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J. M.

Williams

Distortions of Vision and Pain -- LSD

Distortions of Vision and Pain: Two Functional Facets of D-Lysergic Acid Diethylamide [LSD]

by John Michael Williams


jmmwill@comcast.net jwill@BasicISP.net

2012-08-01
An extensive review of the research literature on LSD, with emphasis upon its effects on vision and pain.

Copyright (c) 1979, Perceptual and Motor Skills -- now Ammons Scientific, Ltd. All rights reserved.
The original published version of this article may be obtained at http://www.amsciepub.com/doi/pdf/10.2466/pms.1979.49.2.499.

J. M. Williams

Distortions of Vision and Pain -- LSD

Preface to the 2012 Reprinting


This paper is a manually-entered copy of the complete published text of the 1979 paper. The author thanks the editors of erstwhile Perceptual and Motor Skills for this special permission. The published text pagination has been preserver, except that hyphenated words and REFERENCES crossing page boundaries have been gathered to the page on which they were begun. In addition to this Preface, one minor change has been made to correct a newly-found error on the published p. 518, an error which is explained there, in a footnote. Availability A full copy of the original Monograph Supplement article may be obtained from Ammons Scientific Journals at: http://www.amsciepub.com/doi/pdf/10.2466/pms.1979.49.2.499. Ammons succeeded Perceptual and Motor Skills some years ago. I still have a few of the original P and MS monograph reprints, which I am willing to supply to interested readers.

Additional Commentary
The research peak for LSD was in the 1960's. The popularity of LSD as a drug of amusement waned during the 1970's, but it never vanished entirely. The two major factors in that waning were: (a) Increasingly diligent law enforcement; and, (b) growing awareness of the apparently drug-induced intellectual decline of its most vocal advocates. However, very recently, there has been some journalistic evidence of an increase in illicit use of the drug. So, I thought that this possible increase might be an additional good reason to revive this old paper. Brain Damage My only regret concerning the original 1979 paper has been of my neglect of coverage of some of the long term effects of LSD upon brain-based behavior. Of course, published, reliable research data on the uncontrolled human use of LSD was spotty even during the 1960's and has remained limited. Brain damage in humans, obviously caused by LSD, apparently occurs at all effective dose-levels. Many authors (including those of 2012-05 Wikipedia) ignore or deny this damage. However, such damage is well-documented and widely reported as the "flashback" phenomenon: In some fraction of LSD users, symptoms of brain malfunction caused by the drug spontaneously have reappeared days, months, or years after all ingestion of it

J. M. Williams

Distortions of Vision and Pain -- LSD

has ceased. This reappearance by "flashback" can not be anything but an effect of brain damage, however popularly described in different words. Ingestion of LSD apparently causes damage or destruction of brain tissue, which, in turn, explains some or all the observed effects of the drug. Toward the end of the chemically-active twelve hours or so after initial LSD ingestion, the brain of the majority of users apparently is recovered by substitution of other cells for the lost or damaged ones; this substitution permits the subsequent apparently full recovery. The flashback then occurs when mental or physical stress, sleep loss, anxiety, or other new events reduce the effectiveness of the substituting cells, allowing the original LSD damage to reappear in the form of flashbacked symptoms. Probably a single use, and certainly the repeated use, of LSD apparently will cause permanent degradation of intellectual function, with the precise mode of action varying considerably from one individual to another.

J. M. Williams

Distortions of Vision and Pain -- LSD

J. M. Williams

Distortions of Vision and Pain -- LSD

[format of 1979 printed monograph cover page]

PERCEPTUAL AND MOTOR SKILLS


Monograph Supplement 1-V49
price 4.00

DISTORTIONS OF VISION AND PAIN: TWO FUNCTIONAL FACETS OF D-LYSERGIC ACID DIETHYLAMIDE

JOHN MICHAEL WILLIAMS Southern Illinois University at Carbondale

Perceptual and Motor Skills, 1979, 49, 499-528. Perceptual and Motor Skills 1979 Monograph Supplement 1-V49

DISTORTIONS OF VISION AND PAIN: TWO FUNCTIONAL FACETS OF D-LYSERGIC ACID DIETHYLAMIDE 1 JOHN MICHAEL WILLIAMS Southern Illinois University at Carbondale
Summary ---- D-lysergic acid diethylamide (LSD) produces distortions of visual perception and analgesia. Evidence is advanced from a functional stand-point that the observed visual effects result from an attenuation of light-evoked input to the dorsal lateral geniculate nucleus (LGN) from the purely centripetal pathways of the retina. More slowly responding visual afferents or those with more complex receptive fields seem to be affected most. LSD analgesia, accompanied by severe psychotic symptoms, appears to result from drug actions on a centrifugally controlled pain system involving neurons of the midbrain raphe.

CONTENTS
Actions of LSD _____________________________________________________________________________ Effects on the Visual System ________________________________________________________________ Effects on the Pain System __________________________________________________________________ Resum and Conclusion _____________________________________________________________________ References _________________________________________________________________________________ 502 503 511 517 519

Departing on an old theme of Aristotle's, Korzybski defined three classes of living organism: (a) chemical-binders (plants) which grow by binding or selecting among chemicals in their environments; (b) space-binders (animals) which grow by binding or selecting among spatial locations in their environments; and (c) time-binders (humans) who grow by binding or selecting among events in history, thus modifying their technological and cultural environments (Johnson, 1946, p. 164). The behavior peculiar to space-binding, locomotion, may be used to define object perception operationally as a response which requires of the organism at least one functioning sense modality. Space-binders must locate the objects on which they feed, and movement toward or away from objects is sufficient to define perception of those objects. Sunlight, the same sunlight which powers the chemical-binding of the plants, bathes the surface of the earth in a diffusely reflected ocean of electro-magnetic radiation. It is sunlight, too, which is mirrored weakly by the moon on half of the nights of the month. Hardly any light but sunlight occurs in nature: Occasional fires, lightning, starlight, and a few bioluminescent organisms provide the major exceptions. The ubiquity of sunlight and its independence of terrestrial living organisms places a stringent requirement on any mode of visual _____________________________
1

The author thanks Dr. Luis Baez for help and encouragement in preparing this essay. Thanks also are due to Dr. Alfred Lit for reading the manuscript and offering suggestions. The work was supported in part by the Psychology Department. Reprint requests should be sent to the author at the Psychology Department, Southern Illinois University, Carbondale, IL 62901. [2012-08-01 note: This address no longer is current]

