Am J Psychiatry 137:8, August 1980 909

Opiate Use and Sexual Function

BY STEVEN M. MIRIN, M.D., ROGER E. MEYER, M.D., JACK H. MENDELSON, M.D.,AND JAMES ELLINGBOE, M.D.

Although opiate addicts often equate the drug

experience �t’ith sexual orgasm , diminished libido and

impaired sexual performance are common sequelae of

chronic use. Early clinical studies suggested that

opiates may interfere with sex hormone secretion. The

authors carried out three sequential studies �%‘hich

demonstrated that heroin use in man results in acute

suppression ofluteinizing hormone (LH) release from

the pituitaryfollrni’ed by a secondary drop in plasma

testosterone levels. The time course of these

neuroendocrine events correlates v�’ell with the

tension-reducing effects ofheroin and suggests that

drive reduction is an important component of opiate

reinforcement.

T he dramatic effects produced by an injection ofheroin have been well described by both clinicians

and users (1-4). A briefbut very intense euphoria, fol-lowed by tension relief, seems to be the common de-

nominator in the heroin experience. Chessick (5)

called this sequence of events the ‘ ‘ pharmacogenic or-gasm,” and addicts themselves often describe it insexual terms. In the case of intravenous heroin the im-mediate postinjection “rush” is frequently equated to

sexual orgasm, and subsequent feelings of tension re-lief and relaxation have been likened to ‘ ‘beingwrapped in warm cotton,’ ‘ ‘ ‘returning to the womb,”or similar allusions to warmth, security, and beingcared for.

Presented at the 132nd annual meeting ofthe American Psychiat-ric Association, Chicago, Ill., May 12-18, 1979. Received May 21,1979; accepted July 26, 1979.

From the Department of Psychiatry, Harvard Medical School(Drs. Mirin and Mendelson), the Psychopharmacology Service Out-patient Department (Dr. Mirin), and the Alcohol and Drug AbuseResearch Center (Dr. Mendelson), McLean Hospital, Belmont,Mass; the Department of Psychiatry, University of ConnecticutSchool of Medicine, Farmington, Conn. (Dr. Meyer); and the Dc-partment of Biochemistry, Harvard Medical School, Boston, Mass.(Dr. Ellingboe).

Address reprint requests to Dr. Mirin, McLean Hospital, Bel-mont, Mass. 02178.

This work was supported by grant DA-00257 from the NationalInstitute on Drug Abuse, contract HSM-42 from the National Insti-tute of Mental Health, and grant DA-RGO1O from the Special Officefor Drug Abuse Prevention.

Copyright © 1980 American Psychiatric Association 0002-953X1

80/08/0909/07/$00.50.

In contrast to these retrospective accounts of thedrug experience, untreated male heroin addicts andpatients in methadone maintenance programs reportthat decreased interest in sex, impotence, and delayedejaculation are common problems during opiate Use(6-10), and opiate withdrawal has been associated withrenewed sexual interest and premature ejaculation (11)in many patients. As a result of these observations,interest in the sexual sequelae of opiate use has shiftedfrom an emphasis on intrapsychic factors to the studyof the hormonal correlates of drug administration. Inthis context, a series of clinical and laboratory studieshave explored the effects of opiates on the hypothala-mic-pituitary-gonadal axis. This paper reviews a num-ber ofthese studies in man, including some recent datafrom our laboratory. We will attempt to reconcile thecurious dichotomy between the acute reinforcing ef-fects of opiates, as expressed in the language of sexual

gratification, and the neuroendocrine sequelae ofchronic use, which appear to be somewhat less gratify-ing.

EFFtCTS OF CHRONIC OPIATE USE ON

PITUITARY-GONADAL FUNCTION IN MAN

Early clinical studies (12-14) of the effects of opiateuse on pituitary-gonadal function were hampered by avariety of methodologic problems. In outpatient stUd-ies it was difficult to control for the amount of priordrug use across subjects as well as the amount of timeelapsed between drug administratiOn and hormonalmeasurements. Furthermore the pituitary gonadotro-pins and testosterone are secreted in a pulsatile fash-

ion; thus even individuals with normal gonadal func-tion have considerable moment-to-moment variationin the mean plasma level of these hormones (15). Con-sequently the infrequent plasma sampling (i.e., once ortwice per day) that characterized earlier clinical stud-ies made it difficult to accurately assess drug-induced

changes in the episodic secretory pattern of these hor-

mones. Finally, most early studies lacked the method-ology for direct measurement of pituitary and gonadalhormones. More recent studies (16-21) have usedmodern radioimmunoassay techniques for the quan-titation of these hormones.

