510

NEW WAYS WITH HALLUCINOGENS

OF the various endogenous toxins postulated as causesof schizophrenia, none has had a more lasting appeal thanthe one proposed by Osmond and Smythies.1 Theypointed out that the potent hallucinogen mescaline

(trimethoxphenylethylamine) had structural similarity tosome natural catecholamine derivatives, and the productionof a mescaline-like substance by metabolic aberrationmight be the cause of schizophrenia. At first, attentioncentred on adrenochrome,2 and although this possibilitywas pursued diligently by some it has found little empiricalsupport. In 1962 Friedhoff and van Winkle 3 reported thepresence of a

" pink spot " in the urine of schizophrenicpatients and they later identified it as dimethoxyphenyl-ethylamine (D.M.P.E.A.). This substance, which differs

by only one methoxy group from mescaline, evoked muchinterest. Unfortunately further experiments, with dietarycontrol, 4 5 failed to confirm the finding and, although aLiverpool survey 6 demonstrated preponderance of pinkspots among schizophrenic patients compared withnormal controls, the techniques used probably measuredphenothiazines as well as the pink spot. The validity ofits presence in schizophrenia remains to be conclusivelydemonstrated. Moreover, D.M.P.E.A. was found to have nopsychotomimetic effect.8 9

Nevertheless, preoccupation with the methoxy struc-ture of mescaline persists and is reflected in a search forabnormal methylation (producing such groups) or failureof normal demethylation (converting methoxy to hydroxy)which in this context supposedly inactivates (although theconverse holds for natural products).10 A different

approach has lately been adopted by Shulgin et al.ll Theycollected over 40 derivatives of phenylethylamine or

(x-methylphenylethylamine (amphetamine), the bulk beingin the second category. All these substances were thentested in volunteers and, using mescaline as a

reference compound, Shulgin et al. estimated the psycho-tomimetic potency of each in terms of mescaline units

(dose of mescaline divided by equivalent dose of the com-pound). This potency was then examined in relation tochemical structure. The amphetamine derivatives wereby far the most potent. As amphetamine is not a naturalproduct of the body Shulgin et al. infer that the resistanceof such derivatives to monoamine-oxidase suggests thatthe endogenous toxin is similarly protected from mono-amine-oxidase, perhaps by formation in the synaptic cleft.As for methoxy groups, those in an ortho or para positionenhance activity, while meta substituents decrease it.Three methoxy groups is optimum and two or four lesspotent; a substituent at the 4-position gives stability anda 4-methyl group greatly increases activity. It was also

possible to deduce, by way of much chemical sophistica-tion, the paths by which indoles (which may also bepotent psychotomimetics) can be formed. The most

important result of this approach, however, is thatShulgin et al. were able to predict two candidates for the1. Osmond, H., Smythies, J. R. J. ment. Sci. 1952, 98, 309.2. Hoffer, A., Osmond, H. The Chemical Basis of Psychiatry. Springfield,

Illinois, 1961.3. Friedhoff, A. J., van Winkle, E. Nature, Lond. 1964, 202, 520.4. Perry, T. L., Hansen, S., MacIntyre, L. ibid. p. 519.5. Nishimura, T., Gjessing, L. R. ibid. 1965, 206, 963.6. Bourdillon, R. E., Clarke, C. A., Ridges, A. P., Sheppard, P. M.,

Harper, P., Leslie, S. A. ibid. 1965, 208, 453.7. Howorth, P. J. N. Lancet, 1966, i, 202.8. Hollister, L. E., Friedhoff, A. J. Nature, Lond. 1966, 210, 1377.9. Shulgin, A. T., Sargent, T., Naranjo, C. ibid. 1966, 212, 1606.

10. Himwich, H. E., Kety, S. S., Smythies, J. R. (editors) Amines inSchizophrenia. London, 1967.

11. Shulgin, A. T., Sargent, T., Naranjo, C. Nature, Lond. 1969, 221, 537.

role of endogenous toxin. The first is 3, 4-dimethoxy-phenylethanolamine which (if it occurred as a normal

intermediary) would be rapidly demethylated to

normetanephrine. Failure of such demethylation couldproduce a psychotic state. The second structure proposedis 2-hydroxy-4, 5-dimethoxyphenylethanolamine, whichcould be formed if the enzyme converting tyrosine tohomogentisic acid could also act on dopa and if the

product was methylated.This work is an encouraging departure from the way

most research is conducted in this area. The findings arebased exclusively on human data in which individualvariations have been reduced, as far as possible, by com-paring as many hallucinogens as possible in the samesubject and by the use of a reference hallucinogen,mescaline. The experiments are also novel in the use ofthe " double conscious " technique of Alles 12 ; and,perhaps most important of all, there is the courage tomake predictions on the basis of a detailed analysis ofstructure, psychotomimetic potency, and knowledge ofnaturally occurring processes.To many the toxic hypothesis of schizophrenia,

particularly the variant postulating a methoxylatedendogenous hallucinogen, is a dead duck. Such criticspoint out that seventeen years of intensive research haveproduced little that stands up to critical evaluation. Theywould also argue that " model psychoses " induced byhallucinogens are irrelevant to schizophrenia; and theymay hope to endorse their view by finding in the work ofShulgin et al. questionable details, such as the use of" effective dose " (a mean of the threshold dose capable ofaccurate assessment and the maximum dose where vari-

ability must be considerable). Nevertheless two clearlytestable predictions emerge which can be examined

thoroughly-a welcome departure from the many un-helpful generalisations of the past.

TOPICAL STEROIDS IN CHILDREN

THE application of steroid-containing preparations tothe skin of patients with widespread skin disease mayproduce varying degrees of pituitary-adrenal suppression,especially when occlusive dressings are used. The returnto normal is rapid after treatment is stopped. IS Steroidtherapy has an important place in the management ofchildhood dermatoses,14 and on p. 485 Dr. Feiwel andhis colleagues record evidence suggesting that adrenalfunction was suppressed in 8 out of 19 infants and youngchildren with eczema, who were treated as outpatients withtopical steroids without dressings. 12 of these childrenhad already been treated with other potent steroids by theirfamily doctor. All received betamethasone-17-valeratecream during the investigation. The main side-effect ofsteroid therapy in children is retardation of growth 16; butno association has been reported between topical prepara-tions and growth retardation. Dr. Feiwel and his asso-ciates suggest, however, that percutaneous absorption ofsteroids should be considered as a possible cause in anydisturbance of general health in a child being treated inthis way.

12. Alles, G. A. Neuropharmacology: Fourth Macy Foundation Conference(edited by H. A. Abrahamson). New York, 1959.

13. Lancet, 1967, ii, 1078.14. Thomas, P. Guide to Steroid Therapy. London, 1958.15. Goldman, L. Ann. N. Y. Acad. Sci. 1959, 82, 994.