[Dexfenfluramine and fenfluramine are recalled].
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[Recall of slimming agents fenfluramine and dexfenfluramine--for what reason?].
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Aortic Valve Insufficiency↗
Persistent blockade of potassium-evoked serotonin release from rat frontocortical terminals after fluoxetine administration.
We examined 5-HT and 5-HIAA release from frontal cortex evoked by high potassium chloride concentrations in rats pretreated for 3 days with high doses of the 5-HT uptake blocker fluoxetine or of dexfenfluramine, which both releases 5-HT and blocks its reuptake. The standard fluoxetine dose (30 mg/kg i.p.) was about 4 times the drug's ED50 in producing a serotonin-related behavioral effect, anorexia, while the dexfenfluramine dose (7.5 mg/kg i.p.) was about 6 times its ED50. These high doses were chosen in order to elucidate the mechanism by which similar doses of fluoxetine and dexfenfluramine had been found to produce long-term changes in serotonin dynamics. Fluoxetine decreased the basal release of both compounds; dexfenfluramine decreased basal 5-HIAA efflux without affecting the release of 5-HT release. Potassium-evoked 5-HT release was unchanged after dexfenfluramine pretreatment but was suppressed by fluoxetine doses as low as 7.5 mg per kg per day. Basal release of 5-HT and 5-HIAA returned to normal after 7 days of fluoxetine pretreatment, but evoked release continued to be suppressed. These data suggest that long-term changes in brain serotonin dynamics after high doses of dexfenfluramine or fluoxetine are related to the drug's mechanisms of action, specifically their blockade of 5-HT reuptake.
Animals↗
Effects of methiothepin on changes in brain serotonin release induced by repeated administration of high doses of anorectic serotoninergic drugs.
We previously observed, using in vivo microdialysis, that the potassium-evoked release of frontocortical serotonin (5-HT) is suppressed after rats receive high doses (30 mg/kg, i.p., daily for 3 days) of fluoxetine, a selective blocker of 5-HT reuptake. We now describe similar impairments in 5-HT release after repeated administration of two other 5-HT uptake blockers, zimelidine and sertraline (both at 20 mg/kg, i.p. for 3 days) as well as after dexfenfluramine (7.5 mg/kg, i.p. daily for 3 days), a drug which both releases 5-HT and blocks its reuptake. Doses of these indirect serotonin agonists were about 4-6 times the drug's ED50 in producing anorexia, a serotonin-related behavior. In addition, methiothepin (20 microM), a non-selective receptor antagonist, locally perfused through the dialysis probe 24 h after the last drug injection, enhanced K(+)-evoked release of 5-HT at serotoninergic nerve terminals markedly in control rats and slightly in rats treated with high doses of dexfenfluramine or fluoxetine. On the other hand, pretreatment with methiothepin (10 mg/kg, i.p.) one hour before each of the daily doses of fluoxetine or dexfenfluramine given for 3 days, totally prevented the decrease in basal and K(+)-evoked release of 5-HT. Finally, when methiothepin was injected systemically the day before the first of 3 daily injections of dexfenfluramine, it partially attenuated the long-term depletion of brain 5-HT and 5-HIAA levels induced by repeated administration of high doses of dexfenfluramine. These data suggest that drugs which bring about the prolonged blockade of 5-HT reuptake - such as dexfenfluramine and fluoxetine - can, by causing prolonged increases in intrasynaptic 5-HT levels as measured by in vivo microdialysis, produce receptor-mediated long-term changes in the processes controlling serotonin levels and dynamics.
Animals↗
The prevalence of cardiac valvular insufficiency assessed by transthoracic echocardiography in obese patients treated with appetite-suppressant drugs.