In the face of these methodologic difficulties it is notsurprising that the results of earlier studies often

910 OPIATE USE AND SEXUAL FUNCTION Am J Psychiatry /37:8, August 1980

proved contradictory. Nonetheless some generaltrends can be discerned. Azizi and associates (12)found lower than normal levels of serum testosteronein 8 of 16 heroin addicts and 2 of6 chronic methadoneusers, although levels ofestradiol, luteinizing hormone(LH), and follicle-stimulating hormone (FSH) werenot consistently altered in these subjects. Cushman(13) also reported no change in LH secretion amongactive heroin users and abstinent former addicts. In asubsequent study (14), however, high dose methadoneusers (>40 mg/day) and some untreated heroin addictshad low plasma testosterone levels when comparedwith nonaddict controls; they also reported a varietyof sexual problems during active drug use. In anotherstudy, Martin and associates ( 16) observed decreasedplasma LH and FSH levels in 5 men maintained on 100

mg of methadone per day, but after 1 month of absti-nence their gonadotropin levels were actually in-creased over predrug levels. In 1975 Mendelson andassociates (17) studied a group of patients on heroinmaintenance who, after receiving fixed doses of heroinat fixed intervals, reported diminished interest in sexand potency problems and had a significant decrease inplasma testosterone compared with normal nonaddictcontrol subjects. These investigators also found lowerthan normal levels of plasma testosterone in untreatedheroin addicts who had a recent history of heavy useand in patients on high dose (80-150 mg/day) meth-adone maintenance. In a subsequent study (18) Men-delson and Mello found diminished plasma testos-terone levels in a group ofchronic heroin users; after 1month of abstinence, however, their testosterone 1ev-els were within the normal range for adult males. Fi-nally, Cicero and associates (19) compared 29 patientsmaintained on methadone (mean dose=67 mg/day)with 16 active heroin addicts and 43 drug-free controlsand found that methadone-treated patients hadmarkedly impaired function of their secondary sex or-gans and significantly lower levels of serum testoster-one compared with the other two groups.

Over the last 4 years our research group has carriedout a series of studies on the acute and chronic effectsof opiate administration on pituitary-gonadal function,attempting to avoid some of the methodologic prob-lems found in earlier studies. As part of a multi-disciplinary research project, detoxified heroin addicts

were admitted to a four-bed research ward and al-lowed to self-administer intravenous heroin under avariety of experimental conditions. Their informedconsent was obtained after the procedures had beenfully explained. In all studies individual subjects orgroups of subjects served as their own controls. Her-oin dosage and the timing of plasma sampling for hor-monal determinations was controlled by the experi-menters. Since these studies, including the methodsused to quantitate plasma levels of testosterone andpituitary gonadotropins, have been reported elsewhere

(20-22), we will only summarize our findings here. The

designs of our three experiments are presented in

table 1.

Experiment 1

In our first study (20) we assessed the effects ofchronic heroin use on plasma testosterone levels in 10detoxified addicts, who were permitted self-regulatedaccess to increasing doses of intravenous heroin over a10-day period. Blood samples for plasma testosteronedeterminations were collected each morning at 8 a.m.,approximately 6 hours after the previous heroin injec-tion. The acute hormonal response to heroin or its ef-fect on pituitary gonadotropins was not assessed inthis first study. During study period 2, as the total dailydose of heroin increased, plasma testosterone levelsfell. When the preceding day’s heroin dose was be-tween 45 and 60 mg, testosterone levels fell below 400

ng/lOO ml, significantly lower than during study period1 , when subjects were drug-free (p<.02, matched t

test). Following a period of methadone detoxification(study period 3), testosterone secretion gradually re-turned to predrug levels.

Experiment 2

In our second study (21) we sought to measure theacute effects of heroin on the pituitary-gonadal axis.After 2 weeks on a drug-free regimen and 1 saline con-trol day (periods 1 and 2), 2 detoxified male addictswere given 10 mg i.v. of heroin. The 2 subjects hadvery similar hormonal responses. As illustrated in fig-ure 1 (subject 1) the result was an almost immediatefall in the level ofplasma LH. This acute response wasnot observed when subjects received saline, nor did itoccur when subjects were pretreated with naltrexone,

a narcotic antagonist with few agonistic effects of itsown (23). In both subjects LH suppression was stillobserved 6 hours after heroin injection, although somerecovery in LH secretion was noted in 1 subject. Inter-estingly, pretreatment with naltrexone, 12 hours be-fore heroin administration, resulted in a mean 50% risein plasma LH levels compared with levels on the saline

control day. The number and frequency of LH secre-tory pulses also increased following naltrexone admin-istration. Despite the rise in LH, however, testoster-

one secretion was only marginally increased in 1 sub-ject and unaffected in the other. In none of theexperimental conditions was FSH affected.

