Br J Sp Med 1992; 26(2)

Opiate receptor blockade by naltrexone and moodstate after acute physical activityM. Daniel MSc, A. D. Martin PhD* and J. Carter BScSchool of Kinesiology, Simon Fraser University, Burnaby, British Columbia and *School of Physical Educationand Recreation, University of British Columbia, Vancouver, British Columbia, Canada

Acute mood changes occur with various forms of physicalactivity. Increased levels of endogenous opioids (endor-phins) in response to exercise may mediate activity-induced shifts in mood state. Thirteen female and six maleaerobics class participants aged 20-46 years received theopiate receptor antagonist naltrexone and a placebo inrandomized, double-blind crossover fashion on twoseparate occasions at the same 75-min high-intensityaerobics class. Mood states were assessed before and aftereach class, which were spaced 5 days apart, using theProfile of Mood States questionnaire (POMS), a moodadjective checklist, and a Visual Analogue Scale (VAS)which measured mood in relation to several emotionalextremes. Mood changes over the course of each aerobicsclass were compared in the naltrexone and placebo groups.For men and women, significant differences betweenconditions were observed in overall mood by both thePOMS (P < 0.005) and VAS (P < 0.02). There weresignificant differences between conditions for mostsubscales of each mood instrument (P < 0.05); with theplacebo, mood states became calmer, more relaxed andpleasant, tending away from depression, anger andconfusion. Positive mood shifts did not occur whensubjects were preloaded with naltrexone, suggesting thatactivity-generated mood changes are mediated throughendorphinergic mechanisms.

Keywords: Endorphin, mood, aerobics, exercise

A number of studies have demonstrated alteredendorphin immunoreactivity and increased plasmaconcentrations of endorphin and lipotropic hormonesin response to physical activity. Acute responses ofendogenous opioids have been reported followingrunning events' 2, graded exercise tests3' , bicycleergometer tests5'6 and swimming7, typically resultingin a two-five-fold increase in endorphin levels.Observations such as these suggest that the phe-nomenon of the 'runner's high', an acute positiveshift in mood state, might be related to changes inendorphin levels with physical activity. Such ahypothesis is supported by the observations thatindividuals who exercise regularly do so to relieve

Address for correspondence: Dr Alan Martin, School of PhysicalEducation and Recreation, University of British Columbia, 6081University Boulevard, Vancouver, B.C., Canada V6T lZ1

© 1992 Butterworth-Heinemann Ltd0306-3674/92/020111-05

negative feelings of discomfort, irritability, frustra-tion and nervousness8, and that increases in endor-phin-like immunoreactivity after running correlatewith the shift to a feeling of pleasantness9. Thephenomenon of the 'runner's high' might, therefore,be more appropriately termed the 'runner's calm',since these changes in mood more closely resemblean opioid state characterized by 'calm' than aeuphoric 'high', but whether mood is influenced at allby endorphin response to exercise has not beenestablished.Using opiate receptor antagonists to block any

endorphin effect, and various psychological instru-ments to assess mood state, several studies havefailed to observe differences in mood betweenblocked and unblocked conditions following physicalactivitylO-14. Some studies have demonstrated thatcertain subscales of mood were more positive afterexercise when opiate receptors were not blocked, buthave failed to demonstrate a significant difference inoverall mood15 16. Only Allen and Coen'7 haveimplicated endogenous opiates as exercise-inducedmodulators of mood: administration of the opiatereceptor antagonist naloxone resulted in no change inmood following treadmill running, but positive shiftsin mood were observed overall and for each subscaleof mood when a placebo was administered.Weak relationships and discrepancies between

these studies could be a result of difficulties inquantifying subtle psychological changes; most avail-able mood instruments are best suited for assessmentof pathological conditions with large variation inscores. But results are also heavily influenced bydifferences in the selection and characteristics ofsubjects for study, the nature, amount and intensityof the exercise, and the manner in which investiga-tors attempt to block opiate receptors. For example,whereas investigators reporting no differences inmood state between blocked and unblocked opiatereceptor conditions have typically used low dosagesof a receptor antagonist, Allen and Coen17 used highdosages of naloxone administered intravenously firstas a bolus and then by continuous drip throughoutthe exercise periods. That they observed significantdifferences between conditions might also be attribut-able to the fact that their subjects exercised at 75% ofmaximal oxygen consumption (Vo2max); a criticalintensity of 70% VO2max has been reported byGoldfarb et al.6 as necessary to elevate 13-endorphin

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levels, and few studies have observed an effect at lessthan this.

