrenals remained unchanged45.
DMHP Repeated administration of A'-THC to rats leads to an increase in activity of tyrosine hydroxylase4 ; tryptophane hydroxylase and DOPA decarboxylase were not significantly affected. Because of the possible implication of PEA as one of the adrenergic ergotropic modulators, alterations in its disposition may be responsible for the eu horic effects of A'-THC in man4'. Acute administration of 3 mg/kg of A -THC increased 4-fold the brain levels of PEA and daily administration of 0.3 mg/kg for 8 days doubles PEA brain levels. In contrast A'-THC induces only relatively small changes in the brain levels of serotonin, catecholamines and acetylcholine.
8
Confirming earlier work on ingested marijuana, smoked cannabis has been found to produce little changes in the urinary excretion of epinephrine and NE but decreases VMA excretion by 25% from baseline value at 2 hrs. in humans4'.
-
Summary Even a cursory look at the literature on cannabis would lead one to the conclusion that marijuana is "a drug for all reasons". Perhaps the many biological activities of marijuana impeded its therapeutic use during the past 40 years. A s recently as 1971 the natural material or THC appeared to offer little advantage over currently used medications used as sedatives, analgesics, antidepressants and antihypertensive drugs4'. With the identification in 1964 of A'-THC as the "active" ingredient in marijuana, a new chapter in marijuana research was opened. The possibility of structural modification to enhance activity was again explored. Undoubtedly during the past decade many investigators (especially those in the pharmaceutical industry) have pursued the possibility of modification of the A'-THC structure to delineate activities.
Topics in Biology
258
Wechter, Ed.
An indication of the efforts along these lines has been reported5' by Abbott Laboratories. Compound, ABBOTT 40656 , ~ ~ 1 ,0a6water-soluble benzopyran derivative is presently under Phase I clinical evaluation as a sedative-hypnotic. Time will tell whether the pursuit of structure-activity relationships will lead to therapeutically useful drugs in any or all of the disease areas 'HC1 mentioned in this review. Also new activities might be discovered.
ABBOTT 40656 ( ~ ~ 1 0 6 ) References 1. The term "cannabinoids" has been defined as the group of C21 compounds typical of and present in Cannabis s a t i v a , their carboxylic acids, analogs, and transformation products. 2. R. Mechoulam (Ed.) , "Marijuana" , Academic Press , Inc , New York and London, 1973. 128 (1972). 3. L. Hollister, Psychopharmacologia, 4 . S. Burstein and A. Raz, Prostaglandins, 2, 369 (1972). 5. S. Burstein, E. Levin and C. Varanelli, Biochem. Pharmacol., 22, 2905
.
26,
6. 7.
(1973).
a,
J . R. Vane, Nature New Biol. , 232 (1971). R. D. Sofia, L. C. Kuobloch and H. B. Vassar, Res. Comun. Chem.
Pathol. Pharmacol., 6, 909 (1973). R. D. Sofia, S. D. Nalepa, J. J. Harakal and H. B. Vassar, J. Pharmacol. Exp. Therapeutics, 646 (1973). 9. D. S. Kosersky, W. L. Dewey and L. S. Harris, Eur. J. Pharmacol., 24, 1 (1973). . ~. 10. I. Nir, D. Agalon, A. Tsafriri, T. Cordova and H. R. Linder, Nature,
8.
186,
244 , 470 (1973).
