Pergamon Press
Life Sciences Vol . 16, pp . 1339-1343 Printed in the U.S .A .
TETRAHYDROCANNABINOLS AND SERUM PROLACTIN LEVELS IN MAN Louis Lemberger, Ross Crabtree, Howard Rowe and James Clemens Lilly Research Laboratories, Marion County General Hospital, and Indiana University School of Medicine Indianapolis, Indiana (Received in final form March 31, 1975)
Summary_ p9 -THC, 11-OH-p9-THC or placebo was administered to casual marihuana smokers in a double-blind, crossover study. p9-THC and 11-OH-p9-THC produced marked pharmacologic and psychologic effects (tachycardia, increased symptom score and psychologic high) . In contrast to effects produced by many other centrally acting drugs, the acute administration of these cannabinoids was devoid of any significant effect on prolactin secretion as determined by monitoring changes in serum prolactin levels . It is known that psychoactive drugs such as phenothiazines, L-dope, and the tric clic antidepressants affect the secretion of serum prolactin (1-3i . Recently, Harmon and Aliapoulios (4) reported the increased incidence of gynecomastia in chronic marihuana smokers and suggested that prolactin might play a role in its production . Kolodny et al . (5) were unable to detect any significant differences between the plasma prolactin levels of chronic marihuana subjects and a group of non-marihuana-smoking controls . They did, however, report a decrease in the concentration of plasma testosterone in the marihuana users . p9-THC, the psychoactive principle of marihuana and hashish, has been studied extensively in animals and man (6-8) . More recently, its active metabolite, 11-OH-p9-THC, has also been evaluated in many biologic systems (9-12) . The purpose of the present study was to evaluate the acute effect of single doses of p9-THC and 11-OH-p9-TIfiC on serum prolactin secretion in man. Methods Six normal volunteers, who were casual marihuana smokers and who had not smoked during the past 1-4 weeks, were studied in a double-blind, crossover study Each $ubject was administered either placebo (alcoholic vehicle), pY-THC (1 mg), or 11-OH-p 9THC (1 mg) over a one-minute interval into the tubing of a continuous infusion of dextrose and water (D-S-W) . Serum prolactin was determined by radioimmunoassay using the NIAI~D pituitary standard . 1339
1340
THC and Prolactin Levels
Vol . 16, No . 8
Heart rate was monitored by continuous lead II EKG, symptoms were monitored using a modified Cornell Medical Index, a questionnaire sensitive to adverse drug effects, and psychologic high was scored on a 1-10 rating system as previously described (13) . Blood samples were obtained from an indwelling catheter placed in the antecubital vein of the arm opposite the site of injection . Bloods were drawn for determination of serum prolactin at 0, 5, 10, 30, 60, 120 and 240 min . after drug or placebo administration . All studies were done at the same time each day, under relatively stress-free circumstances . The serum prolactin data were analyzed using an analysis of variance allowing for repeated measurements on each subject . Results The effect of 9-THC and 11-OH-p9 -THC on serum rolactin : or - -p not The in ravenous a m n s ra ono p produce any significant changes in serum prolactin which differed from the placebo control period (Table I, Fig . 1) . Although there appeared to be a slight increase in serum prolactin two hours after the administration of p9-THC, this effect was not evident at four hours, and was not seen after 11-OH-p9THC administration . Figure 1
BERUlI PROLACTIN ng/ml (Change from control)
TI1dS AFTER DRUG
Effect of p9 -THC, 11-OH-p 9 -THC, and placebo on serum prolactin .
Vol. 16, No . 8
1341
THC and Prolactin Levels
TABLE I Effect of p9 -THC and 11-OH-p9-THC on Serum Prolactin Levels . -15 min .
5 min .
10 min .
30 min .
60 min .
120 min,
240 min .
