Norfenfluramine

Norfenfluramine acts as a serotonin–norepinephrine releasing agent (SNRA)^[3][1] and as a potent serotonin 5-HT_2A, 5-HT_2B, and 5-HT_2C receptor agonist.^[4] Both enantiomers of norfenfluramine are active as monoamine releasing agents, although dexnorfenfluramine is more potent than levonorfenfluramine.^[1] Similarly, both enantiomers are active as serotonin 5-HT₂ receptor agonists, but dexnorfenfluramine is likewise more potent than levonorfenfluramine.^[4]

Norfenfluramine is of similar potency as fenfluramine as a serotonin releaser but is substantially more potent as a norepinephrine and dopamine releaser.^[3][1] The drug is also far more potent than fenfluramine as an agonist of the serotonin 5-HT₂ receptors.^[4]

The action of norfenfluramine on serotonin 5-HT_2B receptors on heart valves leads to a characteristic pattern of heart failure following proliferation of cardiac fibroblasts on the tricuspid valve, known as cardiac fibrosis.^[5] This side effect led to the withdrawal of fenfluramine as an anorectic medication worldwide and to the withdrawal of benfluorex in Europe.^[6]

In spite of acting as a serotonin 5-HT_2A receptor agonist, norfenfluramine is described as non-hallucinogenic.^[7] However, hallucinations have occasionally been reported with large doses of fenfluramine, which itself is a much weaker serotonin 5-HT_2A receptor agonist than norfenfluramine but produces norfenfluramine as a major active metabolite.^[7] Dexnorfenfluramine produces the head-twitch response, a behavioral proxy of psychedelic effects, in rodents.^[8]

Norfenfluramine has been found to act as an agonist of the trace amine-associated receptor 1 (TAAR1).^[9] Dexnorfenfluramine is a very weak human TAAR1 agonist (43% of maximum in screen at a concentration of 10,000 nM), whereas levonorfenfluramine is inactive as a human TAAR1 agonist.^[9]

• Substituted amphetamine