effects on humans of delta-9-thc administered by smoking

7/29/2019 Effects on Humans of Delta-9-THC Administered by Smoking

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Effects on Humans of $\Delta ^{9}$-Tetrahydrocannabinol Administered by SmokingAuthor(s): Marc Galanter, Richard J. Wyatt, Louis Lemberger, Herbert Weingartner, Tom B.Vaughan and Walton T. RothSource: Science, New Series, Vol. 176, No. 4037 (May 26, 1972), pp. 934-936Published by: American Association for the Advancement of ScienceStable URL: http://www.jstor.org/stable/1733811 .

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ceptor in the "resting" inaetive eon-figuration. The partial agonist-antago-nist [Gly2]LRF might have affinity forboth states, leaidingat maximum levelsto a distributionof the two states de-termined bly its relative binding affinityfor the two forms. Of eourse, otherhypotheses whiieheould explain our re-sulits based on an indueed fit model[see Koshland and Neet (11)] are alsoplausible.We ihave- reviouslydeserilbeda hy-potlhalamie eleasing faetor analog thatprobably eompetes (with a releasingfaetor) for binding to atbiologieal re-ceptor site: the dipeptidepGlu-His-OMeapparently funletions as a competitiveinhibitor of the plasma enzyme thatinactivates pGlu-His-Pro-NHS (TRF)( 12 ) . Competitive anitagonistsof theaetion of other peptide hormones,vasopressin 13 ), angiotensin 14), andglueagon ( 15) have bfieenreported.Also, another des-histidtine eptide, des-His1-gluvagon, s a competitiveantago-nist of glueagon (15).These two LRF analogs are the firstpeptides reported to be eo!mpetitiveantagonistsof the biologieal aetivity ofLRF. The physiological and potentialclinieal signifieanee of tIheseLRF an-tagonislts s not yet known.WYLIIEALE,GEOFFREYRANTJEANRIVIER,MICHAELONAHANMAX AMOSS,RICHARDLACKWELLROGER URGUS, OGERGUILLEMINSalk Institute} La JollatCalifornia 90237

ceptor in the "resting" inaetive eon-figuration. The partial agonist-antago-nist [Gly2]LRF might have affinity forboth states, leaidingat maximum levelsto a distributionof the two states de-termined bly its relative binding affinityfor the two forms. Of eourse, otherhypotheses whiieheould explain our re-sulits based on an indueed fit model[see Koshland and Neet (11)] are alsoplausible.We ihave- reviouslydeserilbeda hy-potlhalamie eleasing faetor analog thatprobably eompetes (with a releasingfaetor) for binding to atbiologieal re-ceptor site: the dipeptidepGlu-His-OMeapparently funletions as a competitiveinhibitor of the plasma enzyme thatinactivates pGlu-His-Pro-NHS (TRF)( 12 ) . Competitive anitagonistsof theaetion of other peptide hormones,vasopressin 13 ), angiotensin 14), andglueagon ( 15) have bfieenreported.Also, another des-histidtine eptide, des-His1-gluvagon, s a competitiveantago-nist of glueagon (15).These two LRF analogs are the firstpeptides reported to be eo!mpetitiveantagonistsof the biologieal aetivity ofLRF. The physiological and potentialclinieal signifieanee of tIheseLRF an-tagonislts s not yet known.WYLIIEALE,GEOFFREYRANTJEANRIVIER,MICHAELONAHANMAX AMOSS,RICHARDLACKWELLROGER URGUS, OGERGUILLEMINSalk Institute} La JollatCalifornia 90237

References and Notes1. H. Matsuo, Y. Baba, R. M. G. Nair, A.Arimura, A. V. Schally, Biochem. Biophys.Res. Commun. 43, 1344 (1971); Y. Baba,H. Matsuo, A. V. Schally, ibid. 44, 459 (1971).2. R. Burgus, M. Butcher, N. Ling, M.Monahan, J. Rivier, R Fellows, M. Amoss,R. Blackwell, W. Vale, R. Guillemin, C. R.Acad. Sci Paris 273, 1611 (1971); R. Burgus,M. Butcher, M. Amoss, N. Ling, MtMonahan, J. Rivier, R Fellows, R. Blackwell,W. Vale, R. Guillemin, Proc. Nat. Acad.