Inconsistencies regarding a link between an endor-phin response to exercise and positive post-exercisemood shifts indicate the need for further investiga-tion. Furthermore, all studies to date have comprom-ised external validity in an effort to maintain internalvalidity; results of these studies cannot be general-ized since all were conducted within tightly control-led environments. As McMurray et al.3 have recentlydemonstrated, this is important when measuringendorphin changes related to exercise. However, ifopiate receptor activity due to exercise-inducedendorphin production can be controlled by adminis-tration of an opiate receptor antagonist, then exercisein its usual form and environment appears a morevalid and reliable means than standardized testingunder controlled laboratory conditions by which toobserve any related mood shift. Toward this end, wereport here the results of a cross-sectional study inwhich men and women participating in an aerobicsclass were administered an opiate receptor antagonistand a placebo in randomized, double-blind crossoverfashion on two separate occasions, with mood statesassessed before and after each class.

Subjects and methodsSubjectsMen and women from a high-intensity, high-impactaerobics class at a municipal recreation facility tookpart in the study; all were regular participants(attending 3-4 times per week) and had been so for atleast 6 months. Potential participants were informedof the nature and extent of any involvement, butwere not told the experimental hypotheses. Of 28volunteers, 25 completed a screening questionnaireafter which six were excluded due to: (a) history of orcurrent use of opioid medications; (b) use ofprescription or non-prescription drugs within 1month of participation in the study; (c) history of anyendocrine abnormality; (d) poor general health; and(e) in the case of the women, menstrual cycles lessthan 21 or greater than 36 days. The final sample sizewas thus 19 (13 women and six men). All subjectsprovided their informed written consent, and theresearch protocol was approved by the Simon FraserUniversity Ethics Committee for the Protection ofHuman Subjects.

MaterialsThe opiate receptor antagonist naltrexone, 18 (DuPont, Wilmington, Delaware, USA) was adminis-tered orally in 50mg tablet form on one occasion; aplacebo similar in appearance, taste and texture wasadministered on another. Like naloxone, a morecommonly used opiate receptor blocker, naltrexone ishighly effective but, unlike naloxone, does notrequire subcutaneous or intravenous administration,a protocol unsuitable for this investigation.Two mood state instruments were used as psycho-

logical tools to assess mood state before and after an

aerobics class on each of two separate occasions: theProfile of Mood States (POMS)19, and a VisualAnalogue Scale (VAS)20. The POMS is a 65-itemmood adjective checklist in which each adjective isscored from 0 (absent) to 4 (very much). Followingstandard scoring methods, six mood scales arederived: tension-anxiety, depression-dejection, con-fusion-bewilderment, vigour-activity, anger-hostil-ity and fatigue-inertia. Subjects were generally ableto complete the POMS within 10 min. The POMS hasbeen used in previous studies concerning exercise,endogenous opiates and mood changes0' 12' 17. TheVAS was adapted from that used by Allen andCoen17, based on the scale developed by Janal et a115.Subjects made a vertical slash mark on a horizontalline between two extremes of mood for each of sixscales arranged in random order: depressed-euphor-ic, regretful-joyful, pleasant-miserable, very un-calm-very calm, relaxed-uptight and disturbed-atpeace. The intersection of the vertical slash mark withthe horizontal line between the two extremes ofmood was measured with a ruler (yielding con-tinuous data); the positive mood end was alwaystaken as the zero position. The VAS generallyrequired about 5 min to complete.

DesignNaltrexone or the placebo was administered in adouble-blind crossover fashion on two separateoccasions at the same high-intensity, high-impactaerobics class. The same instructor conducted eachclass. Components of each 75-min class were asfollows: 7-min warm-up, 31-min cardiovascular ses-sion, 4-min cooldown, 28-min muscular strength andendurance session and 5-min stretch and flexibilitysession, all set to music. Subjects did not exercise atall for 5 days before the first aerobics class, nor didthey exercise in the 5 days between the first andsecond classes. On each occasion, subjects arrived atthe gym at least 45min before the aerobics classbegan. They ingested orally either naltrexone or theplacebo with some water and immediately completedpre-class POMS and VAS questionnaires. Subjectsthen participated in the aerobics class and completedpost-class POMS and VAS questionnaires (identicalto pre-class forms) as soon as the class concluded.Study design included a crossover, such that eachsubject received naltrexone for one class and theplacebo for the other; administration of naltrexone orplacebo was double-blind and randomized. For thewomen, timing of the menstrual cycle was notstandardized with timing of the interventions.

Statistical analysisData analysis consisted of descriptive and inferentialstatistics; differences in mood disturbances wereassessed by paired t-tests (two tailed), since both thePOMS and VAS scales yielded continuous data.Statistical significance was set at the 0.05 level ofprobability. The total mood disturbance POMS andthe global VAS were calculated for each instrumentby subtracting the sum of all post-class results from

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the sum of all pre-class results. For the total mooddisturbance POMS value, the vigour scale wasnegatively weighted since it pertains to an effectivelypositive mood that is opposite in nature to thenegative emotional experiences assayed by the otherfive scales. StatView SE+ Graphics (Abacus Con-cepts, Berkeley, California, USA) software was usedfor statistical analysis of the data on a MacintoshSE/30 microcomputer (Apple Computer, Cupertino,California, USA).

