Mescaline and lysergic acid diethylamide (LSD) as discriminative stimuli

The observation that a particular drug state may acquire the properties of a discriminative stimulus is explicable on the basis of drug-induced interoceptive cues. The present investigation sought to determine (a) whether the hallucinogens mescaline and LSD could serve as discriminative stimuli when either drug is paired with saline and (b) whether discriminative responding would occur when the paired stimuli are produced by equivalent doses of LSD and mescaline. In a standard two-lever operant test chamber, rats received a reinforcer (sweetened milk) for correct responses according to a variable interval schedule. All sessions were preceded by one of two treatments; following treatment A, only responses on lever A were reinforced and, in a similar fashion, lever B was correct following treatment B. No responses were reinforced during the first five minutes of a daily thirty-minute session. It was found that mescaline and LSD can serve as discriminative stimuli when either drug is paired with saline and that the degree of discrimination varies with drug dose. When equivalent doses of the two drugs were given to the same animal, no discriminated responding was observed. The latter finding suggests that mescaline and LSD produce qualitatively similar interoceptive cues in the rat.Supported in part by Graduate Training Grant 2-T01-GM 00107 from the Division of Medical Sciences, National Institutes of Health and in part by Grant MH 15406 from the National Institute of Mental Health.     

A comparison of the stimulus effects of morphine and lysergic acid diethylamide (LSD)

Morphine and lysergic acid diethylamide (LSD) each was used as a discriminative stimulus for rats. After the injection of drug (morphine or LSD), depression of one lever of an operant test chamber resulted in positive reinforcement according to a variable interval schedule of 15 sec (VI-15 sec). When saline was given, responses on the opposite lever were reinforced. Discriminated responding occurred when either morphine or LSD served as the discriminative stimulus. When animals which were trained to d discriminate morphine from saline were given LSD, they pressed predominantly the saline-correct lever. Similarly, LSD discrimination did not generalize to morphine. Two 5-hydroxytryptamine (5-HT) antagonists, cyproheptadine and methysergide, and one acetylcholine (Ach) antagonist, atropine, did not effect morphine or LSD discrimination. The narcotic antagonist, naloxone, blocked the stimulus effect of morphine, but did not alter LSD discrimination. These results indicate that the morphine and LSD stimuli are dissimilar and that the integrity of 5-HT or Ach nervous systems is not essential for morphine or LSD to serve as a discriminative stimulus.     

Role of serotonin in the discriminative stimulus properties of mescaline

Rats were trained to discriminate intraperitoneally administered mescaline from saline in a two-lever operant chamber for food reinforcement. Reward was contingent upon responses made greater than 15 sec apart (DRL-15) on the appropriate lever paired with either drug or saline administration. Following the establishment of discriminative response control by mescaline, the animals were tested for stimulus generalization produced by mescaline after: (a) blockade of peripheral and central serotonin (5-HT) receptors with cinanserin, methysergide, or cyproheptadine; (b) blockade of peripheral 5-HT receptors with xylamidine tosylate; and (c) depletion of brain 5-HT with the tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA). The results show that all three central 5-HT antagonists greatly reduced the discriminability of mescaline while the peripheral antagonist, xylamidine tosylate, was without effect. Furthermore, these agents at the doses employed did not affect the discriminability of saline. Depletion of 5-HT with PCPA potentiated the effects of a sub-threshold dose of mescaline and slightly reduced the discriminability of saline. The results indicate that mescaline produces its discriminative stimulus properties by directly stimulating central serotonergic receptors.     

Comparison of the discriminative stimulus effects of dimethyltryptamine with different classes of psychoactive compounds in rats

