REL-1017 (esmethadone; d-methadone) does not cause reinforcing effect, physical dependence and withdrawal signs in Sprague Dawley rats

Abstract

REL-1017 (esmethadone, d-methadone) is the opioid-inactive d-isomer of racemic d,l-methadone. REL-1017 may exert antidepressant effects via uncompetitive N-methyl-d-aspartate receptor (NMDAR) channel block. As REL-1017 is expected to exert central nervous system activity, full characterization of its abuse potential is warranted. We evaluated lack of reinforcing effect, physical dependence, and withdrawal of REL-1017 in Sprague Dawley rats. (1) Self-administration Study Rats were trained to self-administer oxycodone intravenously (IV) and then were subjected to 3-day substitution tests where saline, oxycodone, and REL-1017 were self-delivered IV by a fixed number of lever presses; (2) Drug Discontinuation Study Rats were treated for 30 days by oral gavage with vehicle, REL-1017, ketamine or morphine and evaluated for withdrawal with functional observational batteries (FOBs). In the self-administration study, rats treated with saline, vehicle, and all REL-1017 doses showed the typical “extinction burst” pattern of response, characterized by an initial rapid increase of lever-pressing followed by a rapid decrease over 3 days. Rats treated with oxycodone maintained stable self-injection, as expected for reinforcing stimuli. In the withdrawal study, REL-1017 did not engender either morphine or ketamine withdrawal signs over 9 days following abrupt discontinuation of drug exposure. REL-1017 showed no evidence of abuse potential and did not engender withdrawal symptomatology.

Unique pharmacodynamic properties and low abuse liability of the µ-opioid receptor ligand (S)-methadone

“…We found that both (R)-MTD and (S)-MTD produced full agonistic effects on analgesia but only (R)-MTD was reliably self-administered. These ndings are in agreement with results from recent studies indicating that (S)-MTD does not lead to reinforcing effects, physical dependence nor withdrawal signs in rats 40 and that it lacks opioid effects, or withdrawal signs and symptoms in humans 5 , suggesting that the abuse liability of (R,S)-MTD is mediated by (R)-MTD and not by (S)-MTD. Indeed, our data indicate that (S)-MTD can attenuate the abuse liability of (R)-MTD under some conditions.…”

The novel uncompetitive NMDA receptor antagonist esmethadone (REL-1017) has no meaningful abuse potential in recreational drug users

“…In conclusion, the results of these two HAP studies, in accordance with results in preclinical models [ 30 , 59 ], indicate no meaningful abuse potential for esmethadone at all tested doses. These results confirm a recent Drug Enforcement Administration (DEA) publication stating: “The d-isomer lacks significant respiratory depressant action and addiction liability…” [ 65 ].…”

Esmethadone-HCl (REL-1017): a promising rapid antidepressant

“…Furthermore, the results of these earlier preclinical studies were replicated in recent studies that showed esmethadone does not cause reinforcing effects, physical dependence, or withdrawal in rats [ 47 ]. These preclinical studies are corroborated by early human studies indicating no meaningful abuse potential from esmethadone [ 42 , 48 , 49 ] and by more recent clinical studies employing state-of-the-art methodology [ 34 , 35 , 47 ]. Taken together, preclinical and clinical studies confirm this 2019 Drug Enforcement Administration statement: “The d-isomer lacks significant respiratory depressant action and addiction liability, but possesses antitussive activity” [ 50 ].…”

“…Animal studies show a lack of meaningful opioid effects and lack signs of withdrawal after abrupt discontinuation of esmethadone [44][45][46]. Furthermore, the results of these earlier preclinical studies were replicated in recent studies that showed esmethadone does not cause reinforcing effects, physical dependence, or withdrawal in rats [47]. These preclinical studies are corroborated by early human studies indicating no meaningful abuse potential from esmethadone [42,48,49] and by more recent clinical studies employing stateof-the-art methodology [34,35,47].…”