Prior morphine exposure enhances ibogaine antagonism of morphine-induced dopamine release in rats.

The present study examines the effect of prior morphine exposure on ibogaine antagonism of morphine-induced dopamine release. Female Sprague-Dawley rats were pretreated once a day for 2 days with morphine (20 mg/kg, i.p.) or saline and given a low dose of ibogaine (10 mg/kg, i.p.) or saline 5 hr after the last morphine or saline injection. Nineteen hours later, rats (awake and freely moving) were challenged with morphine (5 mg/kg, i.p.), and dopamine and its metabolites were monitored in the striatum and nucleus accumbens using in vivo microdialysis. Neither saline pretreatment, morphine pretreatment, nor ibogaine alone altered morphine-induced increases in extracellular dopamine and dopamine metabolites in either structure. However, when morphine pretreatment was combined with ibogaine, the morphine-induced elevation of dopamine, but not of metabolites, was completely blocked. These data suggest that prior morphine exposure enhances an opioid antagonist action of ibogaine on dopaminergic systems and that prior drug exposure may be a clinically significant determinant of ibogaine efficacy and/or potency in the treatment of opioid addiction.

Effects of ibogaine on acute signs of morphine withdrawal in rats: independence from tremor.

Because of the claim that ibogaine suppresses the symptoms of "narcotic withdrawal" in humans, the effect of ibogaine on naltrexone-precipitated withdrawal signs in morphine-dependent rats was assessed. Morphine was administered subcutaneously through implanted silicone reservoirs for 5 days. Ibogaine (20, 40 or 80 mg/kg, i.p.) or saline was administered 30 min prior to challenge with naltrexone (1 mg/kg, i.p.) and withdrawal signs were counted for the following 2 hr. Ibogaine (40 and 80 mg/kg) significantly reduced the occurrence of four signs (wet-dog shakes, grooming, teeth chattering and diarrhea) during naltrexone-precipitated withdrawal; three other signs (weight loss, burying and flinching) were unaffected. Ibogaine induces head and body tremors lasting for 2-3 hr and the tremors might have interfered with the expression of opioid withdrawal. To examine this issue, another experiment was conducted in which ibogaine (40 mg/kg) or saline was administered 4 hr prior to challenge with naltrexone. Although there was a complete absence of tremors, ibogaine still significantly reduced the occurrence of the same four signs of withdrawal.

Synthesis and biological evaluation of 18-methoxycoronaridine congeners. Potential antiaddiction agents.

Variation of the methoxycarbonyl and C-18 substituents of the antiaddictive compound 18-methoxycoronaridine, and contraction of its isoquinuclidine ring segment, provided 15 congeners for SAR evaluation at opioid and alpha3beta4 nicotinic acetylcholine receptors. The opioid activities were relatively low, and the alpha3beta4 nicotinic acetylcholine receptor activities were found to correlate with in vivo antiaddictive activities.

Pharmacological comparison of the effect of ibogaine and 18-methoxycoronaridine on isolated smooth muscle from the rat and guinea-pig.

Ibogaine and 18-methoxycoronaridine are naturally occurring alkaloids reported to possess antiaddictive properties in several models of drug dependence. We have examined their effect at mu-opioid receptors regulating neurogenic contractions of several smooth muscle preparations and also against spontaneous contractions of the rat isolated portal vein. Ibogaine (pIC(50) 5.28) and 18-methoxycoronaridine (pIC(50) 5.05) caused a concentration-dependent inhibition of cholinergic contractions of the guinea-pig ileum which was not affected by the opioid receptor antagonist naloxone (1 microM). In the rat isolated vas deferens ibogaine and 18-methoxycoronaridine caused a concentration-dependent enhancement of purinergic contractions. Both agents (30 microM) caused a 3 - 5 fold rightward displacement of DAMGO-induced inhibition of purinergic contractions, but similar effects were observed for ibogaine against alpha(2)-adrenoceptor-mediated inhibition of neurogenic responses. In the guinea-pig isolated bladder both ibogaine (10 microM) and 18-methoxycoronaridine (10 microM) caused a 2 fold increase in the purinergic component of neurogenic contractions without significantly altering cholinergic contractions or responses to exogenous ATP. In contrast, ibogaine (1 - 30 microM), but not 18-methoxycoronaridine, caused a concentration-dependent enhancement of spontaneous contractions of the rat isolated portal vein. In summary, while ibogaine and 18-methoxycoronaridine modulated electrically-evoked contractions in the three preparations examined, we have no evidence for a selective interaction with pre-junctional mu-opioid receptors. The pronounced enhancement of purinergic contractions produced by both agents is a novel finding and worthy of further investigation.