Rationale  There has been increased recreational use of dimethyltryptamine (DMT), but little is known of its discriminative stimulus effects. Objectives  The present study assessed the similarity of the discriminative stimulus effects of DMT to other types of hallucinogens and to psychostimulants. Methods  Rats were trained to discriminate DMT from saline. To test the similarity of DMT to known hallucinogens, the ability of (+)-lysergic acid diethylamide (LSD), (−)-2,5-dimethoxy-4-methylamphetamine (DOM), (+)-methamphetamine, or (±)3,4-methylenedioxymethyl amphetamine (MDMA) to substitute in DMT-trained rats was tested. The ability of DMT to substitute in rats trained to discriminate each of these compounds was also tested. To assess the degree of similarity in discriminative stimulus effects, each of the compounds was tested for substitution in all of the other training groups. Results  LSD, DOM, and MDMA all fully substituted in DMT-trained rats, whereas DMT fully substituted only in DOM-trained rats. Full cross-substitution occurred between DMT and DOM, LSD and DOM, and (+)-methamphetamine and MDMA. MDMA fully substituted for (+)-methamphetamine, DOM, and DMT, but only partially for LSD. In MDMA-trained rats, LSD and (+)-methamphetamine fully substituted, whereas DMT and DOM did not fully substitute. No cross-substitution was evident between (+)-methamphetamine and DMT, LSD, or DOM. Conclusions  DMT produces discriminative stimulus effects most similar to those of DOM, with some similarity to the discriminative stimulus effects of LSD and MDMA. Like DOM and LSD, DMT seems to produce predominately hallucinogenic-like discriminative stimulus effects and minimal psychostimulant effects, in contrast to MDMA which produced hallucinogen- and psychostimulant-like effects.     

Stimulus properties of mescaline and N-methylated derivatives: Difference in peripheral and direct central administration

The purpose of this study was to examine the possibility that N-methylated derivatives of mescaline might produce interoceptive stimuli similar to mescaline. Rats were trained in a two-lever operant chamber to discriminate the dragged (mescaline, 25 mg/kg, i.p.) state from the non-drugged state (saline, i.p.). On session days following mescaline administration, only responses on the right lever of the operant chamber were reinforced and on days following saline only responses on the left lever were rewarded. The degree of discrimination between mescaline and saline was determined by the percentage of responding on the state appropriate lever during extinction. Following the acquisition of response control by i.p. mescaline, the subjects were tested for stimulus generalization after i.p. or intraventricular injections of various doses of mescaline, N-methylmescaline (NMM), N,N-dimethylmescaline (DMM), or saline. Intraventricularly administered mescaline exhibited a dose-dependent generalization to the cue produced by systemically injected mescaline, indicating a central nervous system locus of action. NMM demonstrated only saline responses regardless of the dose or route of administration. DMM at a dose of 50 mg/kg, i.p., generated responses characteristic of mescaline, suggesting a similarity in behavioral effects between DMM and mescaline. However, following intraventricular injection of DMM only a transient generalization to the mescaline state resulted. From these results it is concluded that NMM and DMM, two possible metabolites of mescaline, apparently do not play a significant role in the mescaline-induced internal stimuli.This study was a part of a thesis submitted by the first author to the University of Texas Graduate School of Biomedical Sciences in partial fulfillment for the degree Master of Science.     

The effects of 2,5-dimethoxy-4-methylamphetamine (DOM), 2,5-dimethoxy-4-ethylamphetamine (DOET), d-amphetamine,and cocaine in rats trained with mescaline as a discriminative stimulus

The effects of mescaline (3,4,5-trimethoxyphenylethylamine), a hallucinogen, can function as a discriminative stimulus in appropriately trained rats. As a test of the hypothesis that those pharmacologic properties which distinguish hallucinogens and non-hallucinogens in man are reflected in distinctive stimuli in rats, the present experiments examined the effects of 2,5-dimethoxy-4-methylamphetamine (DOM), 2,5-dimethoxy-4-ethylamphetamine (DOET), d-amphetamine, and cocaine in rats trained with mescaline as a discriminative stimulus. Administration of a range of doses of DOM and DOET to subjects in which saline functioned as S^D and mescaline as S revealed that a dose of 0.3 mg of either DOM or DOET was equivalent to the training dose of mescaline. When tested in rats in which mescaline served as S^D, DOM and DOET were likewise found to mimic mescaline. In contrast, doses of d-amphetamine and cocaine (1 and 30 mg/kg, respectively) which were equivalent to the training dose of mescaline as S , did not result in responding appropriate for the mescaline condition when mescaline was trained as S^D. When DOET (0.3 mg/kg) was substituted for saline as S , no evidence of discriminated responding was obtained in the course of 50 sessions. The present data, in conjunction with previous observations, suggest that those effects of mescaline in the rat which function as a discriminative stimulus are better correlated with pre-hallucinogenic LSD-like activity in man then with hallucinogenic activity per se. Thus, these effects in rats represent a necessary but not a sufficient condition for prediction of hallucinogenic activity in man.This investigation was supported in part by Grant 15406 from the National Institute of Mental Health.     

