Dextromethorphan & Bupropion: Pharmacology, Indications, Dosing Guidelines and Adverse Effects

In a nutshell

Dextromethorphan/Bupropion (DXM/BUP) is the first oral NMDA receptor antagonist approved for major depressive disorder (MDD). Bupropion inhibits dextromethorphan’s metabolism, increasing its bioavailability. Its primary clinical advantage is a rapid onset of antidepressant effect, with symptom improvement seen as early as the first week of treatment. Its twice-daily extended-release tablet is convenient, but potent CYP2D6 inhibition, seizure risk, and abuse potential call for careful patient selection and monitoring.

• Dextromethorphan/Bupropion vs. Esketamine:
  • Dextromethorphan/Bupropion targets moderate-to-severe MDD symptoms
  • Esketamine is indicated for treatment-resistant depression (TRD)
  • Initial trials with Dextromethorphan/Bupropion for TRD showed early promise but failed to maintain superiority at trial endpoints ^[1,2]
• Dextromethorphan/Bupropion may be an option when:
  • Rapid antidepressant response is a priority
  • Patients have inadequate responses to first-line treatments (e.g., SSRIs or SNRIs)
  • Depression is accompanied by fatigue or anhedonia (leveraging the bupropion component)
  • SSRI/SNRI-associated sexual dysfunction is a significant concern
• Prefer alternatives when:
  • History of seizure or eating disorders (anorexia/bulimia), absolute contraindications
  • Patient is undergoing abrupt discontinuation of alcohol, benzodiazepines, or sedatives
  • High risk of drug-drug interactions (potent CYP2D6 inhibitor)
  • Cost is a significant barrier
  • Patient is pregnant or breastfeeding
  • Presence of active substance-use disorder or concern for dextromethorphan misuse/diversion

Pharmacodynamics and mechanism of action

• Dextromethorphan (DXM) component:
  • Uncompetitive NMDA-receptor antagonist and high-affinity σ-1 receptor agonist ^[3]
  • Additional actions: SERT/NET inhibition, nicotinic α4β2 antagonism, weak μ-opioid agonism. ^[4]
• NMDA receptor antagonism (dextromethorphan component)
  • Provides glutamatergic modulation similar to ketamine and esketamine ^[4]
  • May contribute to faster onset of antidepressant effects ^[4,5]
  • NMDA blockade indirectly enhances AMPA receptor signaling through increased glutamate release and induces downstream cascades involved in neural plasticity ^[4,6]
    • Increases BDNF release, potentially explaining rapid synaptogenic and antidepressant effects ^[6,7]
    • Activates mTOR signaling pathway, leading to increased protein synthesis and dendritic spine formation in prefrontal cortex ^[8]
• σ-1 receptor agonism (dextromethorphan component)
  • May contribute to antidepressant effects through modulation of neuroplasticity and neuroprotection ^[6,9,10]
• Bupropion component:
  • Norepinephrine- and dopamine-reuptake inhibitor (NDRI) and potent competitive CYP2D6 inhibitor
  • CYP2D6 blockade raises dextromethorphan (DXM) exposure and extends its half-life approximately 3-fold to 22 hours ^[3]

Pharmacokinetics

Metabolism and Pharmacokinetic Interactions

• Dextromethorphan is primarily metabolized by the CYP2D6 enzyme to its major, less active metabolite, dextrorphan ^[3]
• Bupropion and its metabolites are strong, competitive inhibitors of CYP2D6 ^[3]
  • This inhibition significantly increases the plasma concentration and extends the half-life of dextromethorphan

• Bupropion is metabolized in the liver through CYP2B6 to form active metabolite hydroxybupropion (primary pathway) ^[3,11]
• Threohydrobupropion and erythrohydrobupropion are formed through non-CYP-mediated metabolism (secondary pathway)
• Dextromethorphan/Bupropion levels increased by:
  • Strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, quinidine)
    • Further increase dextromethorphan concentrations beyond the effect of bupropion alone
    • Reduce Dextromethorphan/Bupropion dose to one tablet once daily in the morning ^[3]
  • CYP2B6 Inhibitors (e.g., clopidogrel)
    • May increase plasma concentrations of both bupropion and dextromethorphan.
    • Monitor for adverse effects ^[3]
• Dextromethorphan/Bupropion levels decreased by:
  • Strong CYP2B6 inducers (e.g., carbamazepine, rifampin, phenytoin, efavirenz)
    • Significantly decrease plasma concentrations of both bupropion and dextromethorphan, which may reduce efