psychopharmacology of hallucinogens

8/12/2019 Psychopharmacology of Hallucinogens

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cologyl lucinogensEdi tor s

Richard C StillmanRobert ill ttDivision of ResearchNational institute on Drug Abuse

Rociviile Maryland

Pergamon PressNe York / Oxford / Toronto / Sydney / Frankfurt / Pads9 8


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CHARACTERIZATION OF THREE NEW PSYCHOTOMIMETICSby

Alexander T . Shulgin1483 Shulgin RoadLafayette, California 94549and

David E . NicholsDepartment of Medicinal Chemistry and PharmacognosySchool of Pharmacy and Pharmacal SciencesPurdue UniversityLafayette, Indiana 47907

INTRODUCTIONur present understanding of the mechanism of action of thesychotomimetic drugs has come from studies in several disci-lines . Physico-chemical parameters of active compounds areeasily measured and may reflect structural aspects whichinfluence absorption and distribution in the experimental subject.n Meetabolic studies, the fate of these compounds has suggestedpossible intermediate active species, or the formation ofd e t o x i f i c a t i o n p r o d u c t s . Pharmacological research has revealed acomplexity of neurotransmitter involvement during the course ofheir action . In intact animal studies the behavioral changesinduced by these drugs have allowed prediction of potentialactivity levels in clinically untested compounds . A number ofexperimental animal model systems have shown a good correlationbetween performance modification and demonstrated humanp s y c h o t o m i m e t i c p o t e n c yhe only effective challenge to the accuracy of predictions fromsuch in vitro and in vivo studies comes from the eventual evalu-tion of the studied compounds in clinical trials in normalsubjects.three compounds are described in this presentation . Although al:are known chemicals, they have not been previously reported to besychotomimetic in man . They are structurally unrelated toone another, but each is a close analog of a recognized family ofhallucinogens .

74


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Three New Psychotomimetics 7 54-Methylthio-2,5-dimethoxyphenylisopropyl amine, para-DOT, 3

The para-dimethoxy substitution pattern is a structural featurefre q uently associated with high psychotomimetic potency . Suchcompounds are easily converted to quinones, and can potentiallyprovide to the body a new chemical species not usually encounteredin metabolic chemistry . Such an intermediate can undergo a number

carbonyl 1reaction

N R

nucleophilicaddition

0

of chemical reactions with preexisting biochemicals such as aminesor mercaptans . With substituted derivatives of amphetamine, thismethoxy orientation requires a 2,5-disubstitution pattern . In thecase of 2,5-dimethoxy-4emethylphenylisopropylamine (DOM, lc) themetabolically generated hydroquinone has been shown to undergofacile oxidative cyclization to the indoline 2 (Ref . 1) . This

H3C 0H 2lc

2metabolic scheme may apply broadly to 2,5-dimethoxyphenyliso-

---propylamine derivatives which vary in the identity of the substit -uent in the aromatic 4-position . A number of these compounds areestablished psychotomimetic agents, and can be compared with one-another in potency and chronology of action as shown in table 1.2,4,5-Trimethoxyphenylisopropylamine (TMA-2, lb) can, byreplacement of the 4-oxygen atom with the isovalent sulfur atom, give

rise to the para- desoxythio DOT) isomer para-DOT, 3 Ref . 2).The octanol-water partition coefficients of known psychotomimeticshave been correlated with their human potencies Ref . 3,4) . Thevalue obtained for para-DOT 3) suggested that it might have 30xthe potency of mescaline Ref . 2) . A comparison of TMA-2 lb),para-DOT 3) and DOM lc) by the spectrophotofluorometric assay


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7 6 Shulgin andicholsTABLE 1 .omparative Potency of Several P sychotomimeticPhenylisopropylaminesR= Code Human DurationEffective Range

la H 2,5-DMA 30 - 50 mg shortlb OCH3 TMA-2 10 - 30 mg intermediatelc CH3 DOM, STP 1 - 5 mg longld C2H5 DOET 1 - 3 mg longle Br DOB 0 .2 - 1 mg long

as described by Autun et al . Ref . 5) gave the relative intensi-ties 0 .50, 0 .60 and 1 .0 resp . Ref . 6) . These physicalmeasurements suggest that para-DOT 3) may lie between lb and lc in

potency.The psychopharmacologically effective dose of para-DOT in man isin fact intermediate to that of TMA-2 and DOM . Employing theclinical assay protocol described earlier (Ref . 7) the thresholdand active levels of para-DOT in normal experimental subjectsappear to lie between 5 and 15 mg ., administered orally . Thechronology of the induced intoxication is similar to that ofTMA-2. Initial effects are noted at just over one hour followingadministration, with a maximum effect reached at about the end ofthe second hour . Effects maintain a plateau here for about 1 . 52 hours, and are completely dissipated by the end of the sixthhour . Qualitatively there were few visual effects reported withpara-DOT, but in other respects many of the conceptual and inter-pretively disruptive aspects of LSD intoxication were induced.With closed eyes, there was an easy visualization of hypnogogicimages which, although not under voluntary origin as to subjectmatter, could be terminated at will .

3 , + - M e t h y l e n e d i o x y m m e t h a m p h e t a m i n e M D M A , 4 )A second compound to be described in this presentation is the

NH2CH3S OCH3

para-DOT 3)


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Three New Psychotomimetics 77N-methyl homolog of a well-studied psychotomimetic, 3,4-methylene-dioxyphenylisopropylamine MDA, 5) . As with MDA, MDMA chemicallyproperly N-methyl-3,4-methylenedioxyphenylisopropylamine or 1-(3,4-methylenedioxyphenyl)-2-(methylamino)-propane) has thearomatic substitution pattern of the essential oil safrole (6)

NH2H C CH3 H2C 1 \ MDA 5) Safrole 6)

from which it was first synthesized in 1960 (Ref . 8) . The onlytoxicological and behavioral report involving this compound wasan Army Chemical Center study performed in the 1950 s, declassi-fied in 1967, and published in 1973 (Ref . 9) . There are noreports concerning its psychopharmacological action in man,although the compound has had occasional and erratic appearancein the illicit street drug market (Ref . 10) . For this reason, iffor no other, it falls under the purview of the National Instituteof Drug Abuse, and a brief description of the pharmacologicalproperties of this compound in man would seem appropriate.MDMA has a higher threshold level than does MDA, but otherwise itis very similar in potency . Within the effective dosage range,75-150 mg orally, the effects are first noted very quickly,usually within a half-hour following administration . With mostsubjects the plateau of effects is reported to occur in anotherhalf-hour to hour . The intoxication symptoms are largely dissi-pated in an additional 2 hours except for a mild residualsympathomimetic stimulation which can persist for several addi-tional hours . There are few physical indicators of intoxication,and psychological sequelae are virtually non-existent . Qualita-tively, the drug appears to evoke an easily controlled alteredstate of consciousness with emotional and sensual overtones . Itcan be compared in its effects to marijuana, to psilocybin devoidof the hallucinatory component, or to low levels of MDA.

a ,O Dimethylserotonina-methyl-5-methoxytryptamine, 11)The third psychotomimetic compound to be discussed in thisp resentation results from minor modifications of the chemicals tructure of the neurotransmitter serotonin 7) . Compounds suchas serotonin which are active within the central nervous systemCNS) are not centrally active when administered peripherally.The reasons for this inability to enter the CNS are evident inthe nature of the functional groups present . The free hydroxylH 2 C \ MDMA 4) /NHCH3 H


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78 Shulgin and Nicholsgroup at the 5-position is a highly polar site which appears toeffectively prohibit CNS penetration . The rare exceptions to thegeneral rule that phenols and phenol-like compounds are centrallyinactive, are usually examples wherein there is possible intra-molecular hydrogen bonding involving this acidic function (an

serotonin 7)-

adjacent furan oxygen in the case of morphine, ready access tothe neutralizing amine function in the case of psilocin) . Acommonly encountered stratagem found to be effective in circum-venting this obstacle is to form a derivative such as an ester(as an acetyl group) or as an ether (as a methoxyl group).A primary amine function, on the other hand, is generally labileto enzymatic removal, thus leading to inactivation of the drugduring its absorption period and prior to its availability to theCNS . A procedural circumvention of this problem is frequentlyachieved by the parenteral administration of a drug, but a numberof structural modifications are also known to be effective . Theaddition of a carboxylate group alpha to the amine functiongenerates an a-amino acid which can gain entry to the CNS byactive transport systems specific for this structure. Decarboxy-lation in situ then reveals the amine . Conversely, the amine canbe effectively shielded from enzymatic deamination by the substi-tution on it of sterically bulky groups (such as N,N-diisopropylor an N-tert-butyl structure) or by substitution adjacent to itof a methyl group (as seen in the relationship between phenyl-ethylamine and amphetamine).a,O-Dimethylserotonin {11) is a compound that meets thesestructural modifications exactly . It was first prepared in 1958Ref . 11), and has been shown to be both pharmacologicallysimilar to serotonin in it v i t r o studies Ref . 12) and centrallyactive in mice Ref . 13) It is also closely related to thethree known psychotomimetic agents N,N-dimethyltryptamine ( DMT,8), a-methyltryptamine (9), and 5-methoxy-N,N-dimethyltryptaminer5-OCH3-DMT, 10) . A comparison of the structures and potenciesof these compounds in man is shown in table 2, and it isgratifying to see that the logical extrapolations from these three drugsagree closely with the properties reported here for 11 . Thereplacement of the N,N-dimethyl substitution pattern of DMT withan a-methyl (as in 9, a-methyltryptamine) results in a slightincrease in potency, but more importantly, allows the compound tobe effective via the oral route . The retention of the N,N-

dimethyl system but the addition of a 5-methoxy group as in5-OCH3-DMT, 10) maintains the requirement of parenteral adminis-


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TABLE 2 . Potencies and Effective RoutesSeveral Psychotomimetic Tryptamine Derivatives in Manof Administration o

Three New Psychotomimetics 79tration, but results in a several-fold increase in effectiveness.a,O-Dimethylserotonin 11), as shown in table 2, is indeed orallyactive and has an effective dose range of 1 .5 - 3 mg . Unlike theparenterally active drugs, but like the unmethoxylated analog 9,11 has a surprizingly long duration of action . Its use is

N CH3)2

NH

DMT 8)30-75 mg.parenteral)

CN30 CH3)2 CH30NH

NH2

CH3

Ha-methyltryptamine 420-50 mg.

oral)

H5-OCH3-DMT CIO) a,O-dimethylserotonin I5-10 mg . 1 .5-3 mg.parenteral) oral)

generally characterized by extensive physical discomfort . Withinthe first hour following administration there is nausea, frequent-ly accompanied by active vomiting and related stomach cramps . Inthe following period, during the time of central intoxication(2-6 hours), there is reflexive mydriasis, some instances ofdiarrhea, and occasional complaints of difficulty in urination.After the majority of the central sensory effects disappear therecan be a residual headache, and both irritability and insomnia.The subjective effects of a,O-dimethylserotonin are difficult tocharacterize . As has been observed i n several of the reportedstudies of DMT, the intoxication appears to be largely unstruc-tured, and will vary in nature with the individual subject, almostas if he were bringing to the experiment his own preference in thestyle of psychotomimetic action . The two published reports on theclinical effects of a-methyltryptamine Ref . 1 4+) suggest a varietyof evoked responses, mostly unaccompanied by overt impairment ofmental function . It seems probable that additional study with -a,0-dimethylserotonin may show a similar complexity of intoxica-tion .


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80 Shulgin and NicholsNeed for Acute Studies of

P s y c h o t o m i m e t i c s i n u m a n S u b j e c t sThere has been a move in the last few years away from human titra-tion of potential psychotomimetic drugs in favor of biochemicaland behavioral studies in animals . The need for animal toxicologyand metabolic information is no less than it has ever been, but itmust be remembered that the ultimate purpose of research in thisarea is to alleviate human illness and to provide for human needs.One principle rationale for such studies is to gain insight intothe mechanisms of mental illness or, through the development of anunderstanding of the relationship between structure and activity,to design and assay drugs which might reverse endogenous depres-sion or other undesirable mood states . However, such conditions-- schizophrenia, neurosis, autism -- are uniquely humanc o m p l a i n t s . No animal model has yet satisfactorily imitated them.To an extent their symptoms can be pharmacologically induced innormal human subjects, but potentially therapeutic drugs can onlybe verified in man . A less frequently mentioned goal is thesearch for compounds which might enhance creativity, or provideentertainment (Ref . 15) . Again these requirements are uniquelyhuman, and the determination of risk and benefit from suchpharmaceuticals must be made in man as the test animal.There appears to be an intangible but surprizingly effectiveprohibition of human research in this area . . There is concernwith regard to the narcotics laws, and problems associated withthe Drug Enforcement Administration in the approval of researchprotocols involving sheduled drugs. Although the DEA claims toprovide no impediment to such research, there are extensivehurdles which must be overcome none-the-less . Most of thepotentially valuable drugs to be explored in these areas are notdrugs of established abuse potential, are not recognized in thedrug schedules, and are consequently of no concern to the DEA.A more pervasive inhibition comes from the HEW guidelines whichwere originally intended to apply to human experimentationsupported by grants and contracts to universities . These havenow become routinely consulted by human health committeesapproving clinical research, regardless of the source of funds.These guidelines state that there must be potential therapeuticalue, and that there be a high benefit-to-risk ratio, in anyhuman study . Since it is widely held that work with the psycho-tomimetic drugs cannot have value and therefore only presentsrisks, this approval is rarely obtained . The recourse to animalmodels for exploratory research embodies an element of hypocrisyin that all such studies inevitably depend upon human assessmentof pharmacological qualities and potency for achieving a correla-tion . Further, their value in prediction can only be confirmedby human assay, yet there is often an aversion to such experimen-tation.There has been, and will continue to be, much human experimenta-tion with potential hallucinogenic or psychotomimetic drugs.Much of it is self-experimentation, by cautious professors ofpharmacology, curious industrial toxicologists, and adventurous

