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O f int erest is th e potential use of marihuana, 6 9_THC and/or synthetic cannabinoids in the treatment of glau coma. Hepler & Frank (1 971) observed that

marihuana and 6 9-T HC decreased intr aocular pressur e in healthy, normal

voluntee rs in a do se-related manner. They reported decreases in intraocula r pressure

in some instances approximating 35% of the control va lues. These fmdings

hav e been confirrned by others (Perez-R eyes, Wagner, Wall & Davis, 1976; Cooler &

Gregg, 1976; Purnell & Gregg, 1975). This efTect of 6 9-T HC and mar ihuana persists

for about 4-5 hand doe s not a ppea r to result in tolerance as exe mplified by report of

th e continual reduction of intraocular pressure during a 90 day period of chronic

marihuan a administration. In addition to studies in normal volunteers, Hepler &

Petrus (1976) and others (Cu endet, Shapiro, Calanca , Faggioni & Oucrey, 1976) ha ve

demonstrated that the ingestion of 6 9-T HC and the smoking ofmarihu ana produces

a n approximate 30% redu ction in intraocular pr essure in glaucoma pat ients.

The cannabinoids have also been investigated as possibl e antidepressa nts in

pat ients afflicted with un ipol ar depression (Kotin, Post & Goodwin , 1973) and in

patients sufTe ring from terminal illness (Regelson , Butler, Schulz, Kirk, Peek , Green

& Zakis, 197 6). There appear s to be no benefit in th e former group, but 6 9_THC did

appea r to be beneficial in the latter gro up.

Anecdo ta l informa tio n from marihuan a smokers has suggested th at ma rihuana

might be a poten t appetite sti mulant. Clinical studies dealing with this issue ind icat e

that 6 9_THC do es, in fact , have some appetite stimulant efTects; ho wever, this do es

not appear to be ofany major clinica l significance (Ho lliste r, 1971).

Another pot ential use for 6 9-T HC was found by Harris, Munson , Friedman &

Oewey (1 974) who ha ve show n th at 6 9_THC inhibits tumou r growth in certai n

anima l tumour models (suc h as th e Lewis lung tumour). Based on th ese interesting

find ings, further studies in anima l models and in humans appear to be j ustified.

The canna binoids have also been investigated as antia nx iety agents. A lthough it is

sai d th at 6 9_THC and mar ihuana produce rela xant-like efTects, no studies ha ve been

carried out in patients sufTering from an y an xiet y states. Ho wever , studies of th is

nature ha ve been conducted with nabilone, a synthetic cannabinoid. It appears that

nab ilone produced a greater anxiety-reducing efTectthan placebo (Fabre , McClendon

& Stark, 1978) but did not appear to be as efTective as diazepam (Nakano, Gillespie &

Hollister, 1978).

One ofthe earlier studies ofthe potential therapeutic uses ofcannabi s concerned its

use in the treatment of asthma. Tashkin, Shapiro & Frank (1973) and Vachon, Fitzgerald, Soll ida y, Gould & G aen sler (1973) showed that 6 9- THC decreased airway

conductance in normal volunteers. This fmding suggested th at 6 9_THC might

possess bronchodilatory ac tivi ty. In addition to their studies in normal subjects, th ese

investigators evaluated N -THC and marihuana in asthmati c pat ients and demonstrated th at , in fact , th ese drugs could reverse the bronchospasm induced by

methacholine or exercise (Tas hkin, Shapiro, Lee & Ha rper , 197 5).

Perhap s the mo st promisin g potential th erapeutic efTect of 6 9_THC and th e

synthetic cannabinoids is their use as antiemetics in pat ients receiving cancer

chemothe rapy . It was alleged that pat ients su fTeri ng fro m a varicty of cancers could

MARIH UA NA A ND RELATED DR UGS 357

obt ain substantial relief from the devastating nause a and vomiting associated with

the administration of cancer chemotherapeutic med ications if the y smoked

mar ihu ana prior to receiving the ir medication. Although th e phenothiazines are

widely used as antiemetic agents in oth er nau sea-provoking situations, the y appear to

have onl y limited bene fit when given to patients receiving cancer chemotherapy.