11. T L . Keplinger, P.
L. Wright, S. L. Haley, J. B. Plank, M. C. Brande, and J. C. Calandra, Toxicol. Appl. Pharmacol. , 25, 449 (1973). 1 2 . A. Merari, A. Barak and M. Plaves, Psychopharmacologia, 28, 243 (1973). 13. R. Karler, W. Cely and S. A. Turkanis, Life Sci., 13,1527 (1973). 1 4 . J. A. Wada, M. Sato and M. E. Corcoran, Experimental Neurology, 2,
157 (1973). 15. J. A. Wada, M. Corcoran, M. Sat0 and J. McCaughran, Epilepsia, 14,101 (1973). 16. R. Karter,'Fed. Proc., 32, 756 (1973). 17. H. F. Hardman, E. F. Domino and M. H. Seevers, Pharmacol. Rev., 23, 295 (1971). 18. R. B. Williams, L. K. Y. Ng, F. Lamprecht, K. Roth and I. J. Kopin, Psychopharmacologia, 28, 269 (1973). 19. M. K. Birmingham, Br. J. Pharmacol., 48, 169 (1973). 20. G . G . Nahas, I. W. Schwartz, J. Adamee and W. M. Manger, Proc. SOC. Exp. Biol. Med., 142, 58 (1973).
Chap. 26
The Cannabinoids: Therapeutic Potentials
21.
Archer
259
I. Cavero, R. Ertel, J. P. Buckley and B. S. Jandhyala, Eur. J. Pharmacol. , 20, 373 (1972). 22. I. Cavero, J. P. Buckley and B. S. Jandhyala, Eur. J. Pharmacol., 24, 243 (1973). 23. I. Cavero and B. S. Jandhyala, Fed. Proc., 32, 755 (1973). 24. I. Cavero, T. Solomon, J. P. Buckley, B. S. Jandhyala, Eur. J. Pharmacol. , 22, 263 (1973). 25 B. R. Manno and J. E. Manno, Toxicol. Appl. Pharmacol. , ;15, 451 (1973). 26. J . F. Schaffer Jr., R. Loetzer and R. D. Sofia, Arch. Int. Pharmacodyn. 205, 5 (1973). 27. L. Vachon, M. X. FitzGerald, N. H. Solliday, I. A. Gould and E. A. Gaensler, N. Engl. J. Med., 288, 985 (1973). 28. L. Vachon, M. X. FitzGerald, I. A. Gould, E. A. Gaensler and N. H. Solliday, Am. Rev. Respir. Dis., 3, 1099 (1973). 29. D. P. Tashkin, B. J. Shapiro and I. M. Frank, N. Engl. J. Med., 2&, 336 (1973). 30. B. J. Shapiro, D. P. Tashkin and I. M. Frank, Ann. Intern. Med., 78, 832 (1973). 31. P. Beaconsfield, J. Ginsburg and R. Rainsbury, N. Engl. J. Med. 389, 1315 (1973). 32. T. P. Bright, M. A . Evans, R. Martz, D. J. BroTj, and R. B. Forney, Pharmacologist , 15,238 (1973 ) 33. R. D. Sofia, Res. Commun. Chem. Pathol. Pharmacol., 5, 91 (1973). 34. R. D. Sofia and L. C. Kuobloch, Psychopharmacologia, 2,185 (1973). 35. T. S. Vitez, W. L. Way, R. D. Miller and E. I. Eger, Anesthesiology, 38, 525 (1973). 36. R. K. Stoelting, R. C. Martz, J. Gartner, C. Creasser, D. J. Brown and R. B. Forney, Anesthesiology, 3 8 , 521 (1973). 37. M. Fujiwasi and H. E. Himurch, Physiol. Behav., 11,291 (1973). 38. E. S . Barrati and P. M. Adam, Pharmacol. Psychiatry, 6, 207 (1973). 39. K. Consens and A. DiMascio, Psychopharmacologia, 33, 375 (1973). 40. M. B. Wallach and S. Gershan, Eur. J. Pharmacol.,?4, 172 (1973). 41. J. E. Moreton and W. M. Davis, Neuropharmacology, l2, 897 (1973). 42. R. D. Sofia, R. K. Kubena and H. Barry, Psychopharmacologia, 2,1 2 1 (1973). 43. J. Kotin, R. M. Post and F. K. Goodwin, Arch., Gen. Psychiatr., 28, 345 (1973). 44. L. Maitre, P. C. Waldmeier and P. A. Baumann, Life Sci., l3, R 1 1 2 (1973). 45. I. M. Mazurkiewica-Kwilecki and M. Filczewski, Psychopharmacologia, -333 7 1 (1973). 46. B. T. Ho, D. Taylor and L. F. Englert, Res. Commun. Chem. Pathol. Pharmacol. , 5, 851 (1973). 47. H. C . Sabelli, W. A. Pedemonte, C. Whalley, A. D. Mosnaim and A. J. 149 (1974). Vazquez, Life Sci., 48. F. S. Messiha and R. A. Soskin, Res. Commun. Chem. Pathol. Pharmacol 6 , 325 (1973). 49. L. E. Hollister, Science, 172, 2 1 (1971). 50 * W. G. Jochimsen and A. T. Dren, E d . Proc. , 33, 527 (1974). 9
.