Some Comments Concerning the


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Three New Psychotomimeticsraduate students . Most of the results of these inquiries areunpublished and unavailable to the scientific community . At thesame time, many of the rumored drug-effects are anecdotal,anonymous, and completely unreliable . Far too often, new drugs

with a dramatic word-of-mouth reputation appear in social use,often in some misrepresented form, and providing an extremelyhigh potential for tragedy.What can be done to remedy this situation? It might be valuableto consider forming a set a human research standards geared tothe study of drugs in acute trials, rather than to chronic studiesintended for therapy . Such studies might be directed to thedisruption of sobriety as the desired property rather than anundesirable side-effect . The subtle stigma associated with theuse of experienced subjects should be erased . Ethical considera-tions limit the exposure of naive subjects to new sensorye x p e r i e n c e s . Also, their unfamiliarity with the nature of possiblesubjective phenomena to be encountered can make communicationdifficult . The objections raised to self-experimentation mightbe reconsidered, as this provides the epitome of informed consentand the most desirable consistency in the subjective comparisonof two different materials.We cannot afford to wait until an enterprising illicit drug manu-facturer successfully markets some new drug, one which mightreceive enthusiastic public acceptance . We need to be preparedto recognize the symptoms which might be seen in acuteintoxication involving such a new drug . We m u s t b e f a m i l i a r w i t h t h epsychological complications which can accompany exposure to over-dosage . Studies of this drug in animal models will provide awealth of factual information in areas of toxicity and behaviordisruption, but this is of utterly no use to us when the drugsuddenly appears and is used in society . The research whichmight provide practical help in such an emergency is not beingpursued . We must accept the responsibility to remedy thissituation .

REFERENCES1 . a) Zweig, J . S . and Castagnoli, N ., Metabolic 0-Demethyla-tion of the Psychotomimetic Amine 1-(2,5-Dimethoxy-4-methyl-

phenyl)-2-aminopropane, Psychopharm . Commun . 1, 359 1975).b) Zweig, J . S . and Castagnoli, N ., Chemical Conversion ofthe Psychotomimetic Amine I-(2,5-Dimethoxy-4-methylphenyl)-2-aminopropane to 5-Hydroxy-2,6-dimethylindole, J . Med.Chem . 17, 747 {1974).

2.ichols, D.E. and Shulgin, A.T., Sulfur Analogs of Psycho-tomimetic Amines, J . Pharm Sci . 65, 1554 1976).3 . Barfknecht, C . F ., Nichols, D . E . and Dunn, W . J ., Correlationof Psychotomimetic Activity of Phenethylamines and Amphetam-

ines with 1-Octanol-Water Partition Coefficients, J . Med.Chem . 18, 208 19 . 7 5 ) .


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Three New Psychotomimetics 83Psilocybin, JB-329, and IT-290) in Volunteer Subjects,J . Nerv . Ment . Dis . 131, 428 1960).b) Murphree, H . B ., Dippy, R . H ., Jenney, E . H . and Pfeiffer,C . C ., Effects in N ormal Man of alpha-Methyltryptamine andalpha-Ethyltryptamine, Clin . Pharmacol . Therapeut . 2, 7221961).

15 . Huxley, M ., Criteria for a Socially Sanctionable Drug,Interdisciplinary Science Reviews, 1, 176 (1976) .

psychopharmacology of hallucinogens

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