Sci. U.S. 69, 278 (1972).3. The abbreviations and notations for aminoacid residues are as follows: pGlu, pyroglu-tamic acid; His, histidine; Trp, trYPtophan;Ser, serine; Tyr, tyrosine; Gly, glycine; Leu,leucine; Arg, arginine; Pro, proline; thenumbering begins at the residue furthestfrom the NH ) group. [Gly2] means thatglycine has been substituted at position 2;des-His2 means that His has been deleted atposition 2.4. W. Vale, G. Grant, M. Amoss, R. BlackwellR. Guillemin, Endocrinology, in press.5. The rat LH was LER 1240 and was prozvided by Dr. Leo Reichert; rat LH standardwas NIAMD-RP1; the rabbit antibody toovine LH was prepared by Dr. D. Gos-podarowicz.6. M. Monahan, J. Rivier, R. Burgus, MAmoss, R. Blackwell, W. Vale, R. Guillemin,C. R. Acud. Sci. Paris 273, S08 (1971).7. M. Monahan, J. Rivier, W. Vale, R. Guille-min, R. Burgus, Biocheel. Biophys. Res.Commun., in press.8. E. J. Ariens, Arch. Int. Pharmacodyn. Ther.99, 32 (19S4).9. G. Grant, W. Vale, J. Rivier, R. Guillemin,in preparation.10. J. P. Changeux and T. R. Podleski, Proc.Nat. Acad. Sci. U.S. S9, 944 (1968).11. D. E. Koshland and K. E. Neet, Annu.Rev. Biochenl . 37, 359 ( 1968).12. W. Vale, R. Burgus, T. F. Dunn, R. Guille-min, Hormones 2, 193 (1971).13. W. Y. Chan, V. J. Hruby, G. Flouret, V- du Vigneaud, Science 161, 280 (1968).14. G. R. Marshall, W. Vine, P. Needleman,Proc. Nat. Acad. Sci. U.S. 67, 1624 (1970).15. M. Rodbell, L. Birnbaumer, S. Pohl, F. Sunby,ibid. 68, 909 (1971).16. We thank Dr. J. Patrick for suggestions re-garding the preparation of this manuscriptand Mrs. A. Nussey for technical assistance.Supported by AID contract AID/csd 2785,Ford Foundation, and Rockefeller Foundation.

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References and Notes1. H. Matsuo, Y. Baba, R. M. G. Nair, A.Arimura, A. V. Schally, Biochem. Biophys.Res. Commun. 43, 1344 (1971); Y. Baba,H. Matsuo, A. V. Schally, ibid. 44, 459 (1971).2. R. Burgus, M. Butcher, N. Ling, M.Monahan, J. Rivier, R Fellows, M. Amoss,R. Blackwell, W. Vale, R. Guillemin, C. R.Acad. Sci Paris 273, 1611 (1971); R. Burgus,M. Butcher, M. Amoss, N. Ling, MtMonahan, J. Rivier, R Fellows, R. Blackwell,W. Vale, R. Guillemin, Proc. Nat. Acad.

Sci. U.S. 69, 278 (1972).3. The abbreviations and notations for aminoacid residues are as follows: pGlu, pyroglu-tamic acid; His, histidine; Trp, trYPtophan;Ser, serine; Tyr, tyrosine; Gly, glycine; Leu,leucine; Arg, arginine; Pro, proline; thenumbering begins at the residue furthestfrom the NH ) group. [Gly2] means thatglycine has been substituted at position 2;des-His2 means that His has been deleted atposition 2.4. W. Vale, G. Grant, M. Amoss, R. BlackwellR. Guillemin, Endocrinology, in press.5. The rat LH was LER 1240 and was prozvided by Dr. Leo Reichert; rat LH standardwas NIAMD-RP1; the rabbit antibody toovine LH was prepared by Dr. D. Gos-podarowicz.6. M. Monahan, J. Rivier, R. Burgus, MAmoss, R. Blackwell, W. Vale, R. Guillemin,C. R. Acud. Sci. Paris 273, S08 (1971).7. M. Monahan, J. Rivier, W. Vale, R. Guille-min, R. Burgus, Biocheel. Biophys. Res.Commun., in press.8. E. J. Ariens, Arch. Int. Pharmacodyn. Ther.99, 32 (19S4).9. G. Grant, W. Vale, J. Rivier, R. Guillemin,in preparation.10. J. P. Changeux and T. R. Podleski, Proc.Nat. Acad. Sci. U.S. S9, 944 (1968).11. D. E. Koshland and K. E. Neet, Annu.Rev. Biochenl . 37, 359 ( 1968).12. W. Vale, R. Burgus, T. F. Dunn, R. Guille-min, Hormones 2, 193 (1971).13. W. Y. Chan, V. J. Hruby, G. Flouret, V- du Vigneaud, Science 161, 280 (1968).14. G. R. Marshall, W. Vine, P. Needleman,Proc. Nat. Acad. Sci. U.S. 67, 1624 (1970).15. M. Rodbell, L. Birnbaumer, S. Pohl, F. Sunby,ibid. 68, 909 (1971).16. We thank Dr. J. Patrick for suggestions re-garding the preparation of this manuscriptand Mrs. A. Nussey for technical assistance.Supported by AID contract AID/csd 2785,Ford Foundation, and Rockefeller Foundation.

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because of its lack of intrinsic activity.The affinity of the two analogs forthe receptolr re less than that of LRF,as is evidenced bsy the Ihigh ( 103)mola!r ra;tios (antagolnist/LRF) re-qu,ireld or bhe inhibition of LRF. B-e-cause the affinlityolf de.s-His2-LRF orthe LRF recept,or s the same'or higherthan that of [G-ly2]LRF,we can pro-pose that either the preseznceof tthei,midazole ing or a.n amino acid iln ItheL configuration n LRF is importantbutnot olbligatory or the binding of LRFto its receptolr.The competitiveantagonism to LRFby the two analogs, and the lack ofLH releasing activity olf des-His2-LRFat a concentraltion enfold hig,her thta.nthat required to suppressthe responseto LRF indica,te a diissociation of ffiebinding and secretory processes. Thisassumption is supported by our oXbser-vat,ion (9) that des-His2-LRF co,m-petes with [3H-Pro9]LRFIfor specifilcbinding to anterielrpitu,itaryLRF re-cepltors.Thus the histidyl residue in LRF issomehow required not only for therecognition of LRF by its receptor butfor the intr,insicactiv,ityof the mole-cule. Althouglh mportanlt,he imildazolering (or bhelpresenceof an amino acidin the L configuration) s not obligatoryfor LRF intrinsic astivity since sub-st.itution f ,glylcineor histidine n LRFyields a molelculewith al.mosit 0 per-cent of t;he LH releasing activity ofLRF. However, the peptide linkagein the 2-position seems to be a requisitefor the intrinsic actilrityof the LRF de-capeptide, since des-His2-LRFhas littleor no LH releasing ability. In the ab-sence of data on the conformation ofeither LRF or the stru turalanalogs dis-cussed here, we cannot confidently as-,certain whether the pharmacologibalpropertiesof the LRF analogs are a re-sult of alteration of functional groupsor are secondary to changes in the con-formation of the molecule.Several proposed hypotheses couldexplain the otbserved disso;ciation otfliganld-receptornlte,ractionsnld subse-quent biological responses (10, 11).Alccorlding o the model presented byChangeux and Podleslki (10) our re-sults could mean that the LRF receptorsite and ele,mentsmediating the secretory .p,rocess can exist in two fo,r,ms nequilibrium: a secretion-triggeringtate