Placebo
8 .70* +0 .68
9 .25 +1 .52
8 .25 +0 .31
7 .83 +1 .26
9 .83 +1 .54
7 .92 +0 .68
8 .83 +2 .05
9 p -THC
8 .92 +0 .37
6 .83 +1 .61
5 .33 +1 .29
6 .75 +1 .22
6 .58 +1 .70
14 .33 +3 .41
8 .67 +0 .94
11-OHp9-THC
8 .67 +1 .37
8 .33 +2 .26
5 .83 +1 .25
9 .42 +1 .36
7 .08 +1 .24
8 .33 +1 .03
8 .17 +1 .88
*ng/ml . Placebo, p 9 -THC, or 11-OH-p9 -THC administered at 0 time ae described in Methods . Values represent mean + SEM . The effect of 9 -THC and 11-OH- 9 -THC on heart rate s cholo is an s tome : p an - -p pro uc a matte taciycar a . eart rate increased to a mean of 25 be ts/ min . over placebo with p9-Ti~C and 35 beats/min. with 11-OH-p~-THC (Table I) . Both compounds produced marked increases in symptomatology when compared to placebo and both produced a marked psychologic "high' (Table II) . TABLE II Pharmacologic Effects of THC and 11-OH-THC in Man . CMI Placebo
Heart Rate
High
0 .3(_+0 .8)
-1(±2)
0(±0)
THC
24 .87 .6)
25L+6)
41 .4)
11-OH-THC
39 .3 x+9 .8)
35 L9)
8(+1 .0)
Values are the mean change from pre-injection values in six subjects . Values in parentheses - + SEM. Discussion Many paychotropic agents have been reported to affect the secretion of prolactin in man . The phenothiazine antipsychotics, tricyclic antidepressants and centrally-acting antihy ertensives, such as a-methyl dope, alb elevate serum prolactin (1-~), while anti-Parkinsoniam drugs such as L-dope and the ergot drugs Lergotrile and CB-154, ~ower serum prolactin concentrations (14, 15) . The lack of effect in our clinical study of the tetrahydrocannabinola on the secretion of serum prolactin ie of interest, not only because of their marked CNS activity, but in addition
1342
THC and Prolactin Levels
Vol. 16, No . 8
because they have been postulated to roduce gynecomastia in part by a prolactin-dependent mechanism (4~ . Moreover, p9-THC has been shown to have an effect on the secretion of pituitary trophic hormones . In rats, p9-THC prevents the pre-ovulatioy surge of pituitary lutinizing hormone (LH),as evidenced by the failure of serum LH to increase during pro-eatros, in addition to blocking ovulation (16) . The results of the present study in man are dissimilar to two rat studies (17,18) recently published . One study reported that the acute administration of p9-THC significantly lowered serum prolactin levels (17) whereas the other found an increase in serum prolactin (18) . The present study was designed to demonstrate if the acute administration of THC would produce significant changes in serum prolactin concentrations . After the administration of the anti paychotic perphenazine to man, the serum concentration of prolactin increases within 10-15 min . and remains elevated for 8-24 hrs . (1,14) . In contrast, after p9-THC or 11-OH-p9-THC the levels of serum prolactin did not change significantly from those seen after placebo injection, although in two of the six subjects there was a doubling of the serum prolactin concentration two hours after I .V . administration of p9-THC . The lack of an effect of the tetrahydrocannabinols on serum prolactin concentrations occurred despite the fact that these compounds did produce marked pharmacologic and psychologic effects including a pronounced techycardia, significant increases in symptomatology, and a psychologic "high ." The lack of an acute effect of tetrahydrocannabinol on serum prolactin concentration in man seen in this study is consistent with the report by Kolodny et al . (5) who were unable to find any difference in the steady-state concentration of serum prolactin in chronic marihuana smokers . References 1.
R . W . TURICINGTON, Arch . Int . Med . 130 349-354 (1972) .
2.
G . TOLIS M. GOLDSTEIN, and H. G . FRIESEN, J . Clin . Im~est . 52 783-7~8 (1973) .
3.
D . L . KLEINBERG, G. L . NOEL and A . G . FRANTZ, J . Clin . Endocrinol . Metab . 33 873 (971) .
4.
J . HARMON and M. A. ALIAPOULIOS, New End . J . Med . 287 936 (1972) .
5.
