Table I: Studies of Long-term Changes after Neurotoxic MDMA Regimens in Nonhuman Animals
| Species and Strain | MDMA Regimen | Significant Differences in MDMA-treated animals | Measures showing no significant difference | Reference |
| Rhesus Monkeys | 10 mg/kg IM, twice a day, for 4 days | Right shift in MDMA and d-fenfluramine dose-response curve for time estimation, learning task, and motivation tasks at post 1 mo. | Baseline performance on all tasks. | Frederick et al., 1998 |
| Rhesus Monkeys | Escalating doses of 0.10, 0.3, 1.0, 1.75, 3.0, 5.6, 7.5, 10.0, 15.0, and 20 mg/kg, IM, twice daily for 14 consecutive days at each dose. | Right shift in MDMA dose-response curve for time estimation, short-term memory, color and position discrimination, and motivation tasks at post 21 mo. | Baseline performance on all tasks. | Frederick et al., 1995 |
| Rats, Sprague-Dawley | 20 mg/kg SC, twice a day for 4 days | None, although researchers note that 2 of 8 MDMA-exposed rats failed to acquire lever pressing with 20 sec reinforcement delays during the 8 hr session. | Acquisition of and behavior on a lever-press responding task at post 14 days. | Byrne, Baker, & Poling 2000 |
| Rats, Sprague-Dawley | 10 mg/kg SC, twice a day for 4 days | Significant pretreatment x treatment x crossing times interaction, suggesting altered S-MDMA -induced behavioral activation at post 21 days. | Drug-free locomotion at 21 days; RU24969-induced behavioral activation at 21 days. | Callaway & Geyer 1992 |
| Rats, Wistar | 10 mg/kg SC per day for 4 days | Increased core temperature when placed in either 22 °C or 28 °C ambient temperature at post 4 or 14 wks. | None | Dafters & Lynch 1998 |
| Rats, Long-Evans | 40 mg/kg SC, twice a day for 4 days | None | Sexual behaviors at post 10 days; Spontaneous motor activity. | Dornan, Katz, & Ricaurte 1991 |
| Rats, Sprague-Dawley | 20 mg/kg SC, twice a day for 4 days | Decreased electrical-stimulated 5-HT release in DRN at post 2 wks. | Electrical-stimulated 5-HT release in MRN or hippocampus at post 2 wks; Number and firing pattern of classical 5-HT neurons and burst-firing neurons in DRN. | Gartside, McQuade, & Sharp 1996 |
| Rats, Sprague-Dawley | 20 mg/kg SC, twice a day for 4 days | None | DOI-induced head twitch responses, locomotion, and rearing activity. | Granoff & Ashby 1998 |
| Rats, Sprague-Dawley | 20 mg/kg SC, twice a day for 4 days | Increased conditioned place preference response to cocaine in MDMA group at 2 post wks. | Horan, Gardner, & Ashby 2000 | |
| Rats, Sprague-Dawley | 5 mg/kg sc once per day or 20 mg/kg SC, twice a day for 4 days, followed by 5 mg/kg MDMA 2 days later | Increased motor stimulant effects of 5.0 mg/kg SC MDMA in both MDMA-treated groups at post 11 days; Increased motor stimulant effects of 15.0 mg/kg IP cocaine in both MDMA-treated groups at post 11 days; Increased MDMA-stimulated DA release in the nucleus | Basal DA in nucleus accumbens at post 2 wks. | Kalivas, Duffy, White 1998 |
| Rats, Sprague-Dawley | 15 mg/kg IP | Loss of rate-dependence of response of nigrostriatal cells to either quipazine or apomorphine at post 1 wk. | Basal activity of nigrostriatal DA neurons; Quipazine-induced inhibition of nigrostriatal DA cell firing for all cells at post 1 wk. | Kelland, Freeman, & Chiodo 1989 |
| Rats, Sprague-Dawley | 6 mg/kg SC, twice a daily for 4 days | Left shift in MDMA dose-response curve on DRL task in MDMA group. | None | Li et al., 1989 |