BACKGROUND: After case reports of cardiac-valve abnormalities related to the use of appetite suppressants were published, we undertook a study to determine the prevalence of the problem using transthoracic echocardiography. METHODS: We examined patients who had taken dexfenfluramine alone, dexfenfluramine and phentermine, or fenfluramine and phentermine for various periods. We enrolled obese patients who had taken or were taking these agents during open-label trials from January 1994 through August 1997. We also recruited subjects who had not taken appetite suppressants and who were matched to the patients for sex, height, and pretreatment age and body-mass index. The presence of cardiac-valve abnormalities, defined by the Food and Drug Administration and Centers for Disease Control and Prevention as at least mild aortic-valve or moderate mitral-valve insufficiency, was determined independently by at least two cardiologists. Multivariate logistic-regression analysis was used to identify factors associated with cardiac-valve abnormalities. RESULTS: Echocardiograms were available for 257 patients and 239 control subjects. The association between the use of any appetite suppressant and cardiac-valve abnormalities was analyzed in a final matched group of 233 pairs of patients and controls. A total of 1.3 percent of the controls (3 of 233) and 22.7 percent of the patients (53 of 233) met the case definition for cardiac-valve abnormalities (odds ratio, 22.6; 95 percent confidence interval, 7.1 to 114.2; P<0.001). The odds ratio for such cardiac-valve abnormalities was 12.7 (95 percent confidence interval, 2.9 to 56.4) with the use of dexfenfluramine alone, 24.5 (5.9 to 102.2) with the use of dexfenfluramine and phentermine, and 26.3 (7.9 to 87.1) with the use of fenfluramine and phentermine. CONCLUSIONS: Obese patients who took fenfluramine and phentermine, dexfenfluramine alone, or dexfenfluramine and phentermine had a significantly higher prevalence of cardiac valvular insufficiency than a matched group of control subjects.
Adult↗
An investigation of the role of 5-HT(2C) receptors in modifying ethanol self-administration behaviour.
We have previously reported that the 5-HT uptake blocker and releaser, dexfenfluramine, attenuates ethanol intake, and that this may be mediated via a 5-HT(2C) receptor mechanism. Our goals were to further determine the contribution made by this receptor subtype in mediating the reduction in ethanol self-administration induced by dexfenfluramine using the selective 5-HT(2C) antagonist, SB242,084. Additionally, we wanted to compare dexfenfluramine's effects on ethanol motivated responding with those elicited by the 5-HT(2C) receptor agonist Ro60-0175. In male Wistar rats trained to self-administer a 12% w/v ethanol solution on an FR-4 schedule, both dexfenfluramine (0.05--2.5 mg/kg ip) and Ro60-0175 (0.1--1 mg/kg sc) produced a significant dose-dependent reduction in ethanol self-administration, which was reversed by SB242,084 (0.5 mg/kg ip). Interestingly, SB242,084 alone (0.1--1 mg/kg ip) significantly increased ethanol motivated responding in both high and low ethanol drinking animals. While dexfenfluramine had no effect on ethanol's kinetic profile, the selective 5-HT(2C) agents used had opposing effects, with the agonist Ro60-0175 decreasing and the antagonist SB242,084 increasing blood ethanol levels. Since there were incongruent drug effects on ethanol self-administration and blood ethanol levels, these data support a role for 5-HT(2C) receptors in modifying ethanol intake independent of their effects on blood ethanol kinetics. Furthermore, 5-HT(2C) receptors may exert a tonic control over ethanol self-administration behaviour, since agonist and antagonist administration had opposing effects on this behaviour.
Alcohol Drinking↗
A population-based study of appetite-suppressant drugs and the risk of cardiac-valve regurgitation.
BACKGROUND: Recent case reports suggest that a combination of the appetite suppressants fenfluramine and phentermine is associated with an increased risk of cardiac-valve regurgitation. There are also reports of valvular disorders in persons taking fenfluramine or dexfenfluramine alone, particularly for more than three months. METHODS: We conducted a population-based follow-up study and a nested case-control analysis of 6532 subjects who received dexfenfluramine, 2371 who received fenfluramine, and 862 who received phentermine to assess the risk of a subsequent clinical diagnosis of a valvular disorder of uncertain origin. For comparison, we identified a group of 9281 obese subjects who had not taken appetite suppressants who were matched to the treated subjects for age, sex, and weight. All subjects were free of diagnosed cardiovascular disease at the start of follow-up. The average duration of follow-up for all subjects was about four years. RESULTS: There were 11 cases of newly diagnosed idiopathic valvular disorders, 5 after the use of dexfenfluramine and 6 after the use of fenfluramine. There were six cases of aortic regurgitation, two cases of mitral regurgitation, and three cases of combined aortic and mitral regurgitation. There were no cases of idiopathic cardiac-valve abnormalities among the subjects who had not taken appetite suppressants or among those who took only phentermine. The five-year cumulative incidence of idiopathic cardiac-valve disorders was 0 per 10,000 subjects among those who had not taken appetite suppressants (95 percent confidence interval, 0 to 15.4) and among those who took phentermine alone (95 percent confidence interval, 0 to 76.6), 7.1 per 10,000 subjects among those who took either fenfluramine or dexfenfluramine for less than four months (95 percent confidence interval, 3.6 to 17.8; P=0.02 for the comparison with subjects who had not taken appetite suppressants), and 35.0 per 10,000 subjects among those who received either of these medications for four or more months (95 percent confidence interval, 16.4 to 76.2; P<0.001). CONCLUSIONS: The use of fenfluramine or dexfenfluramine, particularly for four months or longer, is associated with an increased risk of newly diagnosed cardiac-valve disorders, particularly aortic regurgitation.