ResultsThe mean(s.d.) age of all participants was 31.1(7.4)years (range 20-46 years). There was no significantdifference in age between the men (32.2(6.4) years)and the women (30.6(7.8) years). All subjects werewithin the college norms for the POMS19 and tendedtoward the lower or 'emotionally stable' end of thescale; no norms were available for the VAS. Thoughwomen demonstrated slightly greater variability thanmen, pre-class mood state values between thenaltrexone and placebo classes were not significantlydifferent for either the women or the men (P > 0.46);mood states were similar for each sex at the start ofeach class.For men and women separately, there were

significant differences in the magnitude of mood stateshifts after the aerobics class as assessed by the pre-minus post-class POMS results (Table 1) and the VASresults (Table 2) between the naltrexone and placeboconditions. By scale, the POMS results for menshowed significant differences in depression (P <0.05), anger (P = 0.05), fatigue (P < 0.05) andconfusion (P < 0.005) between the naltrexone andplacebo conditions; decreases in these negative mood

Table 1. Probability values for differences in mood before andafter exercise between the naltrexone and placebo groups in anaerobics class using the POMS questionnaire

Mood source Men (n = 6) Women (n = 13)

Tension-anxiety 0.056 0.013Depression-dejection 0.046 0.001Anger-hostility 0.050 0.001Vigour-activity 0.061 0.329Fatigue-inertia 0.038 0.169Confusion-bewilderment 0.003 0.003Total mood disturbance 0.002 0.001

Table 2. Probability values for differences in mood before andafter exercise between the naltrexone and placebo groups in anaerobics class using the VAS questionnaire

Mood source Men (n = 6) Women (n = 13)

Depression-euphoria 0.198 0.011Regretful-joyful 0.125 0.394Miserable-pleasant 0.024 0.048Uncalm-calm 0.003 0.012Uptight-relaxed 0.020 0.057Disturbed-at peace 0.019 0.102Global mood change 0.015 0.017

states occurred with the placebo, but not naltrexone.Changes in tension and vigour were of borderlinesignificance (P = 0.056 and P = 0.061, respectively).The total mood disturbance POMS for men indicatedan overall positive mood shift following the placeboclass relative to the naltrexone class (P < 0.005). Forwomen, there were significant differences in tension(P < 0.02), depression (P < 0.002), anger (P < 0.002)and confusion (P < 0.005) between the naltrexoneand placebo conditions, but there were no significantdifferences in vigour and fatigue. As with men,decreases in negative mood states occurred with theplacebo but not with naltrexone, and the total mooddisturbance POMS showed a positive mood shiftoverall (P < 0.002).

Results obtained using the VAS were in agreementwith results obtained using the POMS. By scale, theVAS results for men indicated significant differencesin responses between the extremes of miserable-pleasant (P < 0.05), very uncalm-very calm (P <0.005), uptight-relaxed (P = 0.02) and disturbed-atpeace (P < 0.02), but there were no significantchanges in depression-euphoria and regretful-joy-ful. Overall, the global mood VAS indicated asignificant positive mood shift for men upon comple-tion of the placebo class relative to the naltrexoneclass (P < 0.02). Women were characterized bysignificantly different responses between the ex-tremes of depression-euphoria (P < 0.02), miser-able-pleasant (P < 0.05) and uncalm-very calm (P <0.02), but there were no significant changes inresponses between the extremes of regretful-joyful,uptight-relaxed and disturbed-at peace. The globalmood VAS indicated a significant positive mood shiftoverall upon completion of the placebo class relativeto the naltrexone class in women (P < 0.02).There were significant positive Pearson product-

moment correlations between the total mood disturb-ance POMS and the global VAS in both the placebo(r = 0.82, P = 0.0001) and naltrexone (r = 0.54,P < 0.02) conditions.

DiscussionThe data demonstrate clearly that exercise in ahigh-intensity aerobics class for 75min was followedby significant changes in mood in both men andwomen; mood states became calmer, more peaceful,more relaxed and pleasant, tending away fromtension, depression, anger, fatigue and confusion.This overall positive mood change did not occurwhen subjects were preloaded with a 50-mg dose ofnaltrexone, an opiate receptor blocker, suggestingthat activity-generated mood changes are mediatedthrough endorphinergic mechanisms.Our observations are in agreement with those of

Allen and Coen17, who noted similar responses inmale runners within a controlled laboratory environ-ment. Taken together, these studies are strongevidence for exercise-induced endorphin-mediatedmood changes in humans, especially since theydemonstrate external and internal validity, respec-tively. That Allen and Coen"7 used intravenousnaloxone whereas we used oral naltrexone as ameans of blocking opiate receptors suggests both

