Dextromethadone
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NMDA receptor antagonist (uncompetitive, low-trapping)
Dextromethadone
REL-1017 / esmethadone (investigational; not yet FDA-approved as of mid-2024)
Dextromethadone (also known as esmethadone or REL-1017) is the dextro-enantiomer of methadone, currently in clinical development as a rapid-onset oral antidepressant. Unlike levo-methadone (the opioid-active enantiomer used in opioid agonist therapy), dextromethadone is a relatively selective NMDA receptor antagonist with low channel-trapping properties and minimal μ-opioid activity. The development hypothesis is that targeting NMDA receptors can produce rapid antidepressant response (like ketamine/esketamine/Auvelity) without the dissociative and abuse-liability profile of ketamine. Phase 3 results have been mixed; FDA approval status uncertain as of mid-2024.
Uncompetitive NMDA receptor antagonist with low channel-trapping (binds open channel briefly, then dissociates, less than ketamine's high-trapping). Weak μ-opioid agonist (~30-fold less than levomethadone). Some 5HT2A and sigma-1 binding.
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Effects
In trials: generally well-tolerated. Headache, dizziness, nausea reported. Less dissociation than ketamine.
Pharmacodynamics
Interactions
Fluoxetine via Category:Antidepressants exp n/a/5 outcome n/a (n=1) exp 1.0/5 outcome +33.0 (n=1)
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Summary
Classes
NMDA receptor antagonist (uncompetitive, low-trapping)
Common uses
Investigational for major depressive disorder; trials underway (phase 3 mixed results)
Pharmacy
Starting dose
Trials use 25 mg or 50 mg PO daily
Preparations
Investigational oral capsule
US FDA Max
Not yet approved
Pharmacology
Routes
Oral
Onset
Rapid (within 1 week in trials)
Duration
Daily dosing
Half-life
Not formally established
Bioavailability
Oral bioavailability suitable for daily dosing
Pregnancy
Investigational
Legal status
Investigational
Purported mechanism
The dextro enantiomer of methadone. Unlike the levo enantiomer (l-methadone), which is a potent μ-opioid agonist, the dextro enantiomer is a relatively selective NMDA receptor antagonist with much weaker μ-opioid activity. Investigated as a rapid-onset antidepressant. Low channel-trapping at NMDA receptor may give it a favorable side-effect profile compared with ketamine (less dissociation, less abuse liability).