Effect of marijuana the adrenal gland


Cortical Hormones

Exposure to stressful situations elicits a prompt secretion of adrenocortical steriods which help the organisms to counteract the stress. The adrenal cortex responds to acute cannabinoid treatment with a prompt rise in corticosterone levels in the plasma. Exposure to a wide range of dosages of THC ranging fran 2 to 50 mg/ kg body weight produced increased corticosterone levels in the plasm of both the rat and the mouse. Dewey et al. () showed that ascorbic acid, which is inversely correlated to adrenal cortical hormne secretion, was depleted fran the adrenal cortex of laboratory rats. Maier and Maitre () demonstrated that. the increased corticosterone in plasma of rats pretreated with THC was accompanied by a decrease in adrenal cortical cholesterol, a precursor to adrenal cortical hormones, and an increase in unesterified fatty acids; however, the rabbit did not respond to THC with a similar increase in wrtisol.

Birmingham and Bartova () showed that the response of elevated plasma corticosterone to THC disappeared after 8 days of treatment with a dose of 3 mg/kg body weight. Pertwee () also showed that tolerance developed to the effect of THC on corticosterone levels in muse plasm and did so without impairing the effect of stress in mobilizing wrticosterone release. Mitra et al. () found no evidence of tolerance after 21 days of THC (10 mg/kg/day) administration.

Bromley and Zimmerman () examined the possibility that THC acts as a general systemic stressor. Generally, stress causes an increase in both prolactin and corticusterone levels in male rats. However, their results indicated that, unlike most stressful stimuli, acute administration of THC caused a depression in prolactin while stimulating corticosterone release.

Several studies have indicated that the wrticosterone response to THC was mediated through the pituitary by the action of THC on central nervous structures to modify the secretion or release of ACTH from the hypothalamus. Barry et al. () ruled out the possibility that THC acted directly on the adrenal cortex to elicit corticosterone release. Their study employed hypophysectomized rats which had been administered THC at 2 mg/kg body weight, a dosage which significantly increases plasma corticosterone levels. After hypophysectcmy, THC was unable to increase plasma corticosterone levels. Puder et al. () further showed that adult male rats, bearing complete hypothalamic deafferentations, who were injected with THC (5 mg/kg) had no significantly altered serum concentration of either ACTH or corticosteroids. These results demonstrate that extrahypothalamic sites and/or neural pathways mediate the effect of THC to decrease corticosterone secretion.

Further evidence for a central action of THC comes fran the study of Malor et al. (). Mice treated with THC had a dosedependent rise in plasma nonesterified fatty acids (NEFA) due to THC’s action in elevating corticosterone. The THC induced rise in plasma NEFA was blocked by prior administration of the dopamine receptor antagonists, perphenazine or pimozide. Thus the elevation of plasma NEFA produced in mice, by THC, is probably centrally mediated and requires the presence of functional dopaminergic receptors which presumably cause ACTH to be released to effect the corticosterone induced rise in plasma NEFA. Moreover, pentobarbital (75 mg/kg) () and dexamethasone (), two agents which block ACTH secretion, also prevent the adrenocortical response to THC (10 mg/kg).

Several investigators have examined the accmulation of radioactive THC by various brain structures. Erdmann et al. () showed that the amount of radioactive THC taken up by the preoptic areas, hypothalamus and pituitary, structures which are important for the regulation and release of hormones, did not concentrate more radioactive compound than other brain structures. Also there was a reduction in the amount of radioactive wrticosterone that was accumulated by the hypothalamus and thalamus if rats were treated with THC at high doses (9 mg/kg I.P.). Interestingly, and perhaps in apparent contrast, smaller doses (3 mg/kg I.P.) actually increased corticosterone uptake (). However, Johnson et al. (1978) showed that high doses of cannabinoids (30 and 100 mg/kg) increased uptake of radioactive wrticosterone by the whole brain. The cannabinoids examined were 11-hydroxy-delta-9-THC, THC, and cannabinol (CBN). Pretreatment with THC at 3, 10, or 100 mg/kg SC increased the affinity of the hippocampus for tritiated corticosterone, but its concentration was decreased in the hypothalamus, mid-brain, pons, and medulla.