because of its lack of intrinsic activity.The affinity of the two analogs forthe receptolr re less than that of LRF,as is evidenced bsy the Ihigh ( 103)mola!r ra;tios (antagolnist/LRF) re-qu,ireld or bhe inhibition of LRF. B-e-cause the affinlityolf de.s-His2-LRF orthe LRF recept,or s the same'or higherthan that of [G-ly2]LRF,we can pro-pose that either the preseznceof tthei,midazole ing or a.n amino acid iln ItheL configuration n LRF is importantbutnot olbligatory or the binding of LRFto its receptolr.The competitiveantagonism to LRFby the two analogs, and the lack ofLH releasing activity olf des-His2-LRFat a concentraltion enfold hig,her thta.nthat required to suppressthe responseto LRF indica,te a diissociation of ffiebinding and secretory processes. Thisassumption is supported by our oXbser-vat,ion (9) that des-His2-LRF co,m-petes with [3H-Pro9]LRFIfor specifilcbinding to anterielrpitu,itaryLRF re-cepltors.Thus the histidyl residue in LRF issomehow required not only for therecognition of LRF by its receptor butfor the intr,insicactiv,ityof the mole-cule. Althouglh mportanlt,he imildazolering (or bhelpresenceof an amino acidin the L configuration) s not obligatoryfor LRF intrinsic astivity since sub-st.itution f ,glylcineor histidine n LRFyields a molelculewith al.mosit 0 per-cent of t;he LH releasing activity ofLRF. However, the peptide linkagein the 2-position seems to be a requisitefor the intrinsic actilrityof the LRF de-capeptide, since des-His2-LRFhas littleor no LH releasing ability. In the ab-sence of data on the conformation ofeither LRF or the stru turalanalogs dis-cussed here, we cannot confidently as-,certain whether the pharmacologibalpropertiesof the LRF analogs are a re-sult of alteration of functional groupsor are secondary to changes in the con-formation of the molecule.Several proposed hypotheses couldexplain the otbserved disso;ciation otfliganld-receptornlte,ractionsnld subse-quent biological responses (10, 11).Alccorlding o the model presented byChangeux and Podleslki (10) our re-sults could mean that the LRF receptorsite and ele,mentsmediating the secretory .p,rocess can exist in two fo,r,ms nequilibrium: a secretion-triggeringtateand a resting state, with LRF haviingpreferential affinity for the "secretory"state. The anitagonism f des-His2-LRFwouId be a consequenceof interactionwith and stab,ilizationof bhe LRF re-

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and a resting state, with LRF haviingpreferential affinity for the "secretory"state. The anitagonism f des-His2-LRFwouId be a consequenceof interactionwith and stab,ilizationof bhe LRF re-934

Numerous studies have been carriedout to assess the effects of marijuana(1). In many of these studies,naturalmarijuana or its putative active com-ponent, A9-tetrahydrocannab,inol/\9-THC), was administeredby smoking.Correlations of the concentration ofA9THC in plasma with psychologicaland physiologic effects after adminis-tration by smoking were not, how-ever made.We report here on a comparisonbe-tweerl a 1O-mg dose of synthetic A9-

Numerous studies have been carriedout to assess the effects of marijuana(1). In many of these studies,naturalmarijuana or its putative active com-ponent, A9-tetrahydrocannab,inol/\9-THC), was administeredby smoking.Correlations of the concentration ofA9THC in plasma with psychologicaland physiologic effects after adminis-tration by smoking were not, how-ever made.We report here on a comparisonbe-tweerl a 1O-mg dose of synthetic A9-

THC and placebo marijuanamaterial,both administered to 12 subjects bysmoking. The subjective descriptionof effects was qualitativelysimilar butquantitatively different for the twostates. The magnitude of the syn-drome as described subje tively by in-dividuals reWeiving ive t'9THC cor-related very highly with their respec-tive ptllse increments.In order to assess the time course ofthese variables, we administered tothree of the subjects the same dose ofSCIENCE, VOL 176

THC and placebo marijuanamaterial,both administered to 12 subjects bysmoking. The subjective descriptionof effects was qualitativelysimilar butquantitatively different for the twostates. The magnitude of the syn-drome as described subje tively by in-dividuals reWeiving ive t'9THC cor-related very highly with their respec-tive ptllse increments.In order to assess the time course ofthese variables, we administered tothree of the subjects the same dose ofSCIENCE, VOL 176

Effects on Humans of A9-TetrahydrocannabinolAdministered by Smoking

Abstract. Twelve chronic marijuanausers received L\9-tetrahydrocannabinolysmoking. The magnitude of their pulse increment was highly correlated withtheir subjective experiences. Three of the 12 subjects subsequently receivedA9-tetrahydrocannabinolabeled with carbon-14;the time course of it* concentra-tion in piasma was highly correlated with the pulse increment. Subjectivesymp-tones, however, appeared ater and dis*ipatedmore slowly.

Effects on Humans of A9-TetrahydrocannabinolAdministered by Smoking

Abstract. Twelve chronic marijuanausers received L\9-tetrahydrocannabinolysmoking. The magnitude of their pulse increment was highly correlated withtheir subjective experiences. Three of the 12 subjects subsequently receivedA9-tetrahydrocannabinolabeled with carbon-14;the time course of it* concentra-tion in piasma was highly correlated with the pulse increment. Subjectivesymp-tones, however, appeared ater and dis*ipatedmore slowly.

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a9THC, a portion of which was in theform of [14C]i\9THC.These subjectswere then studied for 24 hours. Thetime courseof the pulse rate was highlycorrelatedwith the time course of theconcentrations of a9THC in plasma.Subjective symptoms, however, ap-peared later and dissipatedmore slow-ly. The setting of the studyproducedastrong effect on the subjectiveexperi-ence.The 12 male subjectsranged in agefrom 21 to 26 years. All had smokedmarijuanaat least 50 to 75 times;sevenhad smoked it at least 500 times, andhad taken lysergic acid diothylamide(LSD) on one or more occasions. Allwere free of significantpsychiatric ormedical illness.In the initial part of the experiment,each of the 12 subjects smoked a dif-ferent one of the following on each of3 days: (i) placebo marijuana ma-teriaI alone, (ii) placebo material in-jected with 10 mg of syntheticA9THC,or (iii) natural marijuanaassayed tocontain 10 mg of A9THC (2). Theorder of administrationwas balancedover the 12 subjects.All subjects were instructed nlot tosmoke marijuana or to drink alcoholfor -the24 hoursprecedingeach experi-mental day, and not to ingest any otherdrug for 48 hours precedingthat day.Urine samples were analyzedfor alka-loids, barbittlrates,and amphetamines.These assays were negative in the urinefor all subjectsTo assure a consistent pattern ofinhalation,only regularcigarette smok-ers were accepted as subjects.A stan-dard smoking technique was practicedand applied: The subjects inhaled fora period of 2 to 4 seconds, maintainedeach inhalation for 15 seconds, thenexhaled,andwaited for 5 seconds.Theyrepeatedthis procedureuntil the ciga-rettes were finished; the time elapsedwas 10 minutes. All data are reportedin terms of time elapsedfrom the onsetof smoking.The- following observations weremade during each session. Radialpulsewas measured 30 minutesbefore smok-ing; this figure was then subtractedfrom the pulse rate measured 25 min-utes after the onset of smoking to givethe pulse increment.Comparativesub-jective "high"was a single assessmentin whichsubjectsratedhow "high" heyfelt during the 90 minutes after theonset of smoking. A scale of O to 10was used in whichOmeant "not high atall" and 10 was the "highest" he sub-ject had ever felt smoking marijuana26 MAY 1972

.01) scores were 18.Ofor placebo and31.6 for i\9THC (P


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Table 1. Companson of residency time at roosts ( = minimum longevity) between alteredand unaltered individuals of H. erato (Mann-Whitney U test). The entries in the table denotethe number of days an individual butterfly was seen returning to the roosts under observation.Table 1. Companson of residency time at roosts ( = minimum longevity) between alteredand unaltered individuals of H. erato (Mann-Whitney U test). The entries in the table denotethe number of days an individual butterfly was seen returning to the roosts under observation.

closely relatedto changesin pulse thanto changes in subjectiveratings.The three subjectsabsorbeddifferentquantities of /\9THC. Nis variationwas apparent n peak /\9THC concen-trations n the plasma for the threesub-jects, namely, 67, 37, and 21 ng/ml.An estimate of the portion o /\9THCabsorbed from the original cigaretteswas made from the portion of totaltracerpresent n the 24-hoururinesam-ples. Lemberger t al. (6) reported hatwhen /\9THC was administered ntra-venously to chronic 1lsers,20 percentof it was excreted in the first day'surine. If the same portion of /\9THCand ,its metabolites administered bysmoking is excreted in the 24-hoururine, then our subjects absorbed41,20, and 15 percent,respectively,of thequantity of /\9THC in the originalcigarettes.