14,
-
Chapter 26. The Cannabinoids: Therapeutic Potentials Robert A. Archer, The Lilly Research Laboratories, Indianapolis, Indiana
This review will survey the literature of the past year with particular reference to those articles which indicate the therapeutic potentials for cannabinoids’. For a comprehensive, up-to-date survey of cannabis chemistry, pharmacology and clinical studies, the reader is referred to a new book’ edited by R. Mechoulam. In regard to marijuana or its active component, AS-THC, the following potential medical applications have been listed3 as areas still t o be explored: analgesia, antihypertensive activity, treatment of migraine, management of dying patients and sexual stimulation. Considering the large number of publications in the marijuana area, few of them examine structure-activity relationships. To date, very little has appeared to show whether the A’-THC molecule can be chemically modified to achieve an enhancement of one particular activity present in A’THC itself. Thus, any therapeutic possibility for the cannabinoids rests mainly on pharmacological and clinical evidence gathered on A’-THC or marijuana itself. New activities were discovered last year. It is still too early to decide which of the following areas represents the best possibility for a useful drug in the cannabinoid area. Anti-Edema, Analgesic, Antipyretic and Anti-Inflammatory Effects - A’-THC inhibits the in v i t r o biosynthesis of staglandin E2 (PGE’) from arachidonic acidfroand the biosynthesis of PGEl from 8,11,14-eicosaH trienic acid’. The inhibition of PGE‘ biosynthesis has been postulated as a mechanism of CH3 . / MH action for such non-steroidal anti-inflammatory agents as aspirin and indomethacin6. Some in CH3 V ~ V Odata’,’ appear to correlate. In the carrageenan-induced rat paw edema, a dose of 10 mg/ A -THC kg AS-THC caused a 40% inhibition of paw swelling. Daily administration of 20 mg/kg A’-THC inhibited the developing adjuvant-induced polyarthritis in rats. In several tests of analgesic activity (acetic acid-induced abdominal constriction, Haffner’s tail pinch, hot plate test and Randall-Selitto test) A’THC showed effectiveness with ED50 of 0.9 to 11.6 mg/kg. At doses up to 20 mg/kg Ag-THC did not affect yeast-induced pyrexis in rats.
fj3 ’
254
Topics in Biology
Wechter, Ed.
In another study’ of the effects of A’-THC on yeast-induced pyrexis, carrageenan-induced edema and yeast-induced rat paw hyperesthesia, the following results were obtained: (1) The oral antipyretic totency of A’THC is approximately 2 times that of phenylbutazone, (2) A -THC was essentially devoid of antinociceptive activity except at elevated doses which produced a marked catatonic-like state, and (3) A’-THC at doses up to and including 100 mg/kg was totally ineffective in reducing or preventing the edematous response. Anti-Fertility Activity - At a dose of 2 mg in rats, A’-THC suppressed the cyclic surge of luteinizing hormone secretion and also su pressed ovulation (a characteristic shared by other CNS-active drugs)”. However , mating and fertility indices were similar for control and all treatment groups in a study of the effect of Ag-THC on reproduction in rats”. At doses of 2 and 3 mg/kg, A9-THC caused a deterioration in the sexual performance of male rats (interpreted as reflecting a decreased motivation to copdate) 2. Anti-Epileptic, Anticonvulsant Action - The anticonvulsant properties of marijuana and Ay-THC have been recognized for several years. Now cannabidiol and cannabinol have also been found to be effective anticonvulsants using a maximal electroshock test in mice13. (EDSO’S: A’-THC, 80 mg/kg: CBD, 105 mg/kg and CBN, 230 mg/kg).