An oral self-administration model of nicotine preference in rats: effects of mecamylamine.

A new oral model of nicotine self-administration in rats has been described. The model utilizes a two-lever operant procedure with rats having a choice between nicotine and water reinforcement. Most (16 of 20) rats exhibited reliable preferences for nicotine solutions equal to or less than 32 micrograms/ml; preferences were inversely related to the concentration of nicotine. Mecamylamine (0.25-5.0 mg/kg), a nicotinic antagonist, reduced preferences for a low nicotine concentration (4 micrograms/ml) and enhanced preferences for a high nicotine concentration (32 micrograms/ml). The relationship of nicotine concentration to nicotine preference appeared to be consistent with previous reports of nicotine self-administration using the intravenous route in rats as well as the respiratory route (i.e., smoking) in humans. The mecamylamine-induced changes in nicotine preference were consistent with its nicotinic antagonist action as well as with effects of mecamylamine reported in humans. This model should be useful in the preclinical assessment of new agents as potential therapies in smoking cessation programs.

Pretreatment with the putative anti-addictive drug, ibogaine, increases the potency of cocaine to elicit locomotor responding: a study with acute and chronic cocaine-treated rats.

RATIONALE: Results of single-dose studies suggest that the effects of pretreatment with the putative anti-addictive compound, ibogaine, on drug-induced locomotor behavior depends on the previous drug history of the animal. OBJECTIVES: To compare the effects of ibogaine pretreatment on the dose-locomotor response function for cocaine in rats treated chronically with either saline or cocaine. METHODS: Rats were chronically treated with either cocaine (15 mg/kg, IP, once daily for 5 days, followed by 2 week withdrawal) or saline. Ibogaine (40 mg/kg, IP) or vehicle was administered and 19 h later, a cocaine dose-locomotor response test was conducted (0, 5, 10, 20 and 40 mg/kg, IP). RESULTS: Chronic cocaine administration augmented the locomotor response to cocaine in chronic cocaine-treated rats, compared to acutely treated controls. Ibogaine pretreatment enhanced the locomotor effects of cocaine in both chronic and acute cocaine groups. Furthermore, due to the shape of the dose-response curve, in chronic cocaine but not in acute cocaine rats, ibogaine pretreatment enhanced the locomotor response to 5 and 10 mg/kg cocaine while decreasing the locomotor response to 40 mg/kg cocaine. CONCLUSIONS: These data demonstrate definitively that ibogaine can enhance sensitivity to the locomotor stimulant effects of cocaine, an effect which depends, in part, on the previous cocaine history of the animal.

Interactions between iboga agents and methamphetamine sensitization: studies of locomotion and stereotypy in rats.

RATIONALE: The phenomenon of sensitization has been theoretically implicated in mediating various aspects of drug addiction. Recent dose-response studies demonstrated that pretreatment with the putative antiaddictive agent, ibogaine (IBO), and a synthetic iboga alkaloid congener, 18-methoxycoronaridine (18-MC), increase the potency of cocaine to elicit behavioral sensitization, an effect proposed to contribute, in part, to their ability to attenuate drug self-administration. OBJECTIVES: As abuse of the methylated amphetamine derivative, methamphetamine (METH), is a growing public health concern, the present study determined the interactions between IBO and 18-MC and the expression of METH-induced behavioral sensitization. METHODS: The effects of pretreatment with 18-MC (40 mg/kg, IP, 19 h earlier) on the expression of METH-induced locomotion (0, 0.25, 0.5, 1 and 2 mg/kg, IP) and the effects of pretreatment with either IBO or 18-MC on the expression of METH-induced stereotypy (2 and 4 mg/kg, IP) were assessed in rats treated chronically with either METH (4 mg/kg daily for 7 days) or saline. RESULTS: Compared to vehicle-pretreated controls, 18-MC produced an overall enhancement in METH-induced locomotion in rats treated chronically, but not acutely, with METH. In addition, both iboga agents increased the stereotypic response to METH. CONCLUSIONS: Iboga agents augment both the locomotor and stereotypic effects of METH in a manner consistent with previous reports for cocaine. Thus, it appears that iboga agents interact in a similar manner with the neural mechanisms mediating motor hyperactivity induced by the chronic administration of stimulant drugs.