Assessment of the discriminative stimulus effects of the optical isomers of ecstasy (3,4-methylenedioxymethamphetamine; MDMA)

The discriminative stimulus effects of the stereoisomers of 3,4-methylenedioxymethamphetamine (MDMA) were studied in rats trained to discriminate 1.25mg/kg of (+)-MDMA or 3.5mg/kg of (-)-MDMA from saline, in a two lever, water-reinforced, drug discrimination situation. The isomers of MDMA and 3,4-methylenedioxyamphetamine (MDA) substituted completely for both training drugs. The stimulants amphetamine and cocaine did not substitute for either MDMA isomer. The hallucinogens (+/-)-2,5-dimethoxy-4-methylamphetamine (DOM), (+)-lysergic acid diethylamide (LSD), and mescaline failed to substitute completely for (+)-MDMA. Similarly, DOM and mescaline did not substitute for (-)-MDMA; however, LSD did substitute for this isomer at a dose of 0.06mg/kg but not at higher doses. Substitution tests with 5-HT-releasing agents revealed that fenfluramine substituted partially for (+)-MDMA and completely for (-)-MDMA, while p-chloroamphetamine substituted completely for both isomers of MDMA. When given in combination with (+)-or (-)-MDMA, neither the 5-HT(2) antagonist pirenpirone nor the less selective 5-HT antagonist metergoline consistently blocked drug-appropriate responding. These results indicate that the stereoisomers of MDMA and MDA have similar discriminative stimulus properties. More importantly, the present findings suggest that 5-HT release may be important for the discriminative stimulus effects of (+)-and (-)-MDMA. Actions at 5-HT(2) receptors, however, do not appear to be critical.     

Discriminative stimulus properties of mescaline: Mescaline or metabolite?

The purpose of this study was to investigate possible similarities in the interoceptive stimuli produced by mescaline and its metabolites. Rats were trained in a 2 lever operant chamber to discriminate between the drugged state (mescaline 25 mg/kg) and the nondrugged state (saline). Following acquisition of discriminative response control the rats were pretreated with either saline, aldehyde dehydrogenase inhibitors or amine oxidase inhibitors and tested stimulus generalization produced by i.p. injections of 3,4,5-trimethoxyphenylethanol (TMPE), 3,4,5-trimethoxyphenylacetaldehyde (TMPA), N-acetylmescaline, mescaline or saline. The results indicated that both aldehyde dehydrogenase and amine oxidase inhibitors enhanced the effects of mescaline, while TMPE, TMPA and N-acetylmescaline failed to exhibit generalization to the mescaline state, regardless of pretreatment. These findings do not indicate the role of a metabolite in the interoceptive cue produced by mescaline.     

Effects of intraocular mescaline and LSD on visual-evoked responses in the rat

The effects of mescaline and LSD on the flash-evoked cortical potential (FEP) were determined in unrestrained rats with chronically-implanted electrodes. Systemic administration of mescaline or LSD significantly attenuated the primary component of the FEP at three stimulus intensities with the greatest effect observed 60-90 minutes following drug administration. The magnitude and specificity of the effects of these agents on the primary response suggest that they produce deficits in conduction through the retino-geniculato-cortical system. The serotonin receptor antagonists, cyproheptadine and methysergide, antagonized the mescaline-induced depression of the FEP in accordance with neurochemical and behavioral evidence that mescaline acts as a partial agonist on serotonin receptors. Topical or intraocular administration of atropine antagonized the actions of systemically-administered mescaline. In addition, intraocular administration of mescaline or LSD attenuated the FEP indicative of an action of these hallucinogens on visual processing in the retina which is modulated by muscarinic receptor activity.     