Adult↗
The comparison of four weight reduction strategies aimed at overweight diabetic patients.
Four weight reduction strategies were investigated in a diabetic population who previously had shown little motivation to lose weight. Some 409 patients, body mass index 28-45 were invited to participate. Only 51% replied, although 22 patients (5.4%) lost > 3 kg by invitation alone. The study comprised 159 patients, randomly allotted to either regular clinic visits, behavioural group therapy, dexfenfluramine (30 mg d-1 for initial 3 months) or combined home and clinic visits. A further 58 patients were monitored as controls. At 3 months the best weight loss (intention to treat) was achieved using dexfenfluramine with mean weight losses of 1.6, 1.2, 3.4, and 1.7 kg, respectively, in each group. At 1 year weight losses were similar (1.2, 1.8, 2.8, 1.2 kg, respectively) but contrasted with a mean 1.2 kg weight gain in the controls. Some 38% lost > 3 kg on dexfenfluramine compared to 19-23% for the others. In those who completed the study, weight loss was similar with behavioural therapy (3 kg) or dexfenfluramine (3.2 kg). We conclude that intensive dietetic efforts can reverse the weight increase in the diabetic population although weight loss is minimal. Dexfenfluramine was most effective in the short term, behavioural therapy useful long term but only in those who remained within the group; home visits offered no advantage.
Adolescent↗
A role for potassium channels in smooth muscle cells and platelets in the etiology of primary pulmonary hypertension.
Plasma serotonin levels are markedly elevated in patients with primary pulmonary hypertension (PPH) and platelet levels of serotonin are low. Furthermore, plasma serotonin levels remain elevated after bilateral lung transplantation, in the absence of any pulmonary hypertension. Dexfenfluramine can cause the anorexigen-induced form of PPH that is clinically and histologically indistinguishable from PPH. We find that dexfenfluramine releases serotonin from platelets and inhibits its reuptake. These observations suggest that serotonin might be involved in, or be a marker for, the mechanism responsible for both forms of PPH. Dexfenfluramine causes inhibition of voltage-sensitive potassium (Kv) channels, membrane depolarization, and calcium entry in pulmonary artery smooth muscle cells and vasoconstriction in isolated perfused rat lungs. We have recently found that dexfenfluramine also inhibits Kv channels in megakaryocytes, the stem cell for platelets. In smooth muscle cells, taken from the pulmonary arteries of PPH patients, Kv channels appear to be dysfunctional. The underlying defect in PPH is likely to be an abnormality of one or more Kv channels in both pulmonary artery smooth muscle cells and platelets. Relatively few patients exposed to dexfenfluramine develop PPH. The factors responsible for susceptibility might be a difference in expression of potassium channels and/or a decrease in the endogenous production of nitric oxide.
Animals↗
Appetite suppressants and valvular heart disease in a population-based sample: the HyperGEN study.