Ibogaine and the dopaminergic response to nicotine.

There is increasing evidence that the rewarding effect of nicotine is mediated by the mesolimbic dopamine system. The first objective of this study was to examine the dopamine response to repeated i.v. infusions of nicotine. Using in vivo microdialysis in awake and freely moving male Sprague-Dawley rats, we demonstrated that i.v. nicotine infusions (0.16 mg/kg or 0.32 mg/kg per infusion) produced increases in extracellular dopamine levels that were dose- and infusion order-dependent. Acute tolerance was evidenced by the smaller dopamine response produced by a second infusion of nicotine, administered 1 h after the first one. Tolerance was reversible, since the dopamine response to a second infusion of nicotine was unchanged when the interval between the infusions was increased to 3 h. Ibogaine, an alkaloid found in Tabernanthe iboga, is claimed to decrease smoking and to have an anti-nicotinic action. The second objective of this study was to establish whether this claim has any neurochemical basis. Pretreatment with ibogaine (40 mg/kg, i.p.) 19 h prior to the first nicotine infusion (0.32 mg/kg per infusion) significantly attenuated the increase in extracellular dopamine levels induced by-the nicotine infusions, suggesting that ibogaine may decrease the rewarding effect of nicotine.

18-Methoxycoronardine attenuates nicotine-induced dopamine release and nicotine preferences in rats.

Two studies were conducted to assess, in vivo, potential anti-nicotinic effects of the iboga alkaloid ibogaine and its synthetic congener 18-methoxycoronaridine (18-MC). As previously demonstrated for ibogaine, using microdialysis, pretreatment (19h beforehand) with 18-MC (40 mg/kg, i.p.) significantly attenuated nicotine-induced dopamine release in the nucleus accumbens of awake and freely moving rats. In an oral model of nicotine self-administration, both ibogaine and 18-MC decreased rats' preferences for nicotine for at least 24 h. Acutely, during the first hour after administration, ibogaine depressed responding for water as well as for nicotine; however, during this same time, 18-MC reduced nicotine intake without affecting responding for water. The results suggest that 18-MC might be the prototype of a new treatment for smoking.

Development of novel medications for drug addiction. The legacy of an African shrub.

Ibogaine, one of several alkaloids found in the root bark of the African shrub Tabernanthe iboga, has been claimed to be effective in treating multiple forms of drug abuse. Problems associated with side effects of ibogaine have spawned a search for more effective and safer structural derivatives. 18-Methoxycoronaridine (18-MC), a novel iboga alkaloid congener, appears to have substantial potential for broad use as an anti-addictive therapy. Like ibogaine (40 mg/kg), 18-MC (40 mg/kg) decreases the intravenous self-administration of morphine and cocaine and the oral self-administration of ethanol and nicotine in rats; unlike ibogaine, 18-MC does not affect responding for a non-drug reinforcer (water). Ibogaine and 18-MC appear to reduce the reinforcing efficacies, rather than the potencies, of drugs of abuse. Both ibogaine and 18-MC decreases extracellular levels of dopamine in the nucleus accumbens while only ibogaine increases serotonin levels in this brain region. Both ibogaine and 18-MC block morphine-induced and nicotine-induced dopamine release in the accumbens; only ibogaine enhances cocaine-induced increases in dopamine levels. Ibogaine produces whole body tremors and, at high doses (at least 100 mg/kg), cerebellar damage; 18-MC does not produce these effects. Ibogaine, but not 18-MC, causes bradycardia at high doses. Ibogaine and its metabolite noribogaine have low microM affinities for kappa and mu opioid receptors, NMDA receptors, 5HT-3 receptors, sigma-2 sites, sodium channels and the serotonin transporter. 18-MC has low microM affinities at all three opioid receptors and at 5HT-3 receptors but much lower or no affinities for NMDA and sigma-2 receptors, sodium channels, and the 5HT transporter. Both 18-MC and ibogaine are sequestered in fat and, like ibogaine, 18-MC probably has an active metabolite. 18-MC also has (+) and (-) enantiomers, both of which are active. Considered together, all of the data indicate that 18-MC should be safer than ibogaine and at least as efficacious as an anti-addictive medication.