Th e initial study demonstrat ing efficacy of /::,9_TH C in pre vent ing nau sea and

vomiting in cancer patients was conducted by Sallan , Zinberg & Frei (1975). Initiall y,

they compared placebo and /::,L T HC in 15 subjects who obt ained no relief with

con ventional antiemetics from the nausea and vomiting produced. Although positive

result s were obtained with /::,9- THC in 12 of 15 subjects, this was accompanied by

major side efTects, including experiencing of a psychologi cal high, somnolence and

psychotomimetic acti vity with visual hallu cinations in two subjects. Many studies

have been conducted to confirrn this observat ion (Chang, Shiling, Stillman, Goldberg, Seipp , Barofsky, Simon & Rosenberg, 1979; Frytak, Moertel , O'Fallon, Rubin,

Creagan, O'Connell, Schutt & Schwartau, 1979) and in addition, the y have been

extended to demonstrate that N - THC was more efTective than th e phenothiazines in

thi s regard.

Nau sea and vom iting in pati ent s receiving can cer chemotherapy can also be

relieved by the oral administration of nabilone (Herman, Jon es, Dean , Leigh, Dorr,

Moon & Salmori , 1977; Herman, Einhorn, Jones, Nagy, Chester , Dean , Furnas,

Will iam s, Leigh, Dorr & Moon, 1979; Nagy, Furnas, Einhorn & Bond , 1978). This

synthetic cannabinoid is particularly efTective again st administration of cis-platinum,

a can cer chemotherapeutic agent which is regarded as one of the most noxious

emetic-producing agent s used in cancer chemotherapy. Like /::,9- TH C, nab ilon e

produced some sedative efTects. However, it produced onl y minimal euphoria at

doses which alle viated nau sea and vomiting (Herm an et al.. 1977). Borison ,

McCarth y & London (1978) and Lond on , McCarthy & Borison (1979) have

confirrned these human findings in the ir cat model. Although nabilone was efTecti ve

in bloc king emesis produced by injected apomorphine and deslano side, thi s was onl y

achieved at doses which produced pronounced behavioural distu rbances in the

animals. In contrast, nabilone was very efTective in pre venting emesis in cats

receiving anticancer agent s, including BCNU, mechl orethamine and cis-platinum. In

these latt er studies, prochlorperazine was inefTecti ve in blocking eme sis in th is

anima l model.

In conclusion , marihuana, /::,9- TH C and its synthetic analogues have been studied

and shown to be of potential use in several clinical conditions. Although marihuana

has been used sociall y by th e inh alation route , the use of this crude preparation,

especially by thi s route of administration , does not appear practical. Thus, attempts

have been made to utili ze /::,9- TH C in apreparation designed for oral administration.

This has been accomplished by dissolving /::,9_THC in sesame oil and placing the

solution in capsules. Thi s compound does not appear to be practi cal as a therapeutic

agent because /::,9_THC is chemically unstable and exists physically as a resin and

becau se it has been shown to und ergo unpredictable absorption, resulting in unpredictable pharmacological efTects. Moreover, /::,9- THC exert s its pharmacological

efTects on several bod ily systems, including the central nervous system and the

cardiovascular system . Thi s lack oftissue specificity suggests that /::,L THC would not

be a useful therapeutic agent , especiall y in the elderl y who may aiso have cardiovascular disease.

In recent years th e observation that synthetic cannabinoid derivati ves do share

some ofthe pharmacolo gical and potential therapeutic usefuI actions of/::,9- THC and

that these compounds do appear to possess a great er degree of organ specificity and

selectivity in the ir actions suggests that new drugs ma y be develop ed from th is class.

Som e of the newer synthetic compounds are crystall ine , readily absorbed, have

reproducible pharmacological efTects, and may ofTer clear adva ntages over /::,9- THC

358 L. LEMBERGER

as potential therapeutic agents. Although these drugs have been studied in a variety

of different c1inical situations, the major area where they appear to have promise and

may be beneficial is in the reduction ofintraocular pressure in patients suffering from

glaucoma, and as an adjunct in patients with cancer who are debilitated due to the

nausea and vomiting produced secondary to the administration of the cancer

chemotherapeutic agents. Although the cannabinoid derivatives do appear to have

some promise , it must be underscored that no cannabinoids of current interest are

devoid ofadverse side effects. Therefore, continued effort should be made in pursuing

these very interesting leads to develop drugs wh ich may be beneficial to patients

suffering from a variety ofdiseases.

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