Quipazine-induced stimulus control in the rat

The present investigation tested the hypothesis that quizapine, a drug thought to act directly or indirectly as an agonist at serotonergic (5-HT) receptors, mimics the stimulus properties of indoleamine and phenethylamine hallucinogens. In a group trained with mescaline (10 mg/kg) and saline in a singlelever response rate task, quipazine yielded intermediate results (58% mescaline-appropriate at 1 mg/kg), i.e., responding was fully appropriate for neither training condition. A second group was then trained with quipazine (3 mg/kg) and saline in a two-lever response choice task. Stimulus control was readily established with a mean of 22 sessions to achieve criterion performance (five consecutive sessions with at least 80% correct responses). When quipazine-trained rats were tested with LSD; responding was intermediate in nature (68% quipazine-appropriate) at a dose of 100 g/kg but complete substitution was observed at 150 g/kg (97% quipazine-appropriate). Similarly, subjects trained with LSD and saline in the two lever task and tested with quipazine responded in a fashion indistinguishable from the LSD training condition. The stimulus properties of quipazine alone and in cross tests in mescaline or LSD-trained subjects were blocked by the serotonergic antagonist, BC-105. Butaclamol, a dopaminergic antagonist, and the -adrenergic antagonist, phentolamine, were without effect upon quipazine. The present data suggest that quipazine produces its stimulus effects by a serotonergic mechanism and that these effects are quite similar to those of LSD and mescaline.     

Discriminative stimulus effects of the optical isomers of 3,4-methylenedioxyamphetamine (MDA)

The isomers of 3,4-methylenedioxyamphetamine (MDA) functioned as discriminative stimuli in rats trained to discriminate either (-) MDA (1.25mg/kg) or (+) MDA (1.25mg/kg) from saline. Dose- and time-response curves indicated that drug lever selection occurred at doses of at least 1.00mg/kg of (-) MDA and 0.75mg/kg of (+) MDA and that drug-appropriate responding for both isomers was maintained for at least 90min. Cross-substitution was observed between the MDA isomers; both (+) and (-) 3,4-methylenedioxymethamphetamine (MDMA) also substituted completely for (+) and (-) MDA. The hallucinogens (+)-lysergic acid diethylamide (LSD) and (+/-)-2,5-dimethoxy-4-methylamphetamine (DOM), substituted for (-) MDA; neither mescaline nor (+) amphetamine or cocaine had (-) MDA-like effects. LSD also substituted for (+) MDA; DOM, mescaline, (+) amphetamine and cocaine failed to have (+) MDA-like effects. The (-) but not the (+) MDA cue was blocked by the 5-HT(2) antagonist pirenpirone; the dopamine (DA) antagonists SCH-23390 and (-) sulpiride had no effect on either the (-) or (+) MDA cues. When animals were trained to discriminate LSD (0.16mg/kg) or (+) amphetamine (1.0mg/kg) from saline, neither (-) MDA nor (+) MDA substituted completely. These results indicate that: (1) the stimulus effects of the isomers of MDA and MDMA are similar; (2) (-) MDA may be more hallucinogenic (or more accurately, LSD- or DOM-like) than (+) MDA; (3) neither (+) nor (-) MDA has potent amphetamine-like effects; and (4) the effects of (-) MDA may be more serotonergic than those of (+) MDA.     

Assessment of tolerance to barbital by means of drug discrimination procedures

This study was designed to determine the relative development of tolerance to the discriminative-stimulus and hypnotic properties of barbital. By selectively reinforcing lever presses only in the presence of one of the drug states, rats were trained in a Skinner Box to discriminate the effect of sodium barbital (80 mg/kg) injection from that of saline injection. After the rats were well trained, the administration of daily hypnotic doses of barbital (240 mg/kg) for 8 days produced marked tolerance to the hypnotic effect of the barbiturate in all animals. The ability of the 80 mg/kg dose to serve as a discriminative stimulus was not impaired in animals which had been trained with the drug as the condition during which bar presses had been reinforced (S ^D condition). Animals for which bar presses had gone unrewarded under barbital (S condition) displayed a tendency to develop tolerance to the stimulus properties of barbital. These findings are interpreted in the light of dose-effect studies, and it is suggested that the acquired polarity of the drug condition determined by its assignment as S ^D or S may influence the discriminability of the drug in future exposures.Supported in part by the Research Institute on Alcoholism of the New York State Department of Mental Hygiene and Grant No. 15406 from the National Institute of Mental Health.     

