Solriamfetol

DNRI wakefulness drug from Axsome (acquired Sunosi from Jazz Pharma in 2022) — A-tier evidence in narcolepsy + OSA EDS, B-tier shift work, fresh 2025 cognitive enhancement signal in OSA (SHARP) and Phase 3 ADHD success (FOCUS). Subjectively cleaner energy than modafinil per 71% switch-preference data, but harder on blood pressure, brand-only $1,100+/mo, and no generic until ≥2031. For Dylan: WATCH-LIST as a modafinil backup if rash/headache/anxiety force a switch — not a primary play given cost and Rx friction.

Solriamfetol is a selective dopamine + norepinephrine reuptake inhibitor (DNRI) — it competitively blocks DAT and NET, raising synaptic DA and NE in cortex, striatum, and brainstem arousal nuclei. Unlike modafinil's multi-system indirect mechanism (DAT inhibition → orexin → histamine cascade), solriamfetol's wake promotion appears to come from direct DAT/NET blockade with sympathomimetic downstream effects.

Key 2024-2025 mechanism updates:

• TAAR1 agonism (Hopkins et al. SLEEP 2024 preclinical): Solriamfetol activates human trace amine-associated receptor 1 in vitro at potencies overlapping its DAT/NET inhibitory range and clinical plasma concentrations. TAAR1 agonism dampens dopaminergic hyperactivity (the basis of the SEP-363856/ulotaront antipsychotic mechanism) and modulates monoaminergic tone — this may explain why solriamfetol has lower abuse liability than expected from a pure DNRI (Schedule IV, similar to phentermine, despite NDRI mechanism that would otherwise predict higher liability).
• 5-HT1A agonism (lower potency): Plausibly contributes to anxiolytic-on-some-users / pro-cognitive signal — 5-HT1A agonism is the buspirone mechanism and is implicated in PFC dopamine modulation.
• Net effect: A wake-promoter that's "more stimulant-feeling" than modafinil but with TAAR1-mediated tempering of the dopaminergic peak — explains the cleaner-than-amphetamine but "more energizing than modafinil" subjective profile users report.

Pharmacokinetics:

• Half-life ~7.1 hr (significantly shorter than modafinil's ~15 hr) — more daily-driver-friendly for late chronotype, cleared by bedtime if dosed AM.
• Tmax ~2 hr fasted; food does not meaningfully delay absorption.
• ~95% renal excretion as unchanged drug — minimal CYP metabolism, so very few liver-mediated drug interactions. Renal impairment matters: half-life extends 1.2× / 1.9× / 3.9× in mild / moderate / severe renal impairment, and >100 hr in ESRD.
• Active tubular secretion is the main clearance route — drugs that compete (e.g., probenecid) could theoretically extend exposure.