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perception; such perception must be efficient in distinguishing among innumerable sources of reflected light. Visually-cued overt responses must be delayed or withheld until numerous light-sources can be discriminated efficiently as "objects" in behaviorally meaningful ways. Other modalities of perception -- auditory, olfactory, gustatory, tactual, etc., tend to depend on energy or materials originating directly from the nutrients or other objects perceived. In these modalities, object-perceptual responses tend to occur whenever the receptors are stimulated. The tendency of objects to stimulate the nonvisual modalities as objects already detected and separated from background sources of sensory input means that stimulation in these modalities may be used to initiate appropriate orienting or locomotor responses immediately following stimulation. The appropriateness of any given set of locomotor responses may be considered in this context to depend on the internal needs of the organism. Hunger or sharp pain might bias the organism to attack at any new nonvisual stimulation; light would not be attacked unless the retinal image of an object were recognized. Thirst might bias a more exploratory approach, as charging, then biting or clawing, does not get water into the gut very efficiently. Visual stimulation, light, requires a constant interpretive effort to separate objects from their backgrounds, regardless of motivational state. If the evolution of the sensory systems is considered in terms of the locomotor requirements of space-binding organisms, it becomes evident that the environmental secondary reinforcers which lead to primary reinforcement must be processed differently in the various modalities. As the Dinsmoore hypothesis states (Zimmerman, 1957), every discriminative stimulus is a secondary reinforcer; so it can be understood that the nonvisual modalities may well have evolved to guide locomotor responses based on centrally controlled biases impressed directly upon the sensory end-organs. Nonvisual stimuli signal objects as such, so little of the nonvisual end-organ need be allocated to object-perception except in terms of the current internal needs of the space-binding organism. In the nonvisual modalities, responses to discriminative stimuli as such begin at the sensory end-organ itself. By comparison, the visual discriminative task in a natural environment requires total use of the resources of the retina just to discover objects which might be in fact present. Central biasing of retinal inputs therefore could be expected to hinder visual object-perception to such an extent that natural selection would reduce the survival rate of organisms which depended heavily on vision for locomotion and which possessed sophisticated centrifugal retinal efferent systems which biased retinal centripetal outputs. In humans it might be anticipated that the effects of drugs on the visual system would be different from effects on other modalities, at least as far as

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object-perception is concerned. In fact, there are numerous reports that psychotomimetic drugs distort colors or shapes of objects but rarely create nonexistent visual objects de novo. In other modalities, hallucinations occur; for example, tactually hallucinated objects such as crawling bugs abound during withdrawal from ethanol or barbiturate addiction (e.g., Wilcox & Levitt, 1975). Similar symptoms are reported during addiction to cocaine (e.g., Krikstone & Levitt, 1975). The substantial centrifugal control of the auditory system at all levels is consistent with clinical observations in humans (Winters, 1969; Malitz, et al., 1962; Forrer & Goldner, 1951) that misperceptions as well as delusions in psychotics commonly find expression in terms of auditory phenomena. Chronic or acute neurotic pain, of course, it not at all rare and may be considered a form of somatosensory illusion. Drug-induced tactual and kinaesthetic symptoms are common (Hoffer, 1965, pp. 203 ff.) in the form of illusions which surely must contribute to psychotomimetic hallucinations. Evidence of a different kind for the unique status of vision may be discovered in the anatomy and the physiology of the various sense modalities: consistent with the functional argument above, all sensory surfaces except the retina (Rodieck, 1973, p. 689) have central centrifugal inputs distal to the second-order primary relay neurons (von Euler, et al., 1968, Part II; Winters, 1969; Winters, 1976; Barber, et al., 1978; Thompson, 1967, pp. 289-292). These centrifugal systems may be interpreted as essential elements of more central object-perceptual response systems. All sensory systems except the visual, then, seem to be in complete double jeopardy, afferent and efferent, of hallucinogenesis. Actually, the question of the existence of retinal centrifugal efferent fibers in mammals is not entirely closed and has been reviewed by Brindley (1960, pp. 107-114), Granit (1962, pp. 552-555, 667-668), and Ogden (1968). Granit (1962, p. 668) concluded that any such fibers, while anatomically not unlikely, do not affect the electroretinogram (ERG). Brindley and Hamasaki (1966) have advanced strong anatomical evidence against any such fibers as a numerically significant subpopulation in the cat's optic nerve. The current prevailing opinion (Rodieck, 1973, p. 689) seems to be that centrifugal efferents to the mammalian retina do not exist, although purely intraretinal efferents such as interplexiform cells have been found and in the past may have been mistaken for centrifugal fibers (Dowling & Ehinger, 1975, 1978). Birds are known to have retinal efferents originating in more central nervous structures (Rodieck, 1973, Sect. XXI, B), but it seems likely that active locomotor responses of birds involve more interaction of the bird with the medium (air) than with object-sources of nutrition. The preceding approach has been introduced to provide a rationale for the pharmacological data to be reviewed. Pharmacological influences may be expected to affect visual afferent sensory systems by altering, but not initiating,

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object perception. This should not hold for the nonvisual modalities in which the centrally linked centrifugal systems might be influenced to initiate drug-induced perceptions properly termed hallucinations. If no centrally initiated perceptual influences can be exerted on the retina, the dual retinal input to thalamus and midbrain provides a unique double assurance of the veridicality of visual perception. There has been a great deal of research on LSD, a drug which acts both on the visual and the pain systems. Complete references to the literature may be found in reviews by Hoffer (1965) and by Brawley and Duffield (1972). Although it always must be remembered that context and suggestion are powerful determinants of the effects of LSD, every attempt has been made here to restrict the discussion to the primary influences of the drug on the sensory systems.

Actions of LSD
LSD is one of a number of substances having psychedelic or psychotomimetic effects coupled with perceptual distortions. For large doses these presumably central effects are accompanied by peripheral symptoms of mydriasis, heightened breathing and cardiovascular activity, and increased skeletal muscle tone. These latter sympathomimetic properties of LSD, as well as biochemical and physiological theories of LSD action, are reviewed by Brawley and Duffield (1972). Psychiatric and phenomenological observations of the effects of LSD may be found especially in Hoffer's paper (1965). LSD crosses the blood-brain barrier readily (Byck, 1975). The mode of action of LSD remains controversial but seems to be depressive in the central nervous system (CNS), and dose-dependent, apparently being based on a competitive antagonism of serotonin (5-HT) at postsynaptic receptor sites. Administration of LSD increases assayed brain levels of 5-HT while at the same time decreasing 5-HT turnover as measured by 5-hydroxyindole acetic acid concentrations. The decrease in turnover is probably by an intracellular negative feedback mechanism (Anden, et al., 1968; Byck, 1975). The action seems to occur first at lower doses in the especially sensitive neurons of the midbrain raphe and then, with increasing dose, at other central and at peripheral sites (Aghajanian, 1972). There is no known effect on the auditory system per se (Key, 1965), evidently because the auditory system has no serotonergic synapses. The LSD congener 2-brom-LSD (BOL 148), given intravenously, antagonizes the peripheral actions of LSD at much lower doses than it does the central actions (Aghajanian, 1972). The cell bodies of the LSD-sensitive raphe neurons probably receive excitatory 5-HT inputs (Brawley & Duffield, 1972). These neurons are less sensitive to parachlorophenylalanine ( pCPA) inhibition at the cell body than at their axonal terminals, suggesting that new tryptophan hydroxylase is manufactured

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in the cell bodies and transported to the terminals (Aghajanian, et al., 1973). If adequate substrate is available, tryptophan hydroxylase controls the rate-limiting step in 5-HT synthesis, so concentration of this enzyme would control 5-HT concentration in the neuron. LSD-blockage of feedback regulating tryptophan hydroxylase synthesis would account for the decreased turnover and increased levels of 5-HT following LSD occupation of postsynaptic receptor sites.