| Rats, Lister Hooded | ascending regimen of 10, 15, and 20 mg/kg IP, each dose given twice daily for one day | Decreased performance in operant delayed match to nonsample task. | Spontaneous behavior, body temperature, and skilled paw reach ("staircase task"). | Marston et al., 1999 |
| Rats, Sprague-Dawley | 20 mg/kg SC, twice a day for 4 days | Increased cocaine-induced dopamine release in nucleus accumbens in MDMA group at 2 wks after neurotoxic regimen. | None | Morgan et al., 1997 |
| Rats, Sprague-Dawley | 20 mg/kg SC, twice a day for 4 days | Increased morphine-induced antinociception (assessed by tail flick test) at post 2 wks. | Baseline behavior in tail flick test. | Nencini, Woolverton, & Seiden 1988 |
| Rats, Sprague-Dawley | 20 mg/kg SC, twice a day for 4 days | Decreased inhibitory effects of DA and SKF38393 on glutamate-evoked firing in nucleus accumbens cells at post 9-15 days. | Inhibitory effects of GABA on glutamate-evoked firing in nucleus accumbens cells at post 9-15 days. | Obradovic, Imel, & White 1998 |
| Rats, Sprague-Dawley | 20 mg/kg SC | Increased 8-OH-DPAT-induced prolactin release at post 2 weeks. Decreased 8-OH-DPAT-stimulated ACTH release at 2 weeks. | Basal ACTH and prolactin concentrations and ACTH and prolactin response to saline injection. | Poland 1990 |
| Rats, Sprague-Dawley | 20 mg/kg SC | Increased d,l-Fenfluramine-stimulated prolactin release at post 2 and 4 months. Decreased d,l-Fenfluramine-stimulated ACTH release at 2-8 months. | d,l-Fenfluramine-stimulated ACTH at 12 months; d,l-Fenfluramine-stimulated prolactin at 8 and 12 months. | Poland et al., 1997 |
| Rats, Sprague-Dawley | 20 mg/kg SC, twice a day for 4 days | Increased d,l-Fenfluramine-stimulated prolactin release at post 4 and 8 months. Decreased d,l-Fenfluramine-stimulated ACTH release at post 4, 8, and 12 months. | Saline-stimulated ACTH and prolactin release at post 2 weeks; d,l-Fenfluramine-stimulated prolactin release at post 12 months. | Poland et al., 1997 |
| Rats, Lister Hooded | 20 mg/kg SC, twice a day for 4 days with entire regimen repeated 2 wks later | None | Performance in a spatial memory task using a T-maze and scopolamine-induced changes in performance on this task. | Ricaurte et al., 1993 |
| Rats, Sprague-Dawley | 10 mg/kg IP, twice a day for 4 days | Increased time to find hidden platfrom in first trial of spatial navigation task at post 2 days. | Spatial navigation task after 1st trial, skilled reaching task, place navigation learning-set task, foraging task, with or without atropine pretreatment. | Robinson, Castaneda, & Whishaw 1993 |
| Rats, Sprague-Dawley | 20 mg/kg SC twice a day for 4 days | Decreased discrimination of 1.0 mg/kg MDMA from saline at post 13-15 days. | Discrimination of 0.5 or 1.5 mg/kg; Conditioned place preference from MDMA. | Schechter 1991 |
| Rats, Sprague-Dawley | 20 or 40 mg/kg SC twice a day for 4 days | Decreased d-fenfluramine-stimulated 5-HT release in frontal cortex at post 2 wks. | None | Series, Cowen, & Sharp 1994 |
| Rats, Sprague-Dawley | 10 mg/kg IP, every 2 h for 4 injections | Decreased behavioral, hyperthermic, and 5-HT-releasing effects of MDMA at 1 wk after neurotoxic regimen. | None | Shankaran & Gudelsky 1999 |
| Rats, Sprague-Dawley | 20 or 40 mg/kg SC twice a day for 4 days | Increased cerebral glucose utilization in molecular layer of dentate gyrus and in CA2 and CA3 fields of Ammon's horn in hippocampus at post 14 days. | Cerebral glucose utilization in neocortex, raphe nuclei, and some hippocampal areas at post 14 days. | Sharkey, McBean, & Kelly 1991 |