Experiment 3

In our third study (22) we examined the acute andchronic effects of unblocked and naltrexone-blockedheroin use on the pituitary-gonadal axis. Our goalswere to replicate our findings from experiment 2 inmore subjects and to better assess the time course ofthe acute suppressant effect of heroin on LH and tes-tosterone. We also wanted to determine whetherchronic heroin and/or naltrexone use altered the acuteresponse to heroin. There were three different double-

FIGURE 1Plasma Testosterone, LH, and FSH Levels Before and After Injection of Saline, Heroin, and Heroin Preceded by Naltrexone (22)a

Day 14-Saline (2 cc iv.)

-� 100 -

w

0 � �OO -

w� 700-00

�2 500-

�- S 300-

300 -

200 -

�i 1O�i� 300-

I-U)Li.

2 1�?11� I

I I

56

Am J Psychiatry 137:8, August 1980 MIRIN, MEYER, MENDELSON, ET AL 911

Day 15-Heroin (10 mg iv.)

I Id-c��’��_I I I I I I

I 1-�c:�.5�-1 � � I I I

- I � I I I I I

2 1 123456

HOURS BEFORE OR AFTER INJECTION

Day 19-Heroin (10 mg iv.) 12hours after naltrexone (50 mg

�cbA/AJI r1:�:1..I U I I I

I I�j�.I I I I 1�U

I J I �c.E?�1 � #{149} 1�-I--

2 1 12345 6

&All injections were given at 10:00 am.

TABLE 1Three Studies of the Acute and Chronic Effects of Opiate Administration on Pituitary-Gonadal Function (22)

StudyPeriod

Experiment 1 (N= 10) Expe riment 2 (N=2) Experi ment 3 (N =8)

Day Condition Day Condition Day Condition

1 1-7 Drug-free 1-13 Drug-free 1-7 Drug-free2 8-17 Heroina l4(lO:OOa.m.) Saline,2mli.v. 7(2p.m.) Heroin, l0mgi.v.

(unblocked)3 18-24 Methadone detoxification 15 (10:00 a.m.) Heroin, 10 mg iv.

(unblocked)

10 (6 p.m.)10 (10 p.m.)

Naloxone, 0.4 mg i.v.Naltrexone, 50mgi.v., or placebo

4 25-34 Drug-free 18 (6 p.m.) Naloxone, 0.4 mg iv.Naltrexone, 50 mg p.o.

11 (2 p.m.) Saline, 2 ml i.v.,plus naltrexone, 50mgp.o., or placebo

5 35-36 Narcotic antagonist 19(10 a.m.) Heroin, 10 mg iv.(blocked)

12-23 (8 a.m.) Naltrexone, 50mgP.O., or placebo

6 37-46 Narcotic antagonist

plus heroin

20-25 Naltrexone, 50 mg p.o. 13 (10 a.m.)

to 23 (8 a.m.)Heroina

7 47-60 Narcotic antagonist alone 23 (2 p.m.) Heroin, 10 mg i.v.

aHeroin was available any time but not more often than every 2 hours to prevent drug accumulation. The allowable intravenous dose escalated from 0.5 mg on day

8 to 5 mg on day 18 to accommodate tolerance. By waiting 4 hours the subject could double the allowable dose; after 6 hours he could triple it. Waiting longer than6 hours resulted in no further increment. Subjects had the option of not self-administering heroin or of taking less than the allowable dose.

blind conditions. After 6 drug-free days 8 subjects re-ceived an injection of 10 mg of heroin; 4 days later allsubjects received intravenous saline 12 hours afterpretreatment with either naltrexone (N4) or anequivalent volume of placebo (N=4). After 10 days ofaccess to heroin (see table 1) naltrexone-treated andplacebo-treated subjects received another 10-mg doseof heroin. Plasma levels of LH and testosterone weredetermined on integrated blood samples collected at30-minute intervals from 4 hours before to 10 hours

after each test injection. Blood samples were collectedwith the use of a constant exfusion pump; thus hor-

monal levels are expressed as the mean value for each30-minute collection period.