Effects On the Visual System


Preretinal Effects Preretinal effects of any drug on vision normally would involve pupillary responses and lens accommodation. Eye movements are not considered in this paper. The pupil of the eye controls retinal illuminance within a factor of about 10 and acts with the lens to regulate the sharpness of the retinal image. The pupillary sphincter muscle responds to cholinergic, such as muscarinic, stimulation and is inhibited by betaadrenergic stimulation (Patil, 1969); the pupillary dilatator responds to alpha-adrenergic stimulation. Atropine, an antimuscarinic agent, causes mydriasis and also cycloplegia. The ciliary muscles of accommodation are innervated by postganglionic parasympathetic fibers. Doses of LSD adequate to produce visual perceptual distortions in humans also produce mydriasis (Isbell, et al., 1956; Isbell, 1959). This mydriasis is effected probably by an adrenergic action on the pupil dilatator (Freedman, 1969; Green, 1975). Chlorpromazine (CPZ), which antagonizes LSD at least physiologically, produces a dosedependent miosis likely to be linearly related to receptor turnover rate at a central site (Hoffer, 1965, p. 226; Freedman, 1969; Smolen, et al., 1975; Sigg & Sigg, 1973). If this latter mechanism happened to be linearly related to the one regulating the retinal effects (below) of LSD, pupil diameter might prove to be an important measure, or at least covariate, of LSD residual response following administration of CPZ. It should be mentioned, too, that visual acuity is reduced by cycloplegia, and that cycloplegia alone might be responsible for reports of "blurring" of vision following toxic doses of poisons such as methyl mercury (Rustam & Hamdi, 1974) or hallucinogenic doses of 2,5-dimethoxy-4-methyl amphetamine (DOM, "STP") (Snyder, et al., 1967) or of LSD (Hoffer, 1965, p. 200). Data on this issue are problematical, though: "blurring" as a phenomenological report must be interpreted to mean something different from "visual distortion" such as a crawling of the hairs on the back of the hand or an apparent "melting" or "flowing" of objects known to be solid (Hoffer, 1965). Again, recalling the possible suggestive influences of the interviewer, it seems likely (but not certain) that "blurring" should be interpreted usually as a loss of acuity (or of high visual spatialfrequency response). This "blurring" presumably can be

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distinguished reliably by the interviewee from a "distortion" of shape or color. Various perennial methodological problems related to the semantics of such phenomenological reports are discussed by Zuckerman (1969). Preretinal effects of LSD and other drugs do occur and may originate either in the eye or more centrally. Such effects would change the illuminance and sharpness of the retinal image but otherwise would not be expected to affect object perception. Retinal Effects The most studied pharmacological influences on the retina (as well as on the LGN ) are those of the visual-distorting drugs LSD, DOM, mescaline, psilocybin, and others of their ilk. With respect to the visual system, at least, the pharmacological mechanism(s) of the effects of these drugs seems to depend on an attenuation of the ordinary light-evoked input from the retina. This attenuation seems mainly to be by an increase in spontaneous retinal activity (Apter & Pfeiffer, 1957; Schwartz & Cheney, 1965a, 1965b; Mouriz-Garcia, et al., 1969). Against an increased background of spontaneous activity, retinal responses to images of real objects would have a reduced effect on responses of the retinal ganglion cells. There are reports that the drugs tend to prolong certain retinal evoked potentials (Apter & Pfeiffer, 1956) and color responses (Keeler, 1965) for periods of seconds or minutes. A fundamental problem related to retinal response to drugs and to concomitant responses of the LGN is that the neurotransmitter released by the optic tract axonal terminals of the retinal ganglion cells may be acetylcholine (ACh) (Brawley & Duffield, 1972, p. 51); but it is not known and may be a substance hitherto unrecognized as a transmitter (Tebecis, 1973). Thus, pharmacologically controlled changes of LGN activity cannot yet be analyzed in the context of pharmacological actions at LGN synapses known to be controlled purely by a retinal input. The retina mediates certain phenomena characteristically affected by drugs. One such purely retinal psychophysical phenomenon is Bloch's law, which states that, for a given small retinal area, a response such as an absolute-threshold jnd or a ganglion-cell output will be the same for stimuli which have the same luminous energy. Thus, two retinal stimuli which are delivered at equal luminous energies will have the same visual effect. Stimulus duration and intensity may be traded off for the same effect, provided their product, Intensity Time, is the same. Bloch's law holds for stimulus-flashes of less than about 0.1 sec., the "critical duration" of summation which itself depends on adaptation and various stimulus parameters (Bartlett, 1965, pp. 170-174). Bloch's law has been shown to hold at the vertebrate receptor-cell level by isolating the retinal photoreceptors pharmacologically (Hood & Grover, 1974). The methods of isolation illustrate some of the functional organization of the retina. These methods include topically applied cobalt ions (Co 2+),

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glutamate, or the glutamate precursor, aspartate. These agents affect the receptor cells only slightly. The cobalt blocks calcium conduction channels, while aspartate or glutamate causes a depolarization block of the horizontal cells combined with a static reversal of polarity of the depolarizing and the hyperpolarizing bipolar cells (Cervetto & MacNichol, 1972; Murakami, et al., 1972; Hood & Grover, 1974; Dacheux & Miller, 1976). The action of aspartate evidently depends on a spreading retinal depression mediated by a spreading local release of glutamate (Hood & Grover, 1974; van Harreveld & Fifkova, 1970). In any case, the isolated vertebrate retinal receptors, like those of invertebrates (Hartline, 1934), seem to display already the same summation of effect that the intact organism shows in psychophysical studies of Bloch's law. Another phenomenon, the McIlwain effect, represents, apparently, an intrinsic response of the entire retina (McIlwain, 1964; Levick, et al., 1965). Here, the firing rate of single retinal ganglion cells (on-center or off-center and regardless of receptive-field size) is increased or otherwise sensitized by moving stimuli up to 90 away in visual angle. The magnitude of this effect is independent of direction of locus of the moving stimulus and depends reliably on distance of the moving stimulus from the receptive field center (Levick, et al., 1965; Fischer, et al., 1975; Barlow, et al., 1977). This effect is not explainable by single receptive-field responses as conventionally defined. The effect seems to arise in a retina-wide interaction of conventional receptive fields (McIlwain, 1966) or possibly in a relatively independent, widespread system of amacrine cells (Barlow, et al., 1977) which respond preferentially to moving edges in the retinal image. Barbiturates as control drugs. Although barbiturates often are used as anaesthetics or as experimental controls for studying the effects of other drugs, barbiturates have been reported to have profound disturbing effects on retinal temporal response (Creutzfeldt & Sakmann, 1969; Schmidt & Creutzfeldt, 1968). Barbiturates are used with caution, therefore, in studies of visual-system single units. As a circulatory mechanism is not likely (Anderson & McIntosh, 1967), it seems reasonable that the selectively temporal action of barbiturates at the retina might be by potentiation of gamma-aminobutyric acid (GABA)-mediated inhibitions, the GABA being controlled by responses of long-distance slowly transmitting stratified amacrine cells (Caldwell, et al., 1978; Werblin, 1977; Nicoll, 1978). The McIlwain effect is abolished by subanaesthetic doses of barbiturates (McIlwain, 1964; Bishop, 1967). However, barbiturates are not known to alter the spatial characteristics of retinal receptive fields, as conventionally defined, in any important way. In particular, the spatial organization of the ganglion-cell receptive fields, being governed evidently by horizontal cell-bipolar cell interactions (Werblin & Dowling, 1969), seems not to be influenced by barbiturates.