Lack of blockade of central dopaminergic receptors by narcotics: comparison with chlorpromazine

d-Amphetamine and saline were used as discriminative stimuli in rats. After 0.6 mg/kg d-amphetamine administration, food reinforcement was contingent upon pressin 1 lever in 2-lever operant chamber. Responding on the other lever was reinforced only after saline injection of equal volume. The animals learned to discriminate between d-amphetamine and saline to a criterion of 85% correct. Administration of 2.5, 5.0 and 7.5 mg/kg morphine, and 0.02 and 0.04 mg/kg fentanyl produced saline-appropriate responses. Pretreatment with morphine and fentanyl had no significant effect on the d-amphetamine induced discriminative stimulus. In contrast, 1.25 and 2.5 mg/kg chlorpromazine antagonized d-amphetamine discrimination. These results indicate that despite their similar effect on brain dopamine turnover, morphine and fentanyl do not act on the same receptor site(s) as the neuroleptics, that is, they probably do not block brain dopamine receptors.     

Antagonism of the effects of the hallucinogen DOM and the purported 5-HT agonist quipazine by 5-HT2 antagonists

Rats trained to discriminate 1.0 mg/kg of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) from saline in a two-lever operant choice task were administered doses of mescaline, LSD, 5-methoxy-N,N-dimethyltryptamine (5-OMe DMT), quipazine, TFMPP and RU-24969. The DOM-stimulus generalized to the three hallucinogenic agents and to quipazine, but not to the purported serotonin agonists TFMPP or RU-24969. Pretreatment of the animals with the 5-HT2 antagonists ketanserin and pirenperone antagonized the effect produced by DOM. Pirenperone also blocked DOM-stimulus generalization to mescaline, LSD, 5-OMe DMT and quipazine. The results of this study suggest that the discriminative stimulus effects of DOM, the three hallucinogenic agents to which DOM-stimulus generalization occurred, and quipazine, may involve those sub-populations of serotonin receptors that are labeled by tritiated ketanserin (i.e. 5-HT2 sites).     

Pentazocine,cyclazocine, and nalorphine as discriminative stimuli

Pentazocine, cyclazocine, and nalorphine are narcotic antagonists that also have analgesic activity of their own. the present investigation compared the stimulus properties of these three drugs in rats. Each drug was used as a discriminative stimulus for a separate group of rats. Depression of one lever resulted in food reinforcement following the administration of drug, and the opposite lever was reinforced after saline. Each drug readily acquired control of discriminated responding. The specific narcotic antagonist, naloxone, which antagonizes many of the effects of pentazocine, cyclazocine, and nalorphine, also antagonized the discrimination of these drugs. Stimulus generalization tests to each other narcotic antagonist, d-amphetamine, morphine, and LSD, showed that each narcotic antagonist has highly specific stimulus properties. Clear generalization occurred only to pentazocine and cyclazocine in the nalorphine-saline group, but neither cyclazocine nor pentazocine generalized to nalorphine.     

In vivo evidence of partial agonist activity exerted by purported 5-hydroxytryptamine antagonists

Using a food-reinforced two-lever operant method, rats (n = 9) were trained to discriminate 0.16 mg/kg LSD from saline. Tests for stimulus generalization in rats so trained indicated that the purported 5-HT antagonists cyproheptadine (1.25 and 10 mg/kg), methysergide (0.16 to 10 mg/kg) and mianserin (2.5 to 40 mg/kg) produced partial generalization with LSD. The hallucinogens mescaline (5 to 40 mg/kg) and quipazine (1.25 to 5 mg/kg) were also generalized with LSD. The data suggest that cyproheptadine, methysergide and mianserin may produce partial agonist effects in addition to their antagonist action at central 5-HT receptor sites.     

Serotonergic-dopaminergic mediation of MDMA's discriminative stimulus effects in a three-choice discrimination

(+/-)3,4-Methylenedioxymethamphetamine (MDMA; "Ecstasy") is a common drug of abuse that is often described as both a psychostimulant and a hallucinogen. Two-choice drug discriminations (i.e. drug vs. nondrug) in nonhumans comparing the discriminative stimulus properties of MDMA to psychostimulants or hallucinogens have produced somewhat inconsistent findings. The relative contribution of serotonergic versus dopaminergic actions to MDMA's discriminative stimulus effects may depend on the training stimulus conditions employed. We have previously demonstrated that rats can learn to discriminate the effects of MDMA and D-amphetamine in a three-choice drug discrimination procedure, and that LSD produced nearly complete substitution for MDMA under these conditions, and fenfluramine fully substituted for MDMA. In the present study, 12 rats were trained to discriminate LSD (0.08 mg/kg) and MDMA (1.5 mg/kg) from saline in a three-choice drug discrimination procedure under a fixed-ratio (FR) 10 schedule of food reinforcement. D-Amphetamine produced only partial substitution for MDMA while fenfluramine produced complete stimulus generalization. Low doses of D-amphetamine and fenfluramine produced greater stimulus generalization when administered in combination than when given alone. The serontonin(2) antagonist MDL-100,907 only partially blocked the MDMA cue, but completely antagonized LSD discrimination. The dopamine antagonist haloperidol also failed to block MDMA discrimination. These results indicate that 5-HT release is a salient feature to MDMA's discriminative stimulus effects but that MDMA produces a compound discriminative stimulus.     