In general, pooled data for these subjects were con-sistent with our earlier findings. As illustrated in the

top panel of figure 2 heroin-induced suppression of LHsecretion was first evident 2-4 hours and was greatest4-6 hours after unblocked heroin injection. In thisstudy the degree of LH suppression was not as great asthat observed previously. Since some subjects weregiven heroin after only 1 week on the research ward,compared with a 2-week drug-free period in the earlierstudies, some may have been partially tolerant to the

FIGURE 2Effects of Heroin (10 mg i.v.) Versus Isotonic Saline on Plasma Levelsof LH and Testosterone (22)�

FIGURE 3Effects of Heroin (10 mg i.v.) Versus Isotonic Saline on Plasma Levelsof LH and Testosterone on Day 1 1 (Before Heroin Phase) (22)�

� Naltrexone plus saline (N =4)

LI Placebo plus salIne (N =4)

� 100],

IE�rrI�iFE�4 ‘�0-2 2-4 4-6 6-8 8-10

� Naltrexone plus saline (N =3)

LIIPlacebo plus saline (N =4)

aln the unblocked heroin condition, accurate data were obtained in 6 of the

8 subjects; all injections were given at 2:00 p.m.

HOURS BEFORE OR AFTER INJECTION

912 OPIATE USE AND SEXUAL FUNCTION Am J Psychiatry /37:8, August 1980

naltrexone-treated subjects. This finding can best be

w 1400z

� 1200-1�(I) I0 I�- I� ��-o I<0 I��- IQ- Iz 600-�< IuJ I

� I4 ‘�l’ 0-2 2-4 4-6 6-8 8-10

effects of heroin on LH. The maximum decline inplasma testosterone occurred 6-8 hours after heroininjection (bottom panel figure 2). As in experiment 2,some recovery in LH secretion was noted 6 hours afterheroin injection and was followed shortly by a rise inplasma testosterone.

As illustrated in figure 3 measurement of plasma LHin subjects on naltrexone or placebo also replicated

our earlier finding-the naltrexone-treated subjectshad consistently higher levels of LH, but their plasmatestosterone levels were no different from the placebo-treated group. After 10 days of unblocked heroin use,there was some indication that tolerance developed tothe drug’s acute suppressant effect on LH and testos-terone, but the timing ofdrug administration and bloodsampling in this study did not allow for accurate as-sessment of this question. Investigation of tolerancedevelopment would require that the hormonal re-sponse to a single dose of heroin be measured on sev-eral consecutive days during a sustained period offixed-dose, fixed-interval drug administration.

DISCUSSION

Opiate Effects on Sexual Functioning

There is ample clinical evidence that sexual driveand performance are diminished in male opiate addicts(6-11). Only recently, however, has a link been forgedbetween these clinical observations and opiate-in-duced changes in the hypothalamic-pituitary-gonadal

aAccu�te data on plasma testosterone levels were obtained in 3 of the 4

naltrexone-treated subjects; all injections were given at 2:00 p.m.

axis. Recent animal studies (24-26) and our data in

man (2 1 , 22) suggest that a prominent neuroendocrine

effect ofopiate administration is suppression of plasmaLH secretion followed by a secondary decline in tes-tosterone production. If the primary effect of heroinwere on testosterone biosynthesis or metabolism, wewould have expected a more rapid fall in plasma tes-tosterone followed by an increase in plasma LH. Thisis the normal response to a fall in plasma testosterone

and results from disinhibition of the tonic control ex-erted by testosterone on the release of luteinizing hor-mone releasing factor (LRF) from the hypothalamus.LRF is released in episodic bursts and, in turn, con-trols LH secretion from the pituitary (27-29). Thatacute heroin administration appears to completely in-hibit episodic LH secretory pulses suggests a centraleffect on the release of hypothalamic LRF. In labora-tory animals the regulation of LH (via LRF secretion)has been localized to ventral and medial areas of thehypothalamus (30), a region that also possesses nu-merous opiate receptor binding sites and a high con-centration of endogenous opiate peptides (31).

In our studies pretreatment with a narcotic antago-nist (naltrexone) not only blocked heroin-mediatedsuppression of LH release but actually increased thefrequency of LH secretory bursts from the pituitary.As a result mean plasma LH levels were elevated in

Am J Psychiatry 137:8, August /980 MIRIN, MEYER, MENDELSON, ET AL 913

explained in light of our advancing knowledge about

the role of endogenous opioids (i.e., endorphins) andopiate receptors in the regulation of hormonal output.The endogenous opioids may play an inhibitory role inthe normal regulation of LH secretion (32), and thisinhibitory effect may be blocked by administration of anarcotic antagonist. One could also explain naltrex-one’s stimulation of LH release as a hormonal con-comitant of precipitated abstinence; however, a recentdouble-blind study by Ellingboe and associates (33) re-vealed that naltrexone given to nonaddicts increasedmean plasma LH levels by 50% over baseline, whichagain suggests the involvement of a hypothalamic-pi-tuitary mechanism.

