What is the mechanism of action (MOA) of bupropion?

Mechanism of Action of Bupropion

Bupropion works primarily as a dopamine and norepinephrine reuptake inhibitor, with additional effects on hypothalamic anorexigenic neurons and nicotinic acetylcholine receptor antagonism. 1, 2

Primary Neurochemical Mechanisms

The FDA states that while bupropion's precise mechanism remains incompletely understood, it is presumed to act through noradrenergic and/or dopaminergic mechanisms 2. Specifically:

• Bupropion is a relatively weak inhibitor of neuronal reuptake of norepinephrine and dopamine 2
• It does not inhibit monoamine oxidase or serotonin reuptake 2
• The American College of Cardiology notes that bupropion activates the central nervous system to release norepinephrine, dopamine, and other neurotransmitters 1

Hypothalamic Effects

Beyond monoamine reuptake inhibition, bupropion has distinct effects on appetite regulation:

• Bupropion activates anorexigenic (appetite-suppressing) neurons in the hypothalamus 3, 1
• However, β-endorphin has auto-inhibitory activity on these neurons, which explains why bupropion monotherapy has relatively weak anorectic effects 3
• This hypothalamic activation contributes to bupropion being weight-neutral or weight-loss promoting, unlike most other antidepressants 4

Nicotinic Receptor Antagonism

Research evidence demonstrates an additional mechanism relevant to smoking cessation:

• Bupropion antagonizes nicotinic acetylcholine receptors, particularly α4β2- and α3β4-nAChRs* 5, 6
• This antagonism may prevent relapse by attenuating the reinforcing properties of nicotine 5
• The drug's effects on withdrawal symptoms appear to work by mimicking nicotinic effects on dopamine and noradrenaline 5

Active Metabolites

An important consideration often overlooked is that bupropion's clinical effects involve its metabolites:

• Bupropion is extensively metabolized, with three active metabolites: hydroxybupropion, threohydrobupropion, and erythrohydrobupropion 2
• CYP2B6 is the principal enzyme forming hydroxybupropion 2
• At steady state, hydroxybupropion reaches peak plasma concentrations approximately 7 times higher than the parent drug, with an AUC about 13 times that of bupropion 2
• The metabolite (2S,3S)-hydroxybupropion specifically contributes to antidepressant and smoking cessation efficacy 6

Clinical Implications of Mechanism

The combined mechanisms explain bupropion's unique clinical profile:

• The dual dopamine/norepinephrine effects differentiate it from serotonergic antidepressants, resulting in lower rates of sexual dysfunction and weight gain 7, 8
• The nicotinic antagonism combined with dopaminergic effects explains efficacy in smoking cessation by both reducing withdrawal symptoms and blocking nicotine reward 5, 6
• Enhanced norepinephrine release (rather than just reuptake inhibition) appears responsible for increased serotonin neuron firing observed with sustained administration 9

Common Pitfalls

• Do not assume bupropion works solely through dopamine reuptake inhibition—it is actually a weak reuptake inhibitor, and its clinical effects likely involve multiple mechanisms including metabolite activity and receptor antagonism 2, 6
• The extended-release formulations provide gradual drug delivery that moderates stimulant-like effects 4
• When combined with naltrexone for weight management, the opioid antagonist blocks β-endorphin's auto-inhibitory effects on hypothalamic neurons, enhancing bupropion's anorectic properties 3