18-Methoxycoronaridine (18-MC) and ibogaine: comparison of antiaddictive efficacy, toxicity, and mechanisms of action.

18-MC, a novel iboga alkaloid congener, is being developed as a potential treatment for multiple forms of drug abuse. Like ibogaine (40 mg/kg), 18-MC (40 mg/kg) decreases the intravenous self-administration of morphine and cocaine and the oral self-administration of ethanol and nicotine in rats; unlike ibogaine, 18-MC does not affect responding for a nondrug reinforcer (water). Both ibogaine and 18-MC ameliorate opioid withdrawal signs. Both ibogaine and 18-MC decrease extracellular levels of dopamine in the nucleus accumbens, but only ibogaine increases extracellular levels of serotonin in the nucleus accumbens. Both ibogaine and 18-MC block morphine-induced and nicotine-induced dopamine release in the nucleus accumbens; only ibogaine enhances cocaine-induced increases in accumbal dopamine. Both ibogaine and 18-MC enhance the locomotor and/or stereotypic effects of stimulants. Ibogaine attenuates, but 18-MC potentiates, the acute locomotor effects of morphine; both compounds attenuate morphine-induced locomotion in morphine-experienced rats. Ibogaine produces whole body tremors and, at high doses (> or = 100 mg/kg), cerebellar damage; 18-MC does not produce these effects. Ibogaine, but not 18-MC, decreases heart rate at high doses. While 18-MC and ibogaine have similar affinities for kappa opioid and possibly nicotinic receptors, 18-MC has much lower affinities than ibogaine for NMDA and sigma-2 receptors, sodium channels, and the 5-HT transporter. Both 18-MC and ibogaine are sequestered in fat and, like ibogaine, 18-MC probably has an active metabolite. The data suggest that 18-MC has a narrower spectrum of actions and will have a substantially greater therapeutic index than ibogaine.

(+/-)Cyclazocine blocks the dopamine response to nicotine.

(+/-)Cyclazocine, synthesized by Archer in 1962, was originally tested as a treatment for heroin addiction. (+/-)Cyclazocine is a mu opioid antagonist and kappa opioid agonist, and because of these actions, would be expected to modulate dopamine release in the nucleus accumbens as well as the reinforcing effects of drugs of abuse. In a recent study (+/-)cyclazocine was reported to decrease cocaine self-administration in rats. The aim of the present study was to determine whether (+/-)cyclazocine would alter the dopaminergic effects of nicotine that are thought to mediate its rewarding effects. Using in vivo microdialysis in awake and freely moving rats, we investigated the effect of (+/-)cyclazocine (0.5 mg/kg, i.p.) on the acute dopamine response to nicotine (0.32 mg/kg, i.v. over a 5 min period, infused 30 min later) in the nucleus accumbens. (+/-)Cyclazocine significantly attenuated the increase in extracellular dopamine levels induced by the nicotine infusion and enhanced nicotine-induced increases in dopamine metabolites. (+/-)Cyclazocine alone did not significantly affect extracellular dopamine levels. However, both the (+) and (-) enantiomers of cyclazocine did alter basal dopamine levels and these effects made it difficult to assess their individual interactions with nicotine. The results suggest that the effects of both enantiomers contribute to the effects of the racemate; (+/-)cyclazocine may decrease the rewarding effect of nicotine and may be the prototype of a potentially novel treatment for smoking.

18-MC reduces methamphetamine and nicotine self-administration in rats.

In previous studies, 18-methoxycoronaridine (18-MC), a novel iboga alkaloid congener, has been found to decrease the intravenous self-administration of morphine and cocaine in rats. In the present study, 18-MC (1-40 mg/kg, i.p.) dose-dependently decreased the i.v. self-administration of methamphetamine and nicotine. As in the previous studies, drug self-administration was reduced for > or = 24 h after the highest dose of 18-MC. A comparison of 18-MC's interactions with all four drugs of abuse studied so far indicated that 18-MC is least effective in decreasing methamphetamine self-administration and most potent in decreasing nicotine self-administration. The results suggest that a nicotinic antagonist action of 18-MC contributes to its putative anti-addictive efficacy.