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Critical flicker fusion frequency. As mentioned above, Bloch's law involves a critical duration of energy-summation which undoubtedly (Kelly, 1972) covaries with the periods of temporal resonances such as may be inferred to govern critical flicker fusion frequency (CFF). A psychophysical treatment of CFF by Kelly and Wilson (1978) suggests that mechanisms determining an upper limit for human psychophysical flicker sensitivity might be localized to the receptor-cell and bipolar-cell layers of the retina. The suggestions above that barbiturates act on temporal properties of the retinal neurons is not inconsistent with data showing that CFF is depressed by barbiturates and other drugs which reduce or depress various kinds of performance (Besser & Duncan, 1967; Hollister, 1968; Misiak, et al., 1966). These actions presumably are central to the retina. CFF also is increased following administration of CNS stimulants (Besser & Duncan, 1967; Smart, et al., 1967). Furthermore, a mixture of individually effective doses of barbiturate and amphetamine can be chosen which leaves CFF unaffected (Turner, 1965). The amphetamine-like appetite suppressant, fenfluramine, not known to be a CNS stimulant, also does not affect CFF (Hill & Turner, 1967). The influence of caffeine on CFF remains controversial (Goldstein, et al., 1965). LSD has been found to improve discrimination of flicker in rats, with mescaline degrading the discrimination antagonistically (Schechter & Winter, 1971). This suggests a retinal site of action for LSD, although no 5-HT-containing neurons have been found yet in the retina. The mescaline antagonism, as discussed below, may be at central sites by a mescaline metabolite resembling 5-HT (Haigler & Aghajanian, 1973). As it happens, observed changes in response-patterns of retinal ganglion cells during dark adaptation support Tebecis' (1974, p. 243) position that dopamine-containing neurons, viz., amacrines and/or interplexiform cells, are involved in dark adaptation in such a manner that dopamine (DA) decreases as light-levels (and concomitant ganglion-cell receptivefield opponent organization) decrease (Yoon, 1972). The decrease in opponent organization entails what probably is a decrease in receptive-field surround inhibition (e.g., Barlow, et al., 1957) resulting in a spread of the center response into regions formerly part of the surround. Tebecis' position also has been supported by recent experimental assays of DA in rats (Iuvone, et al., 1978). Because LSD has been found to stimulate DA receptors (da Prada, et al., 1975), a light-like stimulation at sites normally stimulated by amacrine-released DA could be the source of the color- and shape-distortions of vision commonly reported by humans given LSD. Changes in temporal response-patterns of color-opponent ganglion-cell receptive fields might be sufficient, in fact, to explain the distorting effects of LSD purely at a retinal level. In a purely psychophysical context, Matteson and Lewis (1979) have speculated that high background luminances might favor movement-perception by favoring responses

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of transient retinal units over those of sustained units. The known improvement of CFF by LSD is anomalous behaviorally in that the drug degrades most other kinds of discrimination performance and indeed encourages illusions, including those of highly saturated colors (e.g., Isbell, et al., 1956; Blough, 1957; Carlson, 1958; Edwards & Cohen, 1961; Hartman & Hollister, 1963). However, if LSD tended to spare the activity of the larger retinal Y-like transient cells while inhibiting the other, smaller, ganglion cells, the average frequency response of the retina could improve at the superior colliculus (Anderson & Symmes, 1969; Schiller, 1977) by elimination of input from the more sluggish, smaller-diameter fibers; this improvement in CFF would be at the cost of wavelength discrimination, chromatic-contrast sensitivity, and acuity. All this last is to suggest that, consistent with data of Schwartz and Cheney (l965b), LSD changes retinal responses of sustained more than of transient units. Lateral Geniculate Effects The ordinary spontaneous activity of the LGN depends on an intact retinal input (Levick & Williams, 1964; Rodieck, 1967) but may be increased or sensitized by glutamate or aspartate directly applied to LGN neurons (Morgan, et al., 1972; Curtis, et al., 1972). A similar increased response is evoked by ACh or d,1-homocysteate (DLH) (Curtis, et al., 1972). The actions of glutamate, aspartate, and DLH are antagonized at the LGN by 1-glutamic acid diethyl ether (Curtis, et al., 1972). For appropriate stimulation in their receptive fields, LGN neurons tend to relay single action potentials in response to single optic tract action potentials; this one-in/one-out temporal relation is changed to a one-in/many-out "spike chain" response under light barbiturate anaesthesia, at least in the cat (Hubel & Wiesel, 1961; Rodieck, 1967). The LGN receptive fields are described by Hammond (1973) and Poggio (1974). Visual pathways through the LGN are reviewed by Rodieck (1979). Excitatory retinotopic influences have been found which depend on an intact visual cortex, but these presumably corticogeniculate projections are of unknown pharmacology (Kalil & Chase, 1970). Such extraretinal influences on the LGN are reviewed in Singer (1977) and in Burke and Cole (1978). LSD probably interacts with 5-HT receptors at the LGN, possibly blocking LGN responsiveness to changes in the activity of endogenous 5-HT locally released as well as reducing brain 5-HT turnover (Lin, et al., 1969). LSD and psilocybin (and norepinephrine) depress orthodromic transmission through the LGN (Curtis & Davis, 1961; Phillis, et al., 1967a). LSD prevents photically initiated seizures in the epileptic baboon Papio papio, and this action has been supposed to occur at the LGN (Walter, et al., 1971; Vuillon-Cacciuttolo, et al., 1973). The action of LSD at the LGN has been held to be postsynaptic (Himwich