Collu () injected THC (20 µg) directly into the ventricles of the rat brain and produced an increase in the general activity of cells in the adrenal and pituitary glands which was correlated with an increased corticoceterone production. Chronic treatment of rats and mice with THC produced an increased adrenal weight, which returned to control levels upon cessation of drug treatment (). Pats pretreated with THC (5 mg/kg I.P.) were still able to release corticosterone in response to stress ().

Apparently not all of the effects of cannabinoids on adrenocortical function are due to the effect that they have to stimlate ACTH and corticosterone production by a direct endocrine route. Several investigators have examined the effect of THC, CNB, and CBD on muse and rat adrenal cortical cells grown in tissue culture. Addition of 10-6 to 10-4M cannabinoid to the incubation medium in which the cultured adrenal cortical cells were being grown prevented the cells from responding to added ACTH (Carchman et al. 1976, Warner et al. 1977). The cannabinoids appear to depress the synthesis of adrenal cortical steroids at a site between synthesis of cAMP and of pregnenalone (). Delta-9-tetrahydrocannibinol (3.2 and 16 µM) added to an incubation medium that contained homogenized rat adrenal cells produced an inhibition of cholesterol esterase activity similar to that found in Leydig cells ().

Adrenal Medulla

Several studies have examined the effect of THC on other cannabinoids on catecholamines and 5-hydroxytryptamine turnover in brain and adrenals. Johnson et al. () showed that 30 mg/kg of THC increased the ammount of tritiated tryptophane found in the brains of mice and increased the amount of tritiated 5-hydroxytryptamine that was synthesized during the lo-minute period before decapitation. Previous studies have shown that this effect of THC was mediated by increased levels of plasma corticosterone in the mice produced by treatment with THC, since adrenalectomy inhibited it. Thus, there is a possibility that wrticosterone may mediate the effect of THC on tryptophane disposition and metabolism.

Mazurkiewics-Kwilecki and Filczewski () showed that administration of THC (2 mg/kg daily) for 1 week caused an increase in the synthesis of tritiated catecholamines in the brain and adrenals. However, the endogenous norepinephrine and dopamine concentration in the brain, and epinephrine and norepinephrine levels in the adrenals, were apparently unaltered. The ability of THC to increase serotonin in the brain of mice has been confirmed by Welch et al. (), who showed that intraperitoneal injection of 10 mg/ kg elevated serotonin concentration in the telencephalon by 30% within 10 minutes after injection but had no effect on the endogenous levels of brain norepinephrine or dopmine. Delta-9-tetra-hydrocannabinol, on the other hand, depleted adrenal epinephrine by 25% within 10 minutes. Mitra et al. () showed that administration of a single dose of THC (10 or 50 mg/kg) produced a dose-dependent increase in the content of norepinephrine and epinephrine in the rat adrenal gland and that THC given acutely both at low and high doses decreased the rate of synthesis and increased the rate of depletion of dopamine, decreased the rate of depletion of norepinephrine, and increase the rate of depletion of epinephrine. Biswas et al. () also showed that THC affected the rat adrenal medulla; acute treatment (10 mg/kg) caused a decrease in catecho lamines, and chronic treatment (10 mg/kg for 30 days) produced a similar decrease in total catecholamine content of the adrenal medulla, as well as an hypertrophy of chromaffin substance.


Selections from the book: “Marijuana Effects on the Endocrine and Reproductive Systems”. Monique C. Braude, Ph.D., and Jacqueline P. Ludford, M.S., eds. A RAUS Review Report of animal studies and preclinical and clinical studies of effects of cannabinoids on human endocrine and reproductive functions. National Institute on Drug Abuse Research Monograph 44, 1984.