Behavioural sensitization to cocaine is dissociated from changes in striatal NMDA receptor levels.

Changes in glutamate transmission and alterations in glutamate receptor expression produced by the repeated administration of psychomotor stimulant drugs are considered an important neuroadaptation underlying the development and expression of behavioural and neurochemical sensitization to stimulant drugs. Two parallel experiments investigated the effects of repeated cocaine administration (five, once daily injections of 15 mg/kg, i.p.; 2 weeks withdrawal) on the expression of behavioural sensitization in response to a cocaine challenge (20 mg/kg, i.p.) and the changes in NMDA receptor binding in pooled tissue from the nucleus accumbens and the striatum. Compared with acute cocaine controls (n = 11), animals administered cocaine repeatedly displayed a sensitized stereotypic response to the cocaine challenge injection (n = 8). Despite this, no differences in either NMDA receptor density or affinity were observed between rats administered repeatedly with cocaine or saline, as indexed by [3H]MK-801 binding. The present findings call to question the rationale for NMDA receptor-based pharmacotherapies for the treatment of the enduring symptomatology of stimulant addiction.

Postsynaptic localization and up-regulation of serotonin 5-HT1D receptors in rat brain.

Serotonin lesioning studies were performed to determine the synaptic localization of the 5-HT1D receptor. Four days following p-chloroamphetamine (PCA; 5 mg/kg x 4) [3H]paroxetine-labeled uptake sites (a marker for 5-HT terminals) were reduced to 18% of control values in the cortex and 29% of control values in the striatum, while the number of 5-HT1D receptors remained unchanged. Fourteen days following PCA administration an up-regulation of cortical 5-HT1D receptors was observed. These findings indicate that 5-HT1D receptors are localized postsynaptically in the cortex and striatum, and that denervation of endogenous serotonergic input produces a compensatory up-regulation in the cortex.

Kappa opioid inhibition of morphine and cocaine self-administration in rats.

Two kappa agonists, U50,488 and spiradoline, produced dose-related acute decreases in both morphine and cocaine self-administration in rats; higher doses of both agents were required to decrease rates of bar-pressing for water. On the day after kappa agonist administration, both agents produced extinction-like patterns of responding in many rats self-administering morphine or cocaine but not in rats responding for water. Two days after their administration, both U50,488 and spiradoline produced significant decreases in both morphine and cocaine intake; some rats continued to show decreases in drug self-administration for 5-6 days. Although the kappa antagonist nor-binaltorphimine (10 mg/kg s.c.) had no effect itself on either morphine or cocaine self-administration, it fully antagonized the effects of U50,488 (10 m/kg i.p.). The results suggest that although endogenous kappa opioid systems may not tonically modulate mechanisms involved in drug reinforcement, pharmacological activation of kappa pathways may be a novel and effective pharmacological approach to treating both opioid and stimulant addiction.

Interactions of ibogaine and D-amphetamine: in vivo microdialysis and motor behavior in rats.

Ibogaine, an indolalkylamine, has been proposed for use in treating stimulant addiction. In the present study we sought to determine if ibogaine had any effects on the neurochemical and motor changes induced by D-amphetamine that would substantiate the anti-addictive claim. Ibogaine (40 mg/kg, i.p.) injected 19 h prior to a D-amphetamine challenge (1.25 mg/kg, i.p.) potentiated the expected rise in extracellular dopamine levels in the striatum and in the nucleus accumbens, as measured by microdialysis in freely moving rats. Using photocell activity cages, the same ibogaine pretreatment enhanced the stimulatory motor effects induced by a wide range of D-amphetamine doses (0.625, 1.25, 2.5 or 5 mg/kg, i.p.). These findings suggest that ibogaine might increase the reinforcing efficacy of D-amphetamine. However, since high doses of D-amphetamine can be aversive, the potentiation of D-amphetamine's effects by ibogaine might also lead to a decrease in the reinforcing efficacy of D-amphetamine.

Ibogaine neurotoxicity: a re-evaluation.