R. C . KOLODNY, W . H . MASTERS, R . M . KOLODNER, and G . TORO, New Eng. J . Med . 290 872-874 (1974) .
6.
R. MECHOULAM, Science 168 1159 (1970) .
7.
L . E . HOLLISTER, Science 172 21-29 (1971)
S.
L . LEMBERGER, Adv . Pharmacol . and Chemother . 10 221-251 (1972)
9.
L . LEMBERGER, R . E . CRABTREE, and H . M. ROWE, Science 62-64 (1972) .
177
Vol. 16, No . 8
THC and Prolactin Levels
1343
10 .
L . LEMBERGER, R. MARTZ B . RODDA R, FORNEY, and H. ROWE, J . Clin . Imreat . 52 241-2417 (173) .
11 .
M. PEREZ-REYES, M. C . TIMMONS M . A, LIPTON, K . H. DAVIS, and M. E . WALL, Science 177 6~3-635 (1972) .
12 .
L . E . HOLLISTER, Clin . Pharmacol . Therap . 15 208 (1974) .
13 .
L . LEMBERGER J . L . WEISS, A. M. WATANABE, I, M. GALANTER, R . WYATT, anc~ P . V . CARDON, New Eng . J . Med . 286 685-688 (1972) .
14 .
L . LEMBERGER, R. CRABTREE J . CLEMENS, R. DYKE and R. WOODBURN, J, Clin . Endocr~nol . Matab . 39 579-5~4 (1974) .
15 .
G . M. BESSER, L, PARKE C . R . W . EDWARDS I . A . FORSYTH, and A. S . MCNEILLY, Br~t . Med . J . 669 67~ (1972) .
16 .
I . NIR, D . AYALON A . TSAFRIRI, T . CORDOVA, and H, R . LINDER Nature 243 470-47~ (1973) .
17 .
J . KRAMER and M. BEN-DAVID t Proc . Soc . Exiler, Biol . Med . 147 482-484 (1974) .
18 .
J, D . DALEY, L . A . BRANDA, J, ROSENFELD, and E, V. YOUNGLAI, J . Endocrinol . 63 415-416 (1974) .
Life Sciences Vol . 16, pp . 1339-1343 Printed in the U.S .A .
TETRAHYDROCANNABINOLS AND SERUM PROLACTIN LEVELS IN MAN Louis Lemberger, Ross Crabtree, Howard Rowe and James Clemens Lilly Research Laboratories, Marion County General Hospital, and Indiana University School of Medicine Indianapolis, Indiana (Received in final form March 31, 1975)
Summary_ p9 -THC, 11-OH-p9-THC or placebo was administered to casual marihuana smokers in a double-blind, crossover study. p9-THC and 11-OH-p9-THC produced marked pharmacologic and psychologic effects (tachycardia, increased symptom score and psychologic high) . In contrast to effects produced by many other centrally acting drugs, the acute administration of these cannabinoids was devoid of any significant effect on prolactin secretion as determined by monitoring changes in serum prolactin levels . It is known that psychoactive drugs such as phenothiazines, L-dope, and the tric clic antidepressants affect the secretion of serum prolactin (1-3i . Recently, Harmon and Aliapoulios (4) reported the increased incidence of gynecomastia in chronic marihuana smokers and suggested that prolactin might play a role in its production . Kolodny et al . (5) were unable to detect any significant differences between the plasma prolactin levels of chronic marihuana subjects and a group of non-marihuana-smoking controls . They did, however, report a decrease in the concentration of plasma testosterone in the marihuana users . p9-THC, the psychoactive principle of marihuana and hashish, has been studied extensively in animals and man (6-8) . More recently, its active metabolite, 11-OH-p9-THC, has also been evaluated in many biologic systems (9-12) . The purpose of the present study was to evaluate the acute effect of single doses of p9-THC and 11-OH-p9-TIfiC on serum prolactin secretion in man. Methods Six normal volunteers, who were casual marihuana smokers and who had not smoked during the past 1-4 weeks, were studied in a double-blind, crossover study Each $ubject was administered either placebo (alcoholic vehicle), pY-THC (1 mg), or 11-OH-p 9THC (1 mg) over a one-minute interval into the tubing of a continuous infusion of dextrose and water (D-S-W) . Serum prolactin was determined by radioimmunoassay using the NIAI~D pituitary standard . 1339