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& Alpers, 1970; Bishop, et al., 1958; Bishop, et al., 1959), presumably at a 5-HT stereospecific binding site (Bennett & Snyder, 1975) because exogenous 5-HT also suppresses synaptic transmission at the LGN (Curtis & Davis, 1963; Phillis, et al., 1967a). Postsynaptic sites also have been suggested for DOM (Wallach, et al., 1972). LSD could act at the LGN by a competitive antagonism for 5-HT receptor sites on GABA-releasing inhibitory interneurons, which latter might have either postsynaptic or presynaptic effects on LGN activity. Singer (1977) summarizes evidence that all normal physiological inhibition of LGN primary afferents is postsynaptic. However, Cottrell (1970) has found LSD to increase the size of excitatory postsynaptic potentials (EPSPs) after initially temporarily depressing them. The increase was antagonized by reserpine, so the action of LSD at LGN 5-HT synapses also would seem to be at least indirectly presynaptic, a conclusion compatible with findings of Curtis and Davis (1962). Such presynaptic sites might exist at the terminals of fibers projecting from the midbrain reticular formation, from the dorsal raphe nuclei, or from visual cortex. Tebecis (1974, pp. 130 ff.) has suggested a dose-level dependency of effects induced by LSD or 5-HT at the LGN. Lower doses depress orthodromic transmission only, while higher doses also depress antidromic transmission and the various excitations elicited by drugs. Horn and McKay (1972) have reported dose-dependent changes in the action of LSD at the LGN of urethane-barbitol-anaesthetized cats. A large dose (200 g) of LSD suppressed spontaneous LGN activity as well as orthodromic transmission. A moderate dose (100 g) excited some cells while depressing others. A small dose (25 g) was reported to have only a subtle effect on geniculate receptive fields, distorting some of the center-surround relationships. Such "distortion" of receptive fields of directionally sensitive cells could correspond easily to a perceived movement or flowing in small regions of the visual field. The time-course of inferred perceptual actions at the LGN therefore suggests similar pharmacological courses of action for LSD and exogenous 5HT. Either of these substances given in a large dose might first prevent virtually all retinal inputs, then some minutes later would permit transmission by a limited subpopulation of principal cells (allowing a "simplified" resonant but noisy driving by retinal spontaneous or visual activity). Finally, minutes or hours later, normal functioning of all but the most highly organized receptive fields would be permitted. This action at the LGN could occur in combination with various retinal effects. Again, systematic centrifugally determined actions at the retina could not occur for lack of centrifugal efferent retinal fibers. Inhibition of afferent inputs in the LGN seems likely to be mediated by GABA, which depresses orthodromic transmission (Curtis & Tebecis, 1972; Johnston, 1976) and possibly acts selectively on on-center cells (Morgan, et al., 1975). On this basis, it seems reasonable to the present author, as suggested

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above, that the LGN might include a population of interneurons which release GABA upon being stimulated at 5-HT-sensitive receptor sites. It seems worthwhile to mention also that cannabinoids have been reported to affect on-center cells preferentially (Paton, 1975). Bicuculline reverses GABA-mediated LGN on-inhibition (Morgan, et al., 1975) and spreads the center response-pattern of a receptive field into the surround, and occasionally vice-versa (Cameron & Silleto, 1977). One wonders whether bicuculline would induce LSD-like visual distortions this way, if the drug could be administered locally at the LGN in humans. Cortical interactions. Various anatomical and physiological corticofugal relationships are reviewed by Singer (1977). Smythies, et al. (1960) have reported that cortical-evoked responses following administration of mescaline show an initial depression, then an augmentation, which is reminiscent of the LSD effect at the LGN. These authors also report that the evoked-potential waveform became simpler and more stereotyped when mescaline was given to unanaesthetized rabbits. Stereotypy of the electroencephalogram (EEG) waveform likewise has been reported after doses of DOM or LSD (Wallach, et al., 1972). A reduced variability of retinal inputs could account for this sort of stereotypy. General attenuation of input or selective loss of visual-system variability in response to light also could be used to explain the reported lack of potentiation of LSD effects on humans in sensory deprivation (Cohen & Edwards, 1963; Brawley & Duffield, 1972, pp. 44-45). A lack of variability of response to nothing would of course have little psychotomimetic effect, at least as measured against any conceivable control condition. Rodin and Luby (1966) have analyzed EEG records and concluded that the apparently "activated" desynchronization caused by LSD involves a reduction in EEG amplitude at all frequencies, a reduction which happens to be least at the higher frequencies. Brainstem interactions. Physiological interactions with lower brain regions render all the preceding remarks tentative: DOM, for example, may have its hallucinogenic action purely by virtue of an inhibitory effect on a midbrain mechanism neurologically obscure but evident in EEG records (Himwich & Alpers, 1970). This mechanism may involve raphe projections to the superior colliculus (Fukui & Vogt, 1975) or to the ascending reticular system (Brawley & Duffield, 1972, p. 53). Various known projections are described by Singer (1977) and by Burke and Cole (1978). There is evidence, too, that LSD and mescaline may have different physiological modes of action: in single-cell studies, mescaline applied to the midbrain raphe affects 5-HT-sensitive neurons differently there than does LSD; mescaline may produce its LSD-like effects solely through a peripheral 5-HT-like metabolite capable of crossing the blood-brain barrier (Haigler & Aghajanian, 1973). In an increasing perversity of the physiology of the situation, LSD elevates

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brain 5-HT while depressing brain norepinephrine (NE) (Himwich & Alpers, 1970; see above comments on LSD action and on flicker). Indeed, either ACh or NE is found electrophoretically to excite the principal cells of the LGN, while 5-HT is found to depress them (Satinsky & Salmoiraghi, 1967); see also Phillis, et al. (1967a) who find NE inhibitory in the LGN. However, ACh may not even occur in the primary visual pathways. These complications seem to arise in the reticular formation, which projects to the LGN and apparently modulates visual inputs there by means of excitatory ACh synapses (Phillis, et al., 1967b; Spehlmann, et al., 1971; Curtis & Crawford, 1969; Tebecis, 1973; Tebecis, 1974, p. 137; Miller, et al., 1969; Singer, 1977; Burke & Cole, 1978; Steiner, 1968). In fact, the reticular formation modulates visual-cortical evoked potentials, increasing them in response to brainstem-injected epinephrine and decreasing them in response to ACh (Courville, et al., 1962). The possibility of reticular-system interaction with the cortical modulations of LGN activity found by Kalil and Chase (1970) evidently has not yet been investigated pharmacologically. It seems likely that CPZ reverses the hallucinogenic actions of LSD, mescaline, psilocybin, etc., by depressing NE-mediated excitatory afferents into the reticular formation. Reserpine and amphetamine may exacerbate the psychotomimetic symptoms of LSD by freeing NE from peripheral stores, thus increasing reticular stimulation indirectly (Brodie, et al., 1961; Hoffer, 1965, p. 226; Freedman, 1969; Nakai & Takaori, 1974). Hoffer (1965, pp. 226-227) has found nicotinic acid an effective antidote to the central effects of LSD. This action might be by augmentation of endogenous tryptophan and a resultant increase in available tryptophan for manufacture of 5-HT or some other competitor for LSD binding sites (Lin, et al., 1969). There have been reports that pipradol blocks LSD psychosis (Fabing, 1955), as possibly may the pipradol structural isomer azacyclonol (Bowman, et al., 1968, pp. 602, 619). Such blockage might be explainable by an action on cholinergic receptors of the reticular formation. Behavioral Effects of LSD Some care in interpretation is needed to separate effects which do not depend on the visual system as such. For example, a fall in adrenergic input to the reticular system has been used as an explanation of various decrements in visual performance observed in humans after long periods at vigilance tasks (O'Hanlon, 1965). Such decrements need not be related at all to any decrement in visual function. Also, as mentioned above, atropine degrades visually controlled maze-running in rats (Whitehouse, 1964). Scopolamine reduces stimulus control in three-choice visual discrimination by rhesus monkeys (Evans, 1975). Either of these last two drugs may have reticular effects which far override their known preretinal effects (e.g., Roberts & Bradley, 1967).