CH3 Cannabidiol (CBD)
Cannabinol (CBN)
Treatment of freely moving cats with A’-THC (0.25-0.5 mg/kg) temporarily reduced seizure activity induced by electrical stimulation of subcortical structures14 One study concluded that THC closely resembles acetazolamide rather than diphenylhydantoin’6 .
.
Antihypertensive , Cardiotonic Effects - A previous review” suggested that “the tetrahydrocannabinols warrant evaluation in the treatment of essential hypertension”. A’-THC has since been found to significantly lower the blood pressure of rats and block the appearance of hypertension in immobilized rats”. At 20 mg/kg s.c., the hy-potensive effect persisted over a 96 hr. period and completely counteracted the pressor effects of repeated immobilization stress. In female rats showing adrenal regeneration hypertension, a dose of 3 mg/kg of As-THC was capable of lowering blood pressure” (this moderate dose for a rat does not produce somatic side effects). One study2’ draws attention to the fact that doses of marijuana
Chap. 26
The Cannabinoids: Therapeutic Potentials
255
Archer
which produce marked psychological alterations in man, do not alter blood pressure in a systematic fashion. The same paper notes that tolerance to the hypotensive effects of A’-THC (5-25 mg/kg/day) develops rapidly in the spontaneously hypertensive rat. The mechanism of these blood pressure and other cardiovascular effects has been the subject for much study. Reduction in blood pressure in anesthesized dogs caused by administration of 2.5 mg/kg i .v. of A’-THC is accompanied by a decrease in cardiac output and an increase in local vascular resistance”. The fractional blood flow to the vital coronary, cerebral and renal beds was unchanged“. The reduction in cardiac output appears to result from the action of A9-THC on the heart rate (bradycardia) as well as venous r e t ~ r n ~ ~ , ~A’maximal . degree of bradycardia is produced only when both sympathetic and parasympathetic innervation of the heart is intactz4. A’-THC appears to be devoid of any ganglionic or 6adrenergic blocking properties“. Interestingly, A9-THC produces a doserelated tachycardia in manz5. While both A’-THC and propanolol delay the onset of ventricular ectopic extrasystoles A’-THC does not delay the onset of ouabain-induced arrhythmias’6 .
-
-
Pulmonary Effects Asthma Three groups Yublished last year on the pulmonary effects of marijuana. In one study ‘ Y “ of nine, normal volunteers with previous marijuana smoking experience, airway resistance (measured in a body plethysmograph) fell 38% and specific airway conductance increased 44% at a dose of 84 pg/kg. This effect was accompanied by a 28% increase in heart rate. At a dose of 32 pg/kg, there was no increase in heart rate but there were significant changes in airway dynamics. In another paper‘ thirty-two experienced male marijuana smokers were given A9-THC by smoking or orally (20 mg dose). Again specific airway conductance increased immediately (48% at 1 5 min. after smoking marijuana assayed at 2% A’-THC; 45% at 180 min. after ingestion of 20 mg A’TKC). A study” suggested that these effects operated via a mechanism other than deep breathing or 6-adrenergic stimulation, the dilation being due to, most probably, relaxation of the smooth muscle of the tracheobronchial tree. No data were available on isolated bronchial smooth muscle. These data strongly suggest a therapeutic potential for AS-THC in the treatment of pulmonary congestion; e.g. asthma3’. Nevertheless , one paper32 has pointed out that these pulmonary effects are not reflections of changes in the clinically important peripheral airways (<2 mm diameter). Potentiation of Barbiturates and Anesthetics: - Pretreatment of mice for six successive days at 20 mg/kg of Ay-THC, caused a decrease in the duration of sleeping time after dosing with zoxazolamine and hexobarbital’ . However, under the same experimental conditions, the duration of barbital sleeping time was enhanced. The authors suggest an induction by AS-THC of the hepatic enzyme systems involved in the metabolism of zoxazolamine and hexobarbital, but no metabolism studies are offered in support of this
’
256
Topics in Biology
Wechter, Ed.