1340
THC and Prolactin Levels
Vol . 16, No . 8
Heart rate was monitored by continuous lead II EKG, symptoms were monitored using a modified Cornell Medical Index, a questionnaire sensitive to adverse drug effects, and psychologic high was scored on a 1-10 rating system as previously described (13) . Blood samples were obtained from an indwelling catheter placed in the antecubital vein of the arm opposite the site of injection . Bloods were drawn for determination of serum prolactin at 0, 5, 10, 30, 60, 120 and 240 min . after drug or placebo administration . All studies were done at the same time each day, under relatively stress-free circumstances . The serum prolactin data were analyzed using an analysis of variance allowing for repeated measurements on each subject . Results The effect of 9-THC and 11-OH-p9 -THC on serum rolactin : or - -p not The in ravenous a m n s ra ono p produce any significant changes in serum prolactin which differed from the placebo control period (Table I, Fig . 1) . Although there appeared to be a slight increase in serum prolactin two hours after the administration of p9-THC, this effect was not evident at four hours, and was not seen after 11-OH-p9THC administration . Figure 1
BERUlI PROLACTIN ng/ml (Change from control)
TI1dS AFTER DRUG
Effect of p9 -THC, 11-OH-p 9 -THC, and placebo on serum prolactin .
Vol. 16, No . 8
1341
THC and Prolactin Levels
TABLE I Effect of p9 -THC and 11-OH-p9-THC on Serum Prolactin Levels . -15 min .
5 min .
10 min .
30 min .
60 min .
120 min,
240 min .
Placebo
8 .70* +0 .68
9 .25 +1 .52
8 .25 +0 .31
7 .83 +1 .26
9 .83 +1 .54
7 .92 +0 .68
8 .83 +2 .05
9 p -THC
8 .92 +0 .37
6 .83 +1 .61
5 .33 +1 .29
6 .75 +1 .22
6 .58 +1 .70
14 .33 +3 .41
8 .67 +0 .94
11-OHp9-THC
8 .67 +1 .37
8 .33 +2 .26
5 .83 +1 .25
9 .42 +1 .36
7 .08 +1 .24
8 .33 +1 .03
8 .17 +1 .88
*ng/ml . Placebo, p 9 -THC, or 11-OH-p9 -THC administered at 0 time ae described in Methods . Values represent mean + SEM . The effect of 9 -THC and 11-OH- 9 -THC on heart rate s cholo is an s tome : p an - -p pro uc a matte taciycar a . eart rate increased to a mean of 25 be ts/ min . over placebo with p9-Ti~C and 35 beats/min. with 11-OH-p~-THC (Table I) . Both compounds produced marked increases in symptomatology when compared to placebo and both produced a marked psychologic "high' (Table II) . TABLE II Pharmacologic Effects of THC and 11-OH-THC in Man . CMI Placebo
Heart Rate
High
0 .3(_+0 .8)
-1(±2)
0(±0)
THC
24 .87 .6)
25L+6)
41 .4)
11-OH-THC
39 .3 x+9 .8)
35 L9)
8(+1 .0)
Values are the mean change from pre-injection values in six subjects . Values in parentheses - + SEM. Discussion Many paychotropic agents have been reported to affect the secretion of prolactin in man . The phenothiazine antipsychotics, tricyclic antidepressants and centrally-acting antihy ertensives, such as a-methyl dope, alb elevate serum prolactin (1-~), while anti-Parkinsoniam drugs such as L-dope and the ergot drugs Lergotrile and CB-154, ~ower serum prolactin concentrations (14, 15) . The lack of effect in our clinical study of the tetrahydrocannabinola on the secretion of serum prolactin ie of interest, not only because of their marked CNS activity, but in addition
1342
THC and Prolactin Levels
Vol. 16, No . 8