Finally, our studies indicated little effect of eitherheroin or naltrexone on plasma FSH secretion. Ciceroand associates (24, 25) found the same dichotomousresponse to opiates in the rat. Their data suggest thatthose areas of the hypothalamus which influence thesynthesis and release of pituitary LH may be more

sensitive to the effects of opiates than those which me-

diate FSH levels. Although one study has demon-strated anatomic separation of the centers that controlLH and FSH release in animals (34), there is no clearevidence of such a separation in man. Indeed, thedecapeptide (LRF) that regulates pituitary release ofLH probably plays a role in FSH release as well, al-though the pituitary response is usually of lower mag-nitude.

Correlation ofEndocrine Changes with Mood States

Addicts often cite the acute euphorigenic and ten-sion-relieving effects of opioids as important factors inthe decision to initiate and maintain drug use. At thesame time, laboratory studies of opiate use in manhave consistently demonstrated that chronic adminis-tration of these substances is associated with the de-velopment of increased psychopathology and dysphor-ic mood states (35-38). Recently we have attempted to

relate such events to changes in brain catecholaminelevels (39), but the observed clinical phenomena arethe result of many factors, including expectancy andthe setting in which the data are gathered.

At present there are also sufficient data to explainthe brief (30-60 seconds) but intensely pleasurable

rush that immediately follows intravenous heroin ad-

ministration. The mechanism most likely involvesmassive release of catecholamines at both central andperipheral sites. The rush is followed by a less intense,but more sustained, period of relaxation and tensionrelief lasting 2-4 hours. The strength and duration ofthis effect are influenced by the dose administered, thelevel of plasma morphine achieved (heroin [diacetyl-morphine] is almost immediately converted to mor-phine by the liver), the rate of elimination of the drug,the degree of tolerance developed, and the conditionedand unconditioned stimulus properties of the environ-ment (39-40). The time course of this effect closely

parallels, and may be related to, the acute effects ofheroin on neuroendocrine function-specifically, theacute suppression of LH release followed by a second-ary fall in plasma testosterone. Indeed, heroin actsmuch like the antiandrogen compound cyproteroneacetate, which suppresses the release of pituitary go-nadotropins (especially LH), lowers testosterone 1ev-els, and reduces both sexual drive and performance(41). In low doses acute administration of cyproteroneacetate alters the computerized electroencephalogramin a fashion similar to that of the tricyclic antidepres-sants; larger doses produce a profile much like the ben-zodiazepine anxiolytics (42). On the other hand, aswith heroin, chronic administration of cyproteroneacetate has been reported to produce apathy, restless-ness, and depression (41). The similarity of these datato our observations in heroin users is striking. In con-trast, acute administration of naltrexone raises LHlevels in detoxified opiate addicts (21) and normal vol-unteers (33), while producing a dysphoric mood stateand increased sexual drive (43).

Although no direct link has been demonstrated be-tween sex hormone changes and temporally related al-terations in mood, our data on the acute effects of her-oin suggest a drive reduction model of opiate rein-forcement, in which the drug acts as an antianxietyagent and reduces sexual drive and tension. Whetherthis effect is a direct consequence of acute suppression

of LH and testosterone or is mediated through thesame hypothalamic mechanisms that control LH re-lease (i.e., alterations in catecholamine systems) is un-clear. It is also possible that changes in other hormonesystems (e.g. , the hypothalamic-pituitary-adrenal axis)may also play a role.

With repeated heroin use, tolerance develops to thedrug’s acute positive effects on mood (38) and subjectsmanifest increasing apathy, irritability, depression,and social withdrawal (38, 40). This may be related tothe development of tolerance to its acute suppressanteffect on LH and testosterone or to alterations in thecatecholamine systems that control mood and hor-monal output. Nonetheless, chronic heroin users andpatients on high doses of methadone still have low cir-culating levels of testosterone, a condition common toother groups who manifest high levels of anxiety anddepression, such as soldiers under stress (44, 45), in-toxicated alcoholics (46), and monkeys who have re-cently lost status (47). Although there are data whichsuggest that testosterone may exert a mood-elevatingeffect in man (48, 49), Sachar and associates (50) foundno correlation between testosterone levels and mood.

The relationship between the subjective effects ofopiate use and the neuroendocrine events that accom-pany these phenomena is still unclear. We do not yetunderstand the role of endorphins in the regulation ofsex hormone secretion, the mediation of drive states,and the regulation of mood. We hope that future re-search will help to clarify these issues.

914 OPIATE USE AND SEXUAL FUNCTION Am J Psychiatry 137:8, August 1980

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