possibility. Another paper3‘ from the same laboratory reports that pretreatment of mice with doses of A’-THC (0.625 to 40 mg/kg) caused a significant reduction in the onset to and duration of sleeping time of most of the sedative-hypnotic drugs tested. These studies cast some degree of doubt on the therapeutic potential of A’-THC to potentiate barbiturate sleeping time, unless it is done on an acute dosing basis rather than after chronic treatment. report on the interaction of A’-THC with anestheTwo studies3” tics. The minimum alveolar anesthetic (MAC) requirements for cyclopropane in rats3= and halothane in dogs36 were significantly decreased by pretreatment with A’-THC. Analgesia, sedation and prolonged barbiturate sleeping time after acute A’-THC injection may reflect the potential additive anesthetic-like action of the drug. Alternatively, drugs that deplete norepinephrine in the CNS decrease halothane MAC36. A’-THC and Sleep - A’-THC continues to be studied as a sedative-hypnotic. One study” of the sleep-wakefulness cycle in rabbits was stimulated by the effects of A’-THC on 5HT metabolism in the brain, an effect hypothesized to play an important role in the production of slow wave sleep. No evidence was found that A’-THC in doses of 0.5 and 1.0 mg/kg increased total REM sleep time or prolonged the duration of‘ single episodes3’. In another study3’ in cats, slow wave sleep was significantly decreased.
A clinical study3’ of A’-THC as a hypnotic found that: (1)A’-THC significantly decreases the time it takes to fall asleep in physically healthy insomniacs. ( 2 ) The most significant effect of an oral dose of 30 mg was a “hangover” phenomena or continued ”high” the next day. (3) This “hangover” seemed severe enough to eliminate the 30 mg dose range for clinical use as a hypnotic. A comparison study of A’-THC at doses around 20 mg with a standard hypnotic is in progress. AO-THC when administered to cats at doses of 1-10 mg/kg, i.p. or i.v. , induced sedation and caused a trend toward fewer and lon er REM sleep episodes following initial suppression of paradoxical sleep“. In rats tolerance developed to both the suppression of paradoxical sleep and to behavioral effects (principally excitation)‘l. CH3
CH 3 AO-THC
-
Other CNS Effects: Biogenic Amines With several standard procedures commonly used to detect antidepressant activity, A’-THC was virtually inactive by i.p. administration at doses up to 20 mg/kg42. Clinically, A’-THC (0.3
Chap. 26
The Cannabinoids: Therapeutic Potentials
Archer
257
mg/kg, p.0. twice a day for 7 days) in 8 hospitalized depressed patients failed to produce significant euphoria or antidepressant response43 . The mechanism of the central effects of cannabinoids continues to be investigated. A'-THC, hA-THC and DMHP all increased the amounts of noradrenaline and dopamine accumulated from tyrosine in rat whole brain44. The hypothalmus region was most susceptible to these changes in catecholm i n e biosynthesis. In spite of the observed increase in catecholamine biosynthesis in the brain and adrenals, the endogenous content of NA and DA in the brain and DA and NA in the adrenals remained unchanged45.
DMHP Repeated administration of A'-THC to rats leads to an increase in activity of tyrosine hydroxylase4 ; tryptophane hydroxylase and DOPA decarboxylase were not significantly affected. Because of the possible implication of PEA as one of the adrenergic ergotropic modulators, alterations in its disposition may be responsible for the eu horic effects of A'-THC in man4'. Acute administration of 3 mg/kg of A -THC increased 4-fold the brain levels of PEA and daily administration of 0.3 mg/kg for 8 days doubles PEA brain levels. In contrast A'-THC induces only relatively small changes in the brain levels of serotonin, catecholamines and acetylcholine.