PURPOSE: Previous studies of the association between the use of appetite suppressants and valvular heart disease have not accounted for the effects of valvular structure and aortic root diameter, which are associated with obesity. We assessed whether the use of the appetite suppressants fenfluramine/dexfenfluramine, either alone or with phentermine, was associated with aortic regurgitation while adjusting for these variables. SUBJECTS AND METHODS: The sample included 2524 adult participants in the population-based Hypertension Genetic Epidemiology Network study. Information regarding current drug use was assessed during a clinical examination. Medication use was continued at the time of echocardiographic study. Expert readers blinded to current therapy read echocardiograms centrally at Cornell Medical Center. Analyses of the associations between use of fenfluramine/dexfenfluramine (alone or with phentermine) and aortic regurgitation adjusted for potential confounders, including aortic root dilatation and valve fibrocalcification. RESULTS: Nineteen participants, all of whom had hypertension, were being treated with fenfluramine or dexfenfluramine (5 on these agents alone, 14 also with phentermine). Aortic regurgitation was present in 32% (n = 6) of those taking fenfluramine or dexfenfluramine versus 6% (162/2505) of remaining subjects (P = 0.001). In multivariate-adjusted analyses, treatment with fenfluramine or dexfenfluramine was associated with aortic regurgitation (odds ratio [OR] = 4.9; 95% confidence interval [CI]: 1.7 to 14) and aortic fibrocalcification (OR = 5.2; 95% CI: 1.9 to 15). CONCLUSION: In a population-based sample, use of fenfluramine or dexfenfluramine, alone or in combination with phentermine, was associated with aortic regurgitation independent of aortic dilatation or fibrocalcification.
Aortic Valve Insufficiency↗
The effects of drugs used to treat obesity on the autonomic nervous system.
OBJECTIVE: Body fatness is partly under hypothalamic control with effector limbs, which include the endocrine system and the autonomic nervous system (ANS). In previous studies we have shown, in both obese and never-obese subjects, that weight increase leads to increased sympathetic and decreased parasympathetic activity, whereas weight decrease leads to decreased sympathetic and increased parasympathetic activity. We now report on the involvement of such ANS mechanisms in the action of anti-obesity drugs, independent of change in weight. RESEARCH METHODS AND PROCEDURES: Normal weight males (ages 22 to 38 years) were fed a solid food diet, carefully measured to maintain body weight, for at least 2 weeks, as inpatients at the Rockefeller University General Clinical Research Center. In a single-blind, placebo/drug/placebo design, eight subjects received dexfenfluramine, seven phentermine (PHE), and seven sibutramine (SIB). ANS measures of parasympathetic and sympathetic activity included: determination of amount of parasympathetic control (PC) and sympathetic control (SC) of heart period (interbeat interval), using sequential pharmacological blockade by intravenous administration of atropine and esmolol. These autonomic controls of heart period are used to estimate the overall level of parasympathetic and sympathetic activities. Norepinephrine, dopamine, and epinephrine levels in 24-hour urine collections were measured and also resting metabolic rate (RMR). RESULTS: Sufficient food intake maintained constant body weight in all groups. PHE and SIB produced significant increases in SC but no change in PC or in RMR. In contrast, dexfenfluramine produced marked decreases in SC, PC, and RMR. For all three drugs, the effects on urine catecholamines directly paralleled changes in cardiac measures of SC. DISCUSSION: ANS responses to PHE and SIB were anticipated. The large, and unanticipated, response to dexfenfluramine suggests further study to determine whether there could be any relation of these ANS changes to the adverse cardiovascular effects of treatment with dexfenfluramine.
Adrenergic beta-Antagonists↗
Effects of anorectic drugs on food intake under progressive-ratio and free-access conditions in rats.
The effects of two anorectic drugs, dexfenfluramine and phentermine, on food intake under different food-access conditions were examined. Experiment 1 compared the effects of these drugs on food intake under a progressive-ratio (PR) schedule and free-access conditions. Dexfenfluramine decreased food intake under both conditions, but the doses required to decrease intake under free-access conditions were higher than those required to reduce intake under the PR condition. Intermediate doses of phentermine sometimes increased breaking points, and higher doses decreased them. Phentermine decreased food intake at the same doses under both access conditions. Thus the potency of dexfenfluramine, but not phentermine, to decrease food-maintained behavior depended upon the food-access condition. Experiment 2 used a novel mixed progressive-ratio schedule of food delivery to study the duration of drug effects. Sessions consisted of five components separated by 3-hr timeouts. The ratio requirement reset at the beginning of each component and a new breaking point was obtained. Both dexfenfluramine and phentermine dose-dependently decreased breaking points early in the session. In some rats, compensatory increases in breaking point were observed. That is, breaking points later in the session increased over control levels, resulting in no change in the total number of food pellets earned for the session compared to control. The present findings suggest that the effects of some anorectic drugs depend upon the access conditions for food; increasing the effort to obtain food may enhance their ability to decrease food-maintained behavior.
Animals↗
The comparison of four weight reduction strategies aimed at overweight patients with diabetes mellitus: four-year follow-up.