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Furthermore, even at the level of the LGN, drugs such as LSD could have a direct action on chromatic "memory" mechanisms such as have been hypothesized to exist there by Kruger (1979). Nevertheless, attempts have been made specifically to measure the visual perceptual effects of LSD and similar drugs. Tolerance has been noted for the effects of LSD and mescaline on performance in pigeons (Becker, et al., 1967) and in rats (Freedman, et al., 1958). An animal-behavioral approach has yielded a "limb-flick and abortive grooming" index of the actions of indole-nucleus hallucinogens in cats (Jacobs, et al., 1976, 1977a); this index is valid to the extent of showing tolerance (Jacobs, et al., 1977b), just as hallucination, mydriasis, reduction of IQ, and other LSD-responses show tolerance in humans (Cholden, et al., 1955; Isbell, et al., 1956; Abramson, et al., 1956). LSD slightly elevates absolute visual threshold in the pigeon (Blough, 1957) as well as in the human (Carlson, 1958). Flicker discrimination has been studied in pigeons (Becker, et al., 1967) and in rats (Schechter & Winter, 1971). For both species, as suggested above, flicker sensitivity apparently was increased by LSD. In the latter study of the rat, CFF apparently was decreased by mescaline such that the actions of LSD and mescaline were antagonistic. In a human psychophysical study, Edwards and Cohen (1961) found that simple and discriminative visual reaction times were increased by LSD, as were the measured magnitudes of illusions based on size-constancy or the Muller-Lyer. In addition, skinwarmth detection and two-point tactile threshold were degraded, but the detection of color in white light was not affected. In another study, Hartman and Hollister (1963) reported that hue discrimination was degraded by LSD although subjective reports were that colors were enhanced (saturated). These effects would be consistent with an LSDinduced exaggeration of color-contrasts resulting from a simplification (populationwise or unitwise) of retinal and/or LGN color-opponent receptive fields, as suggested above. The results of Hartman and Hollister (1963) also confirm an earlier study (Hollister & Hartman, 1962) of LSD, mescaline, and psilocybin. The earlier study indicated that colors evoked by flicker are increased by these drugs, but that chip-ordering in the Farnsworth-Munsell hue test is made poorer. It should be mentioned that Abramson, et al. (1955) found LSD increased reaction time significantly when the task was to read names or name colors but not when the task simply was to move a finger in response to a visual or auditory (simple or discriminative) stimulus. In short, except for visual flicker, LSD reduces stimulus control or at least does not improve it as also do atropine and scopolamine.

Effects On the Pain System


Theories of pain have been reviewed in Fields and Basbaum (1978), Dykes (1975), Rosomoff (1969), and Lim (1970), all of whom consider pain

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a distinct sensory input mediated by a specific afferent system. Other approaches to pain, e.g., Melzack & Wall's (1962) pattern theory, are cited by Fraser and Harris (1967). Psychophysical data support a sensory-system approach to pain (e.g., Hall, 1958a, 1958b; Clark, 1978; Mountcastle, 1974), as does a recent paper by Barber, et al. (1978) demonstrating what may be in part a GABAergic presynaptic pain "gate" in the rat substantia gelatinosa of the spinal cord. The midbrain reticular formation or other more central regions also must be involved, because nothing more than loud noise plus music has been an effective analgesic for dentistry (Gardner, et al., 1960). It is known, too, that in many humans the central analgesia caused by morphine can be no different, at least behaviorally, from that caused by a placebo (Criswell & Levitt, 1975, pp. 193-194). Serotonergic Factors The effect of LSD on the dorsal spinal cord seems to be the same as its effect on the LGN: LSD apparently blocks normal tonic inputs. The pharmacology is different, though, in the pain system. LSD has a powerful analgesic action in humans, but unfortunately it evokes severe psychotic symptoms in addition to analgesia (Kast & Collins, 1964). LSD furthermore develops tolerance (but not dependency) extremely rapidly (Cholden, et al., 1955; Isbell, et al., 1956; Abramson, et al., 1956), at least with respect to all its easily observed effects. In rats, LSD, mescaline, and other hallucinogens block ordinary responses to punishment (Schoenfeld, 1976). These actions apparently originate at neurons of the midbrain raphe nuclei (Aghajanian, et al., 1970; Aghajanian, 1972) and probably are effected by inhibition of just those raphe neurons which can be excited by exogenous 5-HT (Boakes, et al., 1970a, 1970b). LSD action at the raphe also may be by direct antagonism of 5-HTmediated synaptic activity (Bradley & Briggs, 1974; Couch, 1976). A presynaptic site of action of LSD in the raphe is suggested by a presumed habenula-mediated suppression of raphe 5-HT neurons (Wang & Aghajanian, 1977) and by the greater sensitivity of raphe neurons to LSD than that of neurons in regions to which the raphe sends projections (Haigler & Aghajanian,1974). If the action of LSD were presynaptic at the spinothalamic pain "gate," the drug could prevent all effects of nociceptive afferent impulses on the more central neurons of the spinal cord. The analgesic action of LSD might be indirectly presynaptic, also, involving a synapse at which LSD potentiated Substance P (Otsuka & Takahashi, 1977, citing Krivoy). Substance-P-containing cell bodies are found in the medial habenula, and their terminals are found throughout the spinal cord and brainstem (Hokfelt, et al., 1975). The extreme sensitivity of raphe neurons to LSD might derive from the known great potency of Substance P, a putative neurotransmitter which might normally act at LSD-sensitive raphe receptor sites to regulate a presynaptic inhibition of pain-mediated