8
Confirming earlier work on ingested marijuana, smoked cannabis has been found to produce little changes in the urinary excretion of epinephrine and NE but decreases VMA excretion by 25% from baseline value at 2 hrs. in humans4'.
-
Summary Even a cursory look at the literature on cannabis would lead one to the conclusion that marijuana is "a drug for all reasons". Perhaps the many biological activities of marijuana impeded its therapeutic use during the past 40 years. A s recently as 1971 the natural material or THC appeared to offer little advantage over currently used medications used as sedatives, analgesics, antidepressants and antihypertensive drugs4'. With the identification in 1964 of A'-THC as the "active" ingredient in marijuana, a new chapter in marijuana research was opened. The possibility of structural modification to enhance activity was again explored. Undoubtedly during the past decade many investigators (especially those in the pharmaceutical industry) have pursued the possibility of modification of the A'-THC structure to delineate activities.
Topics in Biology
258
Wechter, Ed.
An indication of the efforts along these lines has been reported5' by Abbott Laboratories. Compound, ABBOTT 40656 , ~ ~ 1 ,0a6water-soluble benzopyran derivative is presently under Phase I clinical evaluation as a sedative-hypnotic. Time will tell whether the pursuit of structure-activity relationships will lead to therapeutically useful drugs in any or all of the disease areas 'HC1 mentioned in this review. Also new activities might be discovered.
ABBOTT 40656 ( ~ ~ 1 0 6 ) References 1. The term "cannabinoids" has been defined as the group of C21 compounds typical of and present in Cannabis s a t i v a , their carboxylic acids, analogs, and transformation products. 2. R. Mechoulam (Ed.) , "Marijuana" , Academic Press , Inc , New York and London, 1973. 128 (1972). 3. L. Hollister, Psychopharmacologia, 4 . S. Burstein and A. Raz, Prostaglandins, 2, 369 (1972). 5. S. Burstein, E. Levin and C. Varanelli, Biochem. Pharmacol., 22, 2905
.
26,
6. 7.
(1973).
a,
J . R. Vane, Nature New Biol. , 232 (1971). R. D. Sofia, L. C. Kuobloch and H. B. Vassar, Res. Comun. Chem.
Pathol. Pharmacol., 6, 909 (1973). R. D. Sofia, S. D. Nalepa, J. J. Harakal and H. B. Vassar, J. Pharmacol. Exp. Therapeutics, 646 (1973). 9. D. S. Kosersky, W. L. Dewey and L. S. Harris, Eur. J. Pharmacol., 24, 1 (1973). . ~. 10. I. Nir, D. Agalon, A. Tsafriri, T. Cordova and H. R. Linder, Nature,
8.
186,
244 , 470 (1973).
11. T L . Keplinger, P.
L. Wright, S. L. Haley, J. B. Plank, M. C. Brande, and J. C. Calandra, Toxicol. Appl. Pharmacol. , 25, 449 (1973). 1 2 . A. Merari, A. Barak and M. Plaves, Psychopharmacologia, 28, 243 (1973). 13. R. Karler, W. Cely and S. A. Turkanis, Life Sci., 13,1527 (1973). 1 4 . J. A. Wada, M. Sato and M. E. Corcoran, Experimental Neurology, 2,
157 (1973). 15. J. A. Wada, M. Corcoran, M. Sat0 and J. McCaughran, Epilepsia, 14,101 (1973). 16. R. Karter,'Fed. Proc., 32, 756 (1973). 17. H. F. Hardman, E. F. Domino and M. H. Seevers, Pharmacol. Rev., 23, 295 (1971). 18. R. B. Williams, L. K. Y. Ng, F. Lamprecht, K. Roth and I. J. Kopin, Psychopharmacologia, 28, 269 (1973). 19. M. K. Birmingham, Br. J. Pharmacol., 48, 169 (1973). 20. G . G . Nahas, I. W. Schwartz, J. Adamee and W. M. Manger, Proc. SOC. Exp. Biol. Med., 142, 58 (1973).