Mannoet al. (7), using a mechanicalsmoking device, assayedthe portion ofcannabinols n the smoke iof marijuanacigarettes,and found that approximate-ly 50 percentof the /\9THC in the cig-aretteswas deliveredunchanged n thesmoke. This figure is comparable tothat of 41 percent absorbedby one ofour three subjects, but the other twoabslorbed ess than ihalf that am!ount.This is an indication of the markedvariability of /\9THC absorbed whenmarijuana s administeredby smoking,even under standardizedconditions.The subjective experience was re-sponsiveto both placebo and changeinsetting. Althoughthe 12 subjectsratedthemselves as less "high" on placebo,therewas good correlationof symptomsexperienced under the inRuence c)fplacebo and A9THC (rank-order r =544, P < .01). The smlokersappearedto be conditionedto a particularsub-jective syndrometriggeredby the stim-ulus of smoking marijuana-likemate-rial. This may in part explainthe great-er sensitivityto marijuanareportedbyexperiencedsmokers.The 12 most fre-quently -checkedsymptoms while thesubjects were under the inRuence ofi\9THC were: mouth drier, feels high,threat drier, hungrier, dreamier, feelsmore like paying close attention tothings, skin tingling, memory seemswlorse,movemerlts lower,headheavier,sees images when eyes are closed. -Whenthreeof the subjectswere sub-sequentlystudied on the same dose in

closely relatedto changesin pulse thanto changes in subjectiveratings.The three subjectsabsorbeddifferentquantities of /\9THC. Nis variationwas apparent n peak /\9THC concen-trations n the plasma for the threesub-jects, namely, 67, 37, and 21 ng/ml.An estimate of the portion o /\9THCabsorbed from the original cigaretteswas made from the portion of totaltracerpresent n the 24-hoururinesam-ples. Lemberger t al. (6) reported hatwhen /\9THC was administered ntra-venously to chronic 1lsers,20 percentof it was excreted in the first day'surine. If the same portion of /\9THCand ,its metabolites administered bysmoking is excreted in the 24-hoururine, then our subjects absorbed41,20, and 15 percent,respectively,of thequantity of /\9THC in the originalcigarettes.

Mannoet al. (7), using a mechanicalsmoking device, assayedthe portion ofcannabinols n the smoke iof marijuanacigarettes,and found that approximate-ly 50 percentof the /\9THC in the cig-aretteswas deliveredunchanged n thesmoke. This figure is comparable tothat of 41 percent absorbedby one ofour three subjects, but the other twoabslorbed ess than ihalf that am!ount.This is an indication of the markedvariability of /\9THC absorbed whenmarijuana s administeredby smoking,even under standardizedconditions.The subjective experience was re-sponsiveto both placebo and changeinsetting. Althoughthe 12 subjectsratedthemselves as less "high" on placebo,therewas good correlationof symptomsexperienced under the inRuence c)fplacebo and A9THC (rank-order r =544, P < .01). The smlokersappearedto be conditionedto a particularsub-jective syndrometriggeredby the stim-ulus of smoking marijuana-likemate-rial. This may in part explainthe great-er sensitivityto marijuanareportedbyexperiencedsmokers.The 12 most fre-quently -checkedsymptoms while thesubjects were under the inRuence ofi\9THC were: mouth drier, feels high,threat drier, hungrier, dreamier, feelsmore like paying close attention tothings, skin tingling, memory seemswlorse,movemerlts lower,headheavier,sees images when eyes are closed. -Whenthreeof the subjectswere sub-sequentlystudied on the same dose ina more austeresetting and subjected ovenipucture, he variability n the sub-jective experience was apparent. Twoof the subjects vomited while at the