Discriminated conditioned taste aversion for studying multi-element stimulus control

The effects of morphine pre-treatment interval on the stimulus control exerted by a multi-element stimulus consisting of morphine (5.6mg/kg), saccharin (0.2%, w/v), and a ball-bearing drinking nozzle in a discriminated taste aversion procedure were examined. In this discriminated aversion procedure, rats received injections of LiCI following presentation of this multielement stimulus, and injections of saline following the saline, water, and non-ball-bearing nozzle composite stimulus. These paired rats were compared to unpaired rats that received saline injections rather than LiCI injections following presentation of the multi-element stimulus. Morphine pre-treatment times of 5, 10, and 20min were examined in groups of 12 paired and 6 unpaired rats. The discrimination was rapidly learned under all three pre-treatment intervals. In subsequent testing with each individual stimulus element and combinations of two stimulus elements, stimulus control was clearly exerted by both morphine and saccharin. Paired rats drank less saccharin than unpaired rats, and less saccharin than water. Similarly, paired rats drank less fluid following morphine administration than following saline administration, and less fluid than unpaired rats following morphine administration. Control by the nozzle type was also apparent in significant interactions between the nozzle and morphine or saccharin and pairing with LiCI. In general, pre-treatment time did not influence the stimulus control that developed. However, at the two shorter pre-treatment times there was some indication that a conditioned taste aversion to morphine was developing in the unpaired rats. These experiments indicate that such discriminated taste aversion procedures may be viable methods for studying the contextual control of how drugs function as discriminative stimuli, and that longer drug pre-treatment times may be desirable in such procedures.     

Lysergic acid diethylamide (LSD) as a discriminative cue: Drugs with similar stimulus properties

Rats were trained to choose between the arms of a T-maze apparatus according to whether they were injected i.p. with 0.1 mol/kg LSD or 0.9% saline. The LSD drug-state acquired the properties of a discriminative stimulus, possibly by producing interoceptive cues. Doses of 9.0 mol/kg psilocybin and 90 and 120 mol/kg mescaline produced cueing effects which were not significantly different from the cueing effect of LSD. However, d-amphetamine (14.8 and 29.6 mol/kg) did not appear to produce an LSD-like cue. These results suggest that LSD, mescaline and psilocybin, when administered in functionally equivalent doses, produce qualitatively similar interoceptive cues in the rat.Supported by grants from the American Medical Association Education and Research Foundation, and the National Institutes of Health, FR, 5697-01.     

Synthesis and evaluation of substituted 2-phenylcyclobutylamines as analogues of hallucinogenic phenethylamines: lack of LSD-like biological activity

cis- and trans-2-(2,4,5-trimethoxyphenyl)cyclobutylamine and trans-2-(2,5-dimethoxy-4-methylphenyl)cyclobutylamine were synthesized as conformationally restricted analogues of hallucinogenic phenylisopropylamines. In rats trained to discriminate saline from LSD (0.08 mg/kg, ip) in a two-lever drug discrimination paradigm, no generalization of the LSD stimulus to the cis trimethoxy compound occurred at doses up to 20 mg/kg. For both of the trans compounds, partial generalization of the LSD cue occurred at doses of 5 mg/kg or greater. In contrast, complete generalization occurred with trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropylamine. The ED50 for this compound and the doses of the trans cyclobutyl homologues at which significant drug-appropriate responding occurred indicate that the latter are on the order of 50-75 times less potent than the cyclopropylamine analogue. The lack of generalization to the cyclobutylamines indicates either that their discriminative stimulus properties differ from LSD or that they lack discriminative effects.