| Rats, Sprague-Dawley | 5 or 10 mg/kg PO daily for 4 days | None | Auditory startle, emergence from darkened chamber, complex maze navigation, response to hot plate, FI 90 operant behavioral task at post 2 to 4 weeks.. | Slikker et al., 1989 |
| Rat Pups, Sprague-Dawley | 10 mg/kg SC every 12 hrs for 4 or 7 injections | Decreased rate of ultrasonic vocalization measured up to post 11 days. | Behavioral responses to the 5-HT1a agonist 8-OH-DPAT, the 5-HT1b agonist TFMPP, and the 5-HT2 agonist DOI at post 8 days. | Winslow & Insel 1990 |
Table II: Reported Neurofunctional Differences Between Ecstasy Users and Nonusers
| Measure | Selective for Serotonergic Differences? | Relevant Animal Literature? | Correlated with MDMA Exposure? | Evidence for Recovery? | References |
| Putative Serotonergic Measures | |||||
|---|---|---|---|---|---|
| Decreased CSF 5-HIAA in 3 of 4 studies | Yes | Decreased up to 2 weeks after MDMA in squirrel monkeys (Ricaurte et al., 1988) and 14 weeks after MDMA in rhesus monkeys (Insel et al., 1989). | No | No | Decreased in McCann et al.,1999, 1994; Ricaurte et al.,1990. Unchanged in Peroutka et al., 1989 |
| Decreased then Increased 5-HT2a receptor density in 1 of 1 studies | Yes | Decreased at 24 hr,normal at 21 d after MDMA in rats (Scheffel et al., 1992). | Yes | Not reported | Increased in Reneman et al., 2000a; Decreased then increased in Reneman et al., 2000b |
| Decreasedneuroendocrine response to serotonergic drugs, in 3 of 5 studies | Yes | Increased at 2 months, normal at 12 months in rats (Poland et al., 1991) | Yes in Gerra et al., 2000 | No | Decreased in Gerra et al., 2000, 1998; McCann et al., 1999a. Unchanged in Price et al., 1989; McCann et al., 1994. |
| Decreased SERT density, estimated with PET, in 2 of 2 studies | Disputed - ligand kinetics may be altered by other changes (Kuikka & Ahonen 1998). | PET measures apparently decreased in one baboon up to 14 weeks after MDMA (Scheffel et al., 1998). | Yes, though McCann included controls. | Mixed (Yes in Semple; No in McCann) | Semple et al., 1999; McCann et al., 1998. |
| Increased stimulus dependence for ERP EEG N1/P2 amplitudes in 1 of 1 studies | Disputed – 5HT depletion did not change measure in one study (Dierks et al., 1999). | Unknown | No | Not reported | Tuchtenhagen et al., 2000 |
| Nonspecific Neurofunctional Measures | |||||
| Increased brain myo-inositol measured as by 1H MRS in 1 of 1 studies | - | Unknown | Yes | Not reported | Chang et al., 1999 |
| Decreased total sleep time (non-REM and stage 2 sleep) in 1 of 1 study | - | Unknown | No | Not reported | Allen et al., 1993 |
| Altered cerebral blood flow or volume in 2 of 4 studies | - | Increased blood flow 6-9 wks after MDA in rats (McBean et al., 1990) | Yes | Yes | Altered in Reneman et al., 2000b and in Chang et al., 2000 (prospective study). Unchanged in Chang et al., 2000 (user-nonuser study) and Gamma et al., in press. |
| Decreased cerebral glucose utilization in 1 of 1 studies | - | Increased in some hipppocampal areas 2 wks (Sharkey et al., 1991) after MDMA and 6-9 wks after MDA (McBean et al., 1990) in rats | No | No | Obrocki et al., 1999 |
| Increased alpha and beta EEG power in 2 of 2 studies | - | Unknown | Yes | Not reported | Dafters et al., 1999; Gamma et al., 2000 |
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