936

a more austeresetting and subjected ovenipucture, he variability n the sub-jective experience was apparent. Twoof the subjects vomited while at the936

peak of theirsubjective 'hligh,''whereasneitherhad done so on that dose whenit was administeredunder more con-genial circumstances earlier in thestudy. As one of the two reported onthe day of blood drawing, "I justfreaked out when I saw that needle."He checked off "verymuch more thanusual" for the symptoms, "have youfelt less in controlof your body";"feltless in control of your feelings"; and"hada weird feeling."He had checked"not at all" on the previous occasion.MARCGALANTERRICHARD. WYATTLOUISLEMBERGERHERB RTWE NGARTNRTOMB. VAUGHAN,ALTON. ROTHLaboratory of ClinicalPsychopharmacology,National Institute of Mental HealthsSaint Elizabeths Hospital,Washington D.C. 20032

peak of theirsubjective 'hligh,''whereasneitherhad done so on that dose whenit was administeredunder more con-genial circumstances earlier in thestudy. As one of the two reported onthe day of blood drawing, "I justfreaked out when I saw that needle."He checked off "verymuch more thanusual" for the symptoms, "have youfelt less in controlof your body";"feltless in control of your feelings"; and"hada weird feeling."He had checked"not at all" on the previous occasion.MARCGALANTERRICHARD. WYATTLOUISLEMBERGERHERB RTWE NGARTNRTOMB. VAUGHAN,ALTON. ROTHLaboratory of ClinicalPsychopharmacology,National Institute of Mental HealthsSaint Elizabeths Hospital,Washington D.C. 20032

References and Notes1. L. E Hollister [Science 172, 21 (1970)] re-views these studies and discusses some of theproblems implicit in administration of mari-juana by smoking.2. The materials were obtained from the Psychotomimetic Agents Advisory Committee, Na-tional Institute of Mental Health. They wereassayed by gas-liquid chromatography byTRW-Hazleton Laboratories both before andafter the study, as follows: natural marijuana,1.6 percent A9THC, less than 0.05 percent

A8THC, 0.1 percent each of cannabinol andcannabidiol; placebo marijuana material (pro-duced from manjuana plant material byfour extractions in 95 percent alcohol), 0.05percent A9THC, 0.05 percent A8THC, and 0.01percent each of cannabinol and cannabidiol;synthetic A9THC, 92 percent A9THC, 6 percentA8THC, an-d 1 percent each of cannabinol andcannabidiol. Purity of the [l4C]A91lIC wasshown to be greater than 98 percent.3. E. E. Waskow, J. E. Olsson, C. Salzman,M. M. Katz, Arch. Gen. Psychiat. 22, 97(1970).4. A copy of the abbreviated questionnaire isavailable on request.5. L. Lemberger, S. D. Silberstein, J. Axelrod,I. J. Kopin, Science 170, 1320 (1970).6. L. Lemberger, N. R. Tamarliin, J. Axelrod,ibid. 173, 72 (1971).7. J. E. Manno, G. F. Kiplinger, S. E. Haine,I. F. Bennett, R. B. Forney, Clin. Pharmacol.Ther. 11, 808 (1970).18 February 1972 a

References and Notes1. L. E Hollister [Science 172, 21 (1970)] re-views these studies and discusses some of theproblems implicit in administration of mari-juana by smoking.2. The materials were obtained from the Psychotomimetic Agents Advisory Committee, Na-tional Institute of Mental Health. They wereassayed by gas-liquid chromatography byTRW-Hazleton Laboratories both before andafter the study, as follows: natural marijuana,1.6 percent A9THC, less than 0.05 percent