Chap. 26
The Cannabinoids: Therapeutic Potentials
21.
Archer
259
I. Cavero, R. Ertel, J. P. Buckley and B. S. Jandhyala, Eur. J. Pharmacol. , 20, 373 (1972). 22. I. Cavero, J. P. Buckley and B. S. Jandhyala, Eur. J. Pharmacol., 24, 243 (1973). 23. I. Cavero and B. S. Jandhyala, Fed. Proc., 32, 755 (1973). 24. I. Cavero, T. Solomon, J. P. Buckley, B. S. Jandhyala, Eur. J. Pharmacol. , 22, 263 (1973). 25 B. R. Manno and J. E. Manno, Toxicol. Appl. Pharmacol. , ;15, 451 (1973). 26. J . F. Schaffer Jr., R. Loetzer and R. D. Sofia, Arch. Int. Pharmacodyn. 205, 5 (1973). 27. L. Vachon, M. X. FitzGerald, N. H. Solliday, I. A. Gould and E. A. Gaensler, N. Engl. J. Med., 288, 985 (1973). 28. L. Vachon, M. X. FitzGerald, I. A. Gould, E. A. Gaensler and N. H. Solliday, Am. Rev. Respir. Dis., 3, 1099 (1973). 29. D. P. Tashkin, B. J. Shapiro and I. M. Frank, N. Engl. J. Med., 2&, 336 (1973). 30. B. J. Shapiro, D. P. Tashkin and I. M. Frank, Ann. Intern. Med., 78, 832 (1973). 31. P. Beaconsfield, J. Ginsburg and R. Rainsbury, N. Engl. J. Med. 389, 1315 (1973). 32. T. P. Bright, M. A . Evans, R. Martz, D. J. BroTj, and R. B. Forney, Pharmacologist , 15,238 (1973 ) 33. R. D. Sofia, Res. Commun. Chem. Pathol. Pharmacol., 5, 91 (1973). 34. R. D. Sofia and L. C. Kuobloch, Psychopharmacologia, 2,185 (1973). 35. T. S. Vitez, W. L. Way, R. D. Miller and E. I. Eger, Anesthesiology, 38, 525 (1973). 36. R. K. Stoelting, R. C. Martz, J. Gartner, C. Creasser, D. J. Brown and R. B. Forney, Anesthesiology, 3 8 , 521 (1973). 37. M. Fujiwasi and H. E. Himurch, Physiol. Behav., 11,291 (1973). 38. E. S . Barrati and P. M. Adam, Pharmacol. Psychiatry, 6, 207 (1973). 39. K. Consens and A. DiMascio, Psychopharmacologia, 33, 375 (1973). 40. M. B. Wallach and S. Gershan, Eur. J. Pharmacol.,?4, 172 (1973). 41. J. E. Moreton and W. M. Davis, Neuropharmacology, l2, 897 (1973). 42. R. D. Sofia, R. K. Kubena and H. Barry, Psychopharmacologia, 2,1 2 1 (1973). 43. J. Kotin, R. M. Post and F. K. Goodwin, Arch., Gen. Psychiatr., 28, 345 (1973). 44. L. Maitre, P. C. Waldmeier and P. A. Baumann, Life Sci., l3, R 1 1 2 (1973). 45. I. M. Mazurkiewica-Kwilecki and M. Filczewski, Psychopharmacologia, -333 7 1 (1973). 46. B. T. Ho, D. Taylor and L. F. Englert, Res. Commun. Chem. Pathol. Pharmacol. , 5, 851 (1973). 47. H. C . Sabelli, W. A. Pedemonte, C. Whalley, A. D. Mosnaim and A. J. 149 (1974). Vazquez, Life Sci., 48. F. S. Messiha and R. A. Soskin, Res. Commun. Chem. Pathol. Pharmacol 6 , 325 (1973). 49. L. E. Hollister, Science, 172, 2 1 (1971). 50 * W. G. Jochimsen and A. T. Dren, E d . Proc. , 33, 527 (1974). 9
.
14,
-