Ibogaine is claimed to be an effective treatment for opiate and stimulant addiction. O'Hearn and Molliver, however, showed that ibogaine causes degeneration of cerebellar Purkinje cells in rats. The present study re-examined cerebellar responses to the high doses of ibogaine used by O'Hearn and Molliver (100 mg/kg or 3 x 100 mg/kg) and sought to determine whether a lower dose (40 mg/kg), one effective in reducing morphine and cocaine self-administration, produced similar responses. Purkinje cell degeneration was evaluated with a Fink-Heimer II stain, and enhanced glial cell activity with an antibody to glial fibrillary acidic protein. Every rat treated with the high dose of ibogaine displayed clear evidence of Purkinje cell degeneration. The degeneration consistently occurred in the intermediate and lateral cerebellum, as well as the vermis. Purkinje cells in lobules 5 and 6 were particularly susceptible. Given the response properties of cells in these lobules, this finding suggests any long-term motor deficits produced by ibogaine-induced degeneration should preferentially affect the head and upper extremity. In marked contrast, rats given the smaller dose of ibogaine displayed no degeneration above the level seen in saline-treated animals. When combined with information on other compounds, these data suggest that the degenerative and "anti-addictive' properties of ibogaine reflect different actions of the drug.

The potential anti-addictive agent, 18-methoxycoronaridine, blocks the sensitized locomotor and dopamine responses produced by repeated morphine treatment.

18-Methoxycoronaridine (18-MC), a novel synthetic iboga congener, attenuates the reinforcing efficacy of morphine, disrupts some signs of morphine withdrawal in physically dependent rats and attenuates the dopamine response in the nucleus accumbens to acute morphine. The present study further investigated the interactions between 18-MC and morphine by examining the effects of 18-MC (40 mg/kg, i.p., 19 h earlier) on the expression of dopamine sensitization in the nucleus accumbens in response to morphine (20 mg/kg, i.p.) and on the dose-effect curves for morphine-induced locomotion (0-30 mg/kg, i.p.) in rats treated either acutely or repeatedly (five, once daily, injections of 20 mg/kg, i.p.) with morphine. Compared to vehicle pretreated controls, 18-MC increased the potency of morphine, shifting the dose-response curve to the left, in acute morphine treated rats; however, 18-MC did not alter the potency of morphine in rats treated repeatedly with morphine. Repeated morphine administration induced locomotor sensitization in approximately 50% of the rats tested; in vehicle pretreated rats, the morphine dose-response curve was shifted to the left in sensitized as compared to non-sensitized rats. In 18-MC pretreated rats, sensitized and non-sensitized rats responded similarly to morphine, revealing a blockade of sensitization by 18-MC. Consistent with this behavioural finding, 18-MC pretreatment completely abolished the sensitized dopamine response in the nucleus accumbens expressed by rats repeatedly treated with morphine. It is suggested that the potential anti-addictive efficacy of 18-MC might be related to an ability to restore normal functioning to a hypersensitive mesolimbic dopamine system produced by previous repeated morphine administration.

Acute iboga alkaloid effects on extracellular serotonin (5-HT) levels in nucleus accumbens and striatum in rats.

The iboga alkaloid, ibogaine, its metabolite, noribogaine, and the congener, 18-methoxycoronaridine (18-MC) have all been claimed to have anti-addictive properties in animal models, but the mechanisms underlying these effects are unclear. Ibogaine and noribogaine were shown to have affinity for the serotonin transporter, and inhibition of serotonin reuptake has been proposed to be involved in their anti-addictive actions. It is not known yet if 18-MC also has this property. In vivo microdialysis and HPLC (microbore) were used to determine acute changes in extracellular serotonin levels in nucleus accumbens (NAC) and striatum (STR) after both i.p. (40 mg/kg for all drugs) and i.v. (1-10 mg/kg for ibogaine and noribogaine) drug administration in awake freely moving female Sprague-Dawley rats (250-275 g). After i.p. administration, ibogaine, noribogaine and 18-MC had very different effects on extracellular serotonin levels in both NAC and STR: ibogaine elicited large increases (up to 25-fold in NAC and 10- fold in STR), noribogaine produced moderate increases (up to 8-fold in NAC and 5-fold in STR), and 18-MC had no effect in either brain region. These and other data suggest that (1) the serotonergic system may not be an essential factor in the anti-addictive actions of these drugs; (2) ibogaine (or an unidentified metabolite) may release serotonin as well as inhibit its reuptake; (3) stimulation of the ascending serotonergic system may mediate ibogaine's hallucinogenic effect; and (4) 18-MC probably has no affinity for the serotonin transporter, and is unlikely to be a hallucinogen.