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inputs and their concomitant spinal and brainstem reflexes. The pharmacological analysis is complicated by the reduction in 5-HT turnover which occurs with administration of LSD (Lin, et al., 1969), by a possible 5-HT-mediated reward system involving raphe neurons (Miliaressis, et al., 1975), and by a lack of drugs acting specifically enough on 5-HT neurons alone (Chase & Murphy, 1973; cf. Vogt, 1974). The involvement of brainstem 5-HT neurons with psychotomimetic activity is not inconsistent with an involvement with opiate analgesia. Baldessarini and Gerson (1973) found that intraventricular 5,6-dihydroxy tryptamine (5,6-DHT) persistently reduced CNS levels of 5-HT, especially in the lower brainstem and spinal cord. Vogt (1974) used both pCPA and 5,6-DHT to show that reductions in 5-HT in the rat spinal cord also led to a reduced analgesic action of morphine as measured by a foot-pressure test. The 5,6DHT evidently selectively destroyed spinal 5-HT axons so that the analgesia was observed only after relatively high doses. After pCPA treatment, which lowered both spinal and brainstem 5-HT, analgesia could be reestablished only by increasing the dose of morphine beyond that effective after the 5,6-DHT treatment. Electrical stimulation of periaqueductal grey matter near the dorsal raphe produces analgesia correlated with an inhibition of certain spinal interneurons (Liebeskind, et al.,1973). This analgesia can be blocked by local pCPA (Akil & Mayer, 1972; Guilbaud, et al., 1973) or by LSD (Guilbaud, et al., 1973). Electrical stimulation of this sort also increases the amplitude of dorsal root potentials as does local iontophoretic 5-HT (Barasi & Roberts, 1974). In addition, behavioral studies have shown that the stimulus properties of intraperitoneal LSD are closer to those of electrical raphe stimulation than to those of intraperitoneal morphine (Hirschhorn, et al., 1975). This last would be expected if increased raphe activity and morphine had opposite effects on the system mediating these stimulus properties and if LSD and morphine otherwise had very different CNS effects (Kast & Collins, 1964; Schechter & Rosencrans, 1972). Morphine thus could not be confused with either other treatment, leaving the other two treatments somewhat confusable (in their stimulus properties) with each other. It is possible to conclude that stimulation-produced analgesia, like LSD or methylamphetamine analgesia, involves at DA component not necessary to morphine analgesia (Major & Pleuvry, 1971; Akil & Liebeskind, 1975; Deakin, et al., 1978). Indeed, da Prada, et al. (1975) have found that LSD can stimulate DA receptors. But any such DA receptors of nonopiate analgesia cannot exclusively be nigrostriatal, because Price and Fibiger (1975) have shown that destruction of the DA nigrostriatal system with 6-hydroxydopamine (6-OHDA) causes loss of morphine analgesia. Other considerations will be necessary to resolve this problem.

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It has been shown that acute morphine administration can stimulate 5-HT synthesis and that the increase in synthesis, like opiate analgesia, is subject to tolerance over repeated doses (Yarbrough, et al., 1973). Furthermore, methysergide and cinanserin, both considered nonspecific 5-HT antagonists, antagonize morphine analgesia in the periaqueductal grey. This antagonism probably

Fig. 1. Central sites of LSD action in hypothetical system consistent with conclusions drawn in the text. Abbreviations: I = interneuron; P = principal cell of LGN; G = retinal ganglion cell; PAG = neuron of periaqueductal grey matter; arrowhead = effect otherwise not specified. Abbreviations of putative neurotransmitters are as in the text. Axonal terminals at excitatory synapses are drawn in the shape of a cross; those at inhibitory synapses are drawn as a flat bar. Question marks indicate influences considered tenable but for which doubt or controversy has been expressed in print as of 1978.

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is by depression of 5-HT-releasing neurons ordinarily excited by morphine (Yaksh, et al., 1976; Dey & Feldberg, 1975). This suggests that morphine acts to excite or disinhibit serotonergic neurons possibly receiving a tonic inhibitory input from the raphe (Morillo, et al., 1965; Brawley & Duffield, 1972, p. 53). In any case, it seems clear from Vogt's (1974) study using 5,6-DHT that spinal 5-HT neurons are involved in the analgesic action of morphine on opiate receptors in the region of the periaqueductal grey (also Deakin, et al., 1978). These opiate receptors may be the ones which respond to endogenous opiates the endorphins for normal neuroregulatory suppression of dull pain (Snyder, 1977; Snyder & Childers, 1979; Akil, 1977, pp. 300-302; Cooper, et al., 1978, pp. 264-271). Finally, lesions of the raphe are found to prevent morphine analgesia (Proudfit & Anderson, 1975). Such prevention could arise if hypersensitivity developed in those raphe-innervated neurons ordinarily responding to morphine, and if this hypersensitivity then caused an increase in tolerance to subsequent morphine action. Thus morphine analgesia appears likely to originate in cells receiving inputs from 5HT-sensitive neurons with cell bodies in the midbrain raphe (Dey & Feldberg, 1975). Morphine and LSD, therefore, both may be seen to act on a serotonergic component of the pain system, perhaps in some such manner as diagrammed in Fig. 1. Nonserotonergic Factors Biogenic amines. 6-OHDA makes it possible to destroy NE or DA terminals selectively (Thoenen & Tranzer, 1975). It was mentioned above that stimulationproduced analgesia may have a DA component different from any DA component involved in morphine analgesia (Akil & Liebeskind, 1975). In rodents, 6-OHDA has been used to show an attenuation of opiate analgesia (Price & Fibiger, 1975; Blundell & Slater, 1977) and a reversal of morphine tolerance by an action probably related to NE depletion in the brainstem (Nakamura, et al., 1973; Price & Fibiger, 1975). Biogenic amines other than 5-HT therefore would seem to be involved in the pain system, possibly in a circuit including the locus coeruleus (Price & Fibiger, 1975). Cholinergic influences. The modulation of LGN activity discussed above apparently depended not only on a system of 5-HT-sensitive receptors but also on a centrifugal cholinergic component controlled by the reticular formation. The situation may be the same for the dorsal spinal cord junctions of the pain system: cyclic guanosine monophosphate (cGMP) mimics analgesic responses to morphine when the cGMP is administered in the lateral ventricles (Cohn, et al., 1978). The cGMP-analgesia observed is dose-dependent, not antagonized by naloxone, and unaccompanied by respiratory or other behavioral depressions. The suggestion of Cohn, et al. (1978) indeed is that more than one pharmacological mechanism must exist for analgesia and that the opiates and cGMP