Weight change and glycaemic control in 132 diabetic patients previously treated for 1 year by four different methods aimed at weight loss were reanalysed 4 years after the outset. The four treatment groups comprised clinic visits, home visits, behavioural group therapy, and dexfenfluramine given for the initial 3 months followed by clinic visits. When analysed on an intention to treat basis only the dexfenfluramine group maintained a significant weight loss at year 4 (mean -2.46 kg) with 43% of patients losing 3 kg or more; HBA1c was not decreased. The other treatment groups showed overall weight regain from year 1 to year 4. Within the home visit group however, the number of patients losing at least 3 kg doubled between years 1 (21%) and 4 (38%). When analysed on a completion basis, weight loss in the dexfenfluramine group was significant in females but not in males at year 4. During the 4 years of observation a cohort of 54 patients reflecting our routine clinic practice gained on average 0.35 kg. Although now withdrawn, the use of an appetite suppressant dexfenfluramine for just 3 months would appear to have a long-term advantage on weight loss in this diabetic population, although the weight lost was not associated with improvement in glycaemic control.
Ambulatory Care↗
Effects of fluoxetine, phentermine, and venlafaxine on pulmonary arterial pressure and electrophysiology.
The anorexic agents dexfenfluramine and fenfluramine plus phentermine have been associated with outbreaks of pulmonary hypertension. The fenfluramines release serotonin and reduce serotonin reuptake in neurons. They also inhibit potassium current (IK), causing membrane potential depolarization in pulmonary arterial smooth muscle cells. The recent withdrawal of the fenfluramines has led to the use of fluoxetine and phentermine as an alternative anorexic combination. Because fluoxetine and venlafaxine reduce serotonin reuptake, we compared the effects of these agents with those of phentermine and dexfenfluramine on pulmonary arterial pressure, IK, and membrane potential. Fluoxetine, venlafaxine, and phentermine caused minimal increases in pulmonary arterial pressure at concentrations < 100 microM but did cause a dose-dependent inhibition of IK. The order of potency for inhibition of IK at +50 mV was fluoxetine > dexfenfluramine = venlafaxine > phentermine. Despite the inhibitory effect on IK at more positive membrane potentials, fluoxetine, venlafaxine, and phentermine, in contrast to dexfenfluramine, had minimal effects on the cell resting membrane potential (all at a concentration of 100 microM). However, application of 100 microM fluoxetine to cells that had been depolarized to -30 mV by current injection elicited a further depolarization of >18 mV. These results suggest that fluoxetine, venlafaxine, and phentermine do not inhibit IK at the resting membrane potential. Consequently, they may present less risk of inducing pulmonary hypertension than the fenfluramines, at least by mechanisms involving membrane depolarization.
Animals↗
Effects of sibutramine on the appetitive and consummatory aspects of feeding in non-human primates.
This study examined how sibutramine (0.06-4.0 mg/kg, i.m.), a clinically effective weight-loss medication which increases extracellular serotonin and norepinephrine levels, affected the appetitive and consummatory aspects of feeding of non-human primates. The effects were compared to the effects of the positive control dexfenfluramine (2.0-6.0 mg/kg, p.o.), which primarily increases extracellular serotonin levels. Baboons had access to food 24 h each day, but they had to complete a two-phase operant procedure in order to eat. Responding on one lever during a 30-min appetitive phase was required before animals could start a consumption phase, where responding on another lever led to food delivery, i.e., a meal. Responding during the appetitive phase resulted in presentations of food-related stimuli only. Sibutramine increased the latency to the first meal of the session in females, and decreased consummatory behavior without affecting other appetitive behavior in males and females. In contrast, dexfenfluramine, increased the latency to the first meal of the session, and decreased both appetitive and consummatory behavior in males and females. The behavioral mechanism by which sibutramine decreases food intake is distinct from other anorectic drugs, including dexfenfluramine, that have been tested in this paradigm.
Animals↗
Impact of antenatal exposure of mice to fenfluramine on cardiac development and long-term growth of the offspring.