A8THC, 0.1 percent each of cannabinol andcannabidiol; placebo marijuana material (pro-duced from manjuana plant material byfour extractions in 95 percent alcohol), 0.05percent A9THC, 0.05 percent A8THC, and 0.01percent each of cannabinol and cannabidiol;synthetic A9THC, 92 percent A9THC, 6 percentA8THC, an-d 1 percent each of cannabinol andcannabidiol. Purity of the [l4C]A91lIC wasshown to be greater than 98 percent.3. E. E. Waskow, J. E. Olsson, C. Salzman,M. M. Katz, Arch. Gen. Psychiat. 22, 97(1970).4. A copy of the abbreviated questionnaire isavailable on request.5. L. Lemberger, S. D. Silberstein, J. Axelrod,I. J. Kopin, Science 170, 1320 (1970).6. L. Lemberger, N. R. Tamarliin, J. Axelrod,ibid. 173, 72 (1971).7. J. E. Manno, G. F. Kiplinger, S. E. Haine,I. F. Bennett, R. B. Forney, Clin. Pharmacol.Ther. 11, 808 (1970).18 February 1972 a

H. W. Bates and F. Muller, in theirtheories on protective mimicry, pro-vided the first models of the coevelu-tion of species under-the influence ofnaturalselection (l). The original the-ories were deduced from limited em-pirical evidence;however, a vast bodyof supportivedata has since ibeen ac-cumulated. Most of these data havebeen naturalhistlorical, posterioricor-relative, or based on laboratory ex-periments (2). Direct quantitativeem-dence supporting the hypothesis that

H. W. Bates and F. Muller, in theirtheories on protective mimicry, pro-vided the first models of the coevelu-tion of species under-the influence ofnaturalselection (l). The original the-ories were deduced from limited em-pirical evidence;however, a vast bodyof supportivedata has since ibeen ac-cumulated. Most of these data havebeen naturalhistlorical, posterioricor-relative, or based on laboratory ex-periments (2). Direct quantitativeem-dence supporting the hypothesis that

naturalselection operates in nature topromote the evolution of mimicry israre. There exist only one "natural"(3) and one manipulative (4) experi-mental field study with living insectsdem!onstratinghe selective advantageof Batesian mimicry in nature.This report descrilbesa set of ex-perimentsgiving evidence that naturalselection is a factor maintainingmono-morphism within and similarities be-tweenunpalatable pecies evidenceforthe operation of Mulllerianmimicry.

naturalselection operates in nature topromote the evolution of mimicry israre. There exist only one "natural"(3) and one manipulative (4) experi-mental field study with living insectsdem!onstratinghe selective advantageof Batesian mimicry in nature.This report descrilbesa set of ex-perimentsgiving evidence that naturalselection is a factor maintainingmono-morphism within and similarities be-tweenunpalatable pecies evidenceforthe operation of Mulllerianmimicry.

Number of days returningto roostumber of days returningto roost Meanean1968 experiment*52.5 42.5 32 32 27.5 26

>71 70 >64 62 57 53

1968 experiment*52.5 42.5 32 32 27.5 26>71 70 >64 62 57 53

31.71.7AlteredUnaltered-V ontrols

AlteredUnaltered-V ontrols

10.552 22 21

10.552 22 21 52.42.4

1969 experimentJfAltered 63 47.5 25.5 23.5 22 14 3 28.4Unaltered-controls 48.5 40 36.5 19 14.5 8 3 24.2

SCIENCE, VOL. 176

1969 experimentJfAltered 63 47.5 25.5 23.5 22 14 3 28.4Unaltered-controls 48.5 40 36.5 19 14.5 8 3 24.2

SCIENCE, VOL. 176

Natural Selection for Mullerian Mimicry inHeliconius erato in Costa Rica

Abstract. The natural color pattern of individuals of the unpalcltableandmimetic butterfl{yHeliconius erato was altered to a unique nonmimetic pat-tern. When returned to natural populations, the nonmimetic individuals re-ntainedfor shorter periods of time and received more wing damage indicativeof predator sttacks than did the controls. The results indicate that Mullerianmimicry was functioningto protect the butterflZiesrom predation.

Natural Selection for Mullerian Mimicry inHeliconius erato in Costa Rica

Abstract. The natural color pattern of individuals of the unpalcltableandmimetic butterfl{yHeliconius erato was altered to a unique nonmimetic pat-tern. When returned to natural populations, the nonmimetic individuals re-ntainedfor shorter periods of time and received more wing damage indicativeof predator sttacks than did the controls. The results indicate that Mullerianmimicry was functioningto protect the butterflZiesrom predation.

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effects on humans of delta-9-thc administered by smoking

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