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act on different ones (Liebeskind, 1978). An admitted problem, however, seems to be that in rat striatum, at least, opiates themselves can induce an increase in cGMP (Cohn, et al., 1978). Thus, an ACh-cGMP analgesic mechanism in this region would not be entirely independent of a similar (endogenous?) opiate mechanism. Also, Pedigo and others (1975) have produced analgesia by direct application of ACh in the cerebral ventricles. This ACh-analgesia, presumably correlated with, if not caused by, a rise of ventricular (or septal) cGMP, was antagonized by various opiate antagonists. Furthermore (Pedigo, et al., 1975), the antagonistic potency of the opiate antagonists tested was exactly in the order of their potency in antagonizing morphine. The data therefore suggest that there is only a single mechanism for analgesia. The pharmacology of this mechanism may yet link it to the habenula or the dorsal spinal cord. Substance P. This polypeptide readily crosses the blood-brain barrier in rats (Stern & Hadzovik, 1973). Applied iontophoretically, Substance P specifically excites units in the dorsal horn which are activated by heavy pressure in the limbs or by noxious thermal stimuli, or which fire to volleys of off-responses in A-delta and C fibers of spinal laminas I, II, and III (Randic & Miletic, 1977). These effects of Substance P are antagonized by beta-(4-chlorophenyl)-GABA (baclofen, Lioresal), which may be a specific Substance P antagonist (Saito, et al., 1975) or a general spinal depressant (Ben-Ari & Henry, 1976). Substance P has been located by histofluorescence in various subcortical structures including spinal and trigeminal ganglia, the periaqueductal grey matter, and the substantia gelatinosa (Hokfelt, et al., 1975); it is in these regions that habenular fibers may exert a central pain-reducing effect. The action of Substance P has been studied in the spinal motor regions. Injected intramuscularly, Substance P increases spinal glycine and thereby probably inhibits efferents in these regions (Stern, et al., 1974). In sensory regions, transection studies of dorsal root neurons suggest that Substance P is formed in cell bodies in the spinal ganglia and transported to synaptic terminals within the spinal cord (Takahashi & Otsuka, 1975). Although Substance P therefore seems to be an afferent transmitter at one or more stages of the primary somatosensory pathway (Otsuka, et al., 1978), it probably does not mediate the specifically aversive properties of pain because LSD, a powerful analgesic, potentiates the action of Substance P in the dorsal roots (Krivoy, 1961). Substance P increases brain ACh and potentiates LSD tremor in mice (Stern, 1973). Substance P also abolishes the morphine abstinence syndrome precipitated by nalorphine in mice (Stern & Hadzovik, 1975). As suggested, Substance P may act as a centrally controlled neurotransmitter to suppress 5-HT-sensitive raphe neurons which tonically inhibit a set of 5-HT-sensitive

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neurons excited by morphine to produce the typical opiate analgesia (Fig. 1). At a minimum, an inhibitory effect on spinal motor efferents would augment any painsuppressive action of Substance P by reducing motor responses commonly used operationally to define pain in experimental animals. Pain-detection and Analgesia Reviews of neurological theories of pain are presented by Rosomoff (1969), Domino (1962), and Mountcastle (1974). A basic clinical problem with opiate analgesics is that tolerance develops. Doses then must be increased to achieve a given analgesic effect, and the increased doses also increase the ill effects of withdrawal of the drug. Moreover, tolerance may not develop to the positively reinforcing effects of the drug (the "high" feeling) (Esposito & Kornetsky, 1977). This dual mechanism of opiate addiction may explain findings that analgesia can be effective by interaction of the drug with a tolerance-vulnerable mechanism. At the same time thresholds for pain-detection may not rise because the drug also heightens sensory-related activity by a tolerance-resistant mechanism (Lineberry & Kulics, 1978; Chapman, et al., 1965). A patient may report pain but have no difficulty responding as though there were no pain present. Consistent with multiple mechanisms for pain-response, acupunctural analgesia has been reported not to impair pain detection (Clark & Yang, 1974). A dual mechanism may function in the case of the nonopiate marijuana, which is liable to increase sensitivity to pain (Hill, et al., 1974) but yet to potentiate barbiturate or ether anaesthesia as measured by the righting reflex (Malor, et al., 1975). These findings and others similar, coupled with the known considerable placebo effect found for morphine and other analgesics (above), lead to the conclusion that analgesia is a higher-order response probably including a motor component absent in the simple detection of painful (noxious) stimuli. Comparing LSD-analgesia with LSD-hallucinogenesis, the physiological correlates of delirium might seem more closely related to LSD-analgesia than would the physiological correlates of perceptual distortion.

Resum and Conclusion


(1) It is suggested that object perception is essential to the survival of any spacebinding organism. Human beings bind space as well as time and so also depend upon object perception. (2) The visual system is unique in that it necessarily has evolved to process information at an enormous rate, a rate which makes possible object perception mediated solely by interaction of the omnipresent electromagnetic radiation of the sun with the various nutrient-related environmental objects. (3) It is argued that ground-dwelling mammals, including humans, lack central efferent retinal fibers because such fibers would reduce object-mediated

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visual information input. Such a reduction would render mammalian space-binding less efficient in terms of nutrient-object perception. (4) One consequence of this lack of central retinal efferents, a relatively wellestablished anatomical fact, is that hallucinogenic drugs cannot act selectively on the visual periphery (as they may, for example, in the auditory system) to impose nonveridical perceptual inputs. Psychoses therefore tend not to involve visual hallucinations other than those entailed in profoundly deluded, more centrally disturbed, behavior. Hallucinogenic drugs which act on the visual system thus tend to act solely by reducing and rendering ambiguous the visual effects of otherwise easily perceptible environmental objects. (5) Data on LSD are reviewed and presented in a functionalistic context. It is proposed that the major sites of action of LSD in the visual system are the dorsal lateral geniculate nucleus and the retina. At these sites, the drug tends to reduce spatiallyacute sustained-unit inputs and to substitute transient, more or less randomly perturbed, inputs by the larger retinogeniculate, retinocollicular, and retinocortical* afferent fibers. These transient fibers are those normally especially sensitive to image motion across the retina, so one effect of LSD is to superimpose "crawling" movements on objects as though the objects were in fact moving in randomly located small regions of the field of view. An additional inference is that retinal and geniculate cells which normally are coloropponent either are (a) directly disorganized by the random effects of LSD or (b) respond more or less normally to the transient "locally-crawling" contours as though such regions were chromatically as well as dynamically distinct. The mechanism in the latter alternative might be by chromatic enhancement of random inputs normally determined by local retinal-illuminance transients ( e.g., Bowen & Nissen, 1979). Either or both alternative mechanisms could produce the "kaleidoscopic" color-impressions often reported by observers under the influence of LSD. (6) LSD reduces stimulus control (and behavioral performance) although it enhances visual flicker sensitivity. Flicker sensitivity very likely is mediated by those same larger fibers of the visual afferent system that best resist the drug. LSD thus may slightly improve the visual "signal-to-noise" ratio in a flicker detection task. (7) LSD has powerful analgesic effects possibly mediated at the dorsal raphe by means of descending serotonergic inputs to a spinal pain "gate." Doses of LSD high enough to produce analgesia evidently also produce psychotic behavior. (8) All effects of LSD in the visual and in the pain systems seem to be subject to extremely rapid tolerance. The drug is not known to be addicting, although evidence is presented to suggest that LSD, some forms of brain electrical stimulation, endorphins, and the opiate drugs act on the same pain-suppressing mechanisms. * There is a typing error here in (5) which found its way both into the final draft and the published
Monograph Supplement: This word should be geniculocortical, not retinocortical. The lateral geniculate nucleus (LGN), not the retina, connects to the cortex.

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In conclusion, because the visual system has evolved to process stimuli which for the most part hardly are related to any specific response of the seeing organism, drugs, including LSD, can be expected to have direct visual effects mostly unrelated either to motor responses or to object perceptions which would initiate such motor responses reflexly. The pain system, however, has evolved specifically to initiate motor (and other) responses for terminating conditions which would be harmful, disorganizing, or damaging to the organism as such. Drugs acting on the pain system, therefore, including LSD, can initiate direct, centrifugally induced perceptual responses such as analgesia without necessarily involving generalized or debilitating delusions. REFERENCES
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