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naloxone and naltrexone have similar effects uponthe opiate receptors subserving mood state, but thesespecific receptors remain to be defined. Farrell et al. 13,using naltrexone, failed to implicate an endorphinlink between exercise and mood, as have similarinvestigations using naloxonel0-l4.That the present investigation observed significant

results whereas most others have not, might beattributable to the environment within which subjectswere observed; we did not require participants toexercise under unfamiliar conditions in a clinicallaboratory situation where associated stress may haveinfluenced answers to questions regarding moodstate. For example, because psychological stressinvokes significant increases in plasma levels of3-endorphin and other hormones released in associ-

ation with adrenocorticotropin21,22, a foreign en-vironment and unfamiliar activity may profoundlyinfluence the validity and reliability of mood stateresponses and measurements of endorphin levels. Inthis manner, baseline levels of endorphin and moodmay be distorted such that no difference is observedbetween the pre- and post-exercise conditions.The uniqueness of observing participants in an

aerobics class deserves comment. We are not awareof any investigations of exercise-induced mood shiftsinvolving aerobics classes. Exercise intensity in thepresent study can only be speculated on but, thoughsubjective, it is worth stating that the 75-min aerobicsclass was worthy of its 'high-intensity' rating,presenting a unique challenge unmatched by mostother classes. It is a reasonable assumption that thesubjects were working at a relatively high percentageof their VO2maX at least for most of the 31-mincardiovascular portion of the class, but no claim canbe made as to how this approximated the criticalintensity of 70% Vo2max reported by Goldfarb et al.6as necessary to increase levels of 3-endorphin. Theadditional stipulation by Goldfarb et al.6 of a 15-minminimum duration of exercise was exceeded bysubjects in the present study in both the cardiovascu-lar and muscular endurance portions of the aerobicsclass, and it is also possible that lactate productionduring the muscular endurance portion of the classmight have contributed to endorphin response, sincelactate and f3-endorphin levels are positively corre-lated23.Although we observed similar shifts in mood with

both the POMS and VAS, we feel that results of thePOMS should be weighted more heavily than thoseof the VAS, even given our observations of significantcorrelations between the total mood disturbancePOMS and global VAS in both the naltrexone andplacebo conditions. Also, while the VAS appeared toassess mood changes rather well in relation to thePOMS in the placebo condition (r = 0.82), the lowercorrelation coefficient of the VAS with the POMS inthe naltrexone condition (r = 0.54) suggests somedegree of inadequacy in the ability of the VAS tomeasure negative mood state with the refinement ofthe POMS. The POMS is a validated psychologicaltool, the VAS is not. As a 65-item mood adjectivechecklist from which six basic mood scales arederived, the POMS ensures considerable difficulty inbiasing responses, but even when mood extremes are

arranged in random order on the VAS it is stillpossible to demonstrate a bias.However, this is not to say that the POMS is

without problems. The measure of vigour did notshow a significant shift in either men or women inthis study, and female values for change in fatiguewere not significant. It may be that psychological andphysical responses to questions concerning vigourand fatigue were confused: a subject may physicallyperceive fatigue and a lack of vigour, even whenpsychologically feeling refreshed and vigorous.Irrespective of the perceived validity of these moodsubscales, the total mood disturbance POMS, whichis the best indicator of mood shift between theplacebo and naltrexone conditions, still indicatedhighly significant differences. Another problem withthe POMS is that the vigour scale pertains to aneffectively positive mood that is opposite in nature tothe negative emotional experiences assayed by theother five scales; we resolved this by giving thevigour scale a negative weight in calculating the totalmood disturbance POMS value. Thus, for all fivescales, a downward or lower score indicated apositive mood shift.

In conclusion, the present investigation of bothmen and women found significant differences inmood state following a high-intensity aerobics classbetween conditions in which naltrexone, an opiatereceptor antagonist, and a placebo were adminis-tered. Post-class mood was characterized by a calm,unstressed frame of mind when subjects received theplacebo, but these positive mood shifts did not occurwith administration of naltrexone. The results impli-cate endogenous opioids as mediators of activity-generated mood changes.

AcknowledgementsAppreciation is expressed to Dr John Dickinson, Director, Schoolof Kinesiology, Simon Fraser University for providing facilities forthe study. The authors acknowledge Murray Allen MD, School ofKinesiology, Faculty of Applied Sciences, Simon Fraser Universityfor assistance, particularly with drug administration; we also thankDesmond Coen PhD, Department of Psychology, Faculty of Arts,Simon Fraser University for advice regarding the measurement ofmood states. We are grateful for the cooperation of the NorthVancouver Recreation Commission in allowing use of its facilitiesand to Ms Donna Stewart for typing the manuscript.

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