The objective of this investigation was to determine, in a placebo-controlled manner, whether antenatal exposure to formulations of fenfluramine and dexfenfluramine impacted cardiac development and long-term growth of exposed mice offspring. One hundred forty-four CD-1 mice were randomized to six treatment groups (n=23 or 25) to obtain, per group, 5 gravids for killing on gestational day (GD) 15 and < or =10 deliveries for assessing growth of the offspring. Either fenfluramine preparation was administered in feed bars in two doses: 1 and 3.2 times the equivalent human daily dosage according to body surface area. The drugs were given from 2 weeks before mating until GD 15. The mice ingested each drug at target values, averaging 10.5+/-0.3 and 31.8+/-1.9 mg/kg/d for fenfluramine and 5.0+/-0.2 and 16.2+/-0.4 mg/kg/d for dexfenfluramine. The drug concentration was about 36% in the fetal brain compared with the adult brain. The maternal and the offspring hearts, including mitral and aortic valves, of fenfluramine-exposed mice were indistinguishable from the placebo-exposed mice. The duration of gestation and the litter size were the same between the treatment groups. The mean body weights, body lengths, and head circumferences and early functional testing did not differ significantly between the fenfluramine or dexfenfluramine-exposed offspring and the placebo-exposed offspring. There were no significant treatment differences in growth measured as body weights to PND 120. Neither fenfluramine formulation, given before conception and during gestation, impacted cardiac development and long-term growth of the mice offspring.
Abnormalities, Drug-Induced↗
Risk of valvular heart disease associated with use of fenfluramine.
BACKGROUND: Estimates of excess risk of valvular heart disease among prior users of fenfluramine and dexfenfluramine have varied widely. Two major forms of bias appear to contribute to this variability and also result in a systematic under-estimation of risk. The first, a form of nondifferential misclassification, is the result of including background, prevalent cases among both exposed and unexposed persons in calculations of risk. The second bias results from not considering the relatively short duration of exposure to drugs. METHODS: We examined data from all available echocardiographic studies reporting the prevalence of aortic regurgitation (AR) and mitral regurgitation (MR) among persons exposed to fenfluramine or dexfenfluramine and a suitable control group. We also included one study in which previously existing AR or MR had been excluded. We corrected for background prevalent cases, estimated incidence rates in unexposed persons, and performed a person-years analysis of apparent incidence rates based on exposure time to provide an unbiased estimate of relative risk. RESULTS: Appearance of new AR was strongly related to duration of exposure (R2 = 0.75, p < 0.0001). The summary relative risk for mild or greater AR was 19.6 (95% CI 16.3-23.5, p < 0.00001); for moderate or greater MR it was 5.9 (95% CI 4.0-8.6, p < 0.00001). CONCLUSION: These findings provide strong support for the view that fenfluramine and dexfenfluramine are potent causal factors in the development of both aortic and mitral valvular heart disease.
Aortic Valve Insufficiency↗
Involvement of central serotonergic systems in dextromethorphan-induced behavioural syndrome in rats.
Dextromethorphan, a noncompetitive blocker of the N-methyl-D-aspartate (NMDA) type of glutamate receptor, at 45, 60 and 75 mg/kg, ip doses induced a behavioural syndrome characterised by reciprocal forepaw treading, lateral head-weaving, hind-limb abduction and flat body posture. Such type of behavioural syndrome is induced by 8-hydroxy-2- (di-n-propylamino) tetralin (8-OH-DPAT) by directly stimulating the central postsynaptic 5-hydroxytryptamine (5-HT, serotonin) receptors of the 5-HT1A type. Pretreatment with buspirone (5, 10 mg/kg, ip) and l-propranolol (10, 20 mg/kg, ip) antagonised the behavioural syndrome induced by 8-OH-DPAT and dextromethorphan. Pretreatment with p-chlorophenylalanine (100 mg/kg/day x 4 days) antagonised the behavioural syndrome induced by dextromethorphan and dexfenfluramine but had no significant effect on 8-OH-DPAT induced behavioural syndrome. This indicates that dextromethorphan induces the behavioural syndrome by releasing 5-HT from serotonergic neurons with resultant activation of the postsynaptic 5-HT1A receptors by the released 5-HT. Pretreatment with fluoxetine (10 mg/kg, ip) significantly potentiated the behavioural syndrome induced by dextromethorphan and 5-hydroxytryptophan but significantly antagonised dexfenfluramine induced behavioural syndrome. This indicates that dextromethorphan releases 5-HT by a mechanism which differs from that of dexfenfluramine. Dextromethorphan may be releasing 5-HT by blocking the NMDA receptors and thereby counteracting the inhibitory influence of l-glutamate on 5-HT release.
8-Hydroxy-2-(di-n-propylamino)tetralin↗