because they have been postulated to roduce gynecomastia in part by a prolactin-dependent mechanism (4~ . Moreover, p9-THC has been shown to have an effect on the secretion of pituitary trophic hormones . In rats, p9-THC prevents the pre-ovulatioy surge of pituitary lutinizing hormone (LH),as evidenced by the failure of serum LH to increase during pro-eatros, in addition to blocking ovulation (16) . The results of the present study in man are dissimilar to two rat studies (17,18) recently published . One study reported that the acute administration of p9-THC significantly lowered serum prolactin levels (17) whereas the other found an increase in serum prolactin (18) . The present study was designed to demonstrate if the acute administration of THC would produce significant changes in serum prolactin concentrations . After the administration of the anti paychotic perphenazine to man, the serum concentration of prolactin increases within 10-15 min . and remains elevated for 8-24 hrs . (1,14) . In contrast, after p9-THC or 11-OH-p9-THC the levels of serum prolactin did not change significantly from those seen after placebo injection, although in two of the six subjects there was a doubling of the serum prolactin concentration two hours after I .V . administration of p9-THC . The lack of an effect of the tetrahydrocannabinols on serum prolactin concentrations occurred despite the fact that these compounds did produce marked pharmacologic and psychologic effects including a pronounced techycardia, significant increases in symptomatology, and a psychologic "high ." The lack of an acute effect of tetrahydrocannabinol on serum prolactin concentration in man seen in this study is consistent with the report by Kolodny et al . (5) who were unable to find any difference in the steady-state concentration of serum prolactin in chronic marihuana smokers . References 1.
R . W . TURICINGTON, Arch . Int . Med . 130 349-354 (1972) .
2.
G . TOLIS M. GOLDSTEIN, and H. G . FRIESEN, J . Clin . Im~est . 52 783-7~8 (1973) .
3.
D . L . KLEINBERG, G. L . NOEL and A . G . FRANTZ, J . Clin . Endocrinol . Metab . 33 873 (971) .
4.
J . HARMON and M. A. ALIAPOULIOS, New End . J . Med . 287 936 (1972) .
5.
R. C . KOLODNY, W . H . MASTERS, R . M . KOLODNER, and G . TORO, New Eng. J . Med . 290 872-874 (1974) .
6.
R. MECHOULAM, Science 168 1159 (1970) .
7.
L . E . HOLLISTER, Science 172 21-29 (1971)
S.
L . LEMBERGER, Adv . Pharmacol . and Chemother . 10 221-251 (1972)
9.
L . LEMBERGER, R . E . CRABTREE, and H . M. ROWE, Science 62-64 (1972) .
177
Vol. 16, No . 8
THC and Prolactin Levels
1343
10 .
L . LEMBERGER, R. MARTZ B . RODDA R, FORNEY, and H. ROWE, J . Clin . Imreat . 52 241-2417 (173) .
11 .
M. PEREZ-REYES, M. C . TIMMONS M . A, LIPTON, K . H. DAVIS, and M. E . WALL, Science 177 6~3-635 (1972) .
12 .
L . E . HOLLISTER, Clin . Pharmacol . Therap . 15 208 (1974) .
13 .
L . LEMBERGER J . L . WEISS, A. M. WATANABE, I, M. GALANTER, R . WYATT, anc~ P . V . CARDON, New Eng . J . Med . 286 685-688 (1972) .
14 .
L . LEMBERGER, R. CRABTREE J . CLEMENS, R. DYKE and R. WOODBURN, J, Clin . Endocr~nol . Matab . 39 579-5~4 (1974) .
15 .
G . M. BESSER, L, PARKE C . R . W . EDWARDS I . A . FORSYTH, and A. S . MCNEILLY, Br~t . Med . J . 669 67~ (1972) .
16 .
I . NIR, D . AYALON A . TSAFRIRI, T . CORDOVA, and H, R . LINDER Nature 243 470-47~ (1973) .
17 .
J . KRAMER and M. BEN-DAVID t Proc . Soc . Exiler, Biol . Med . 147 482-484 (1974) .
18 .
J, D . DALEY, L . A . BRANDA, J, ROSENFELD, and E, V. YOUNGLAI, J . Endocrinol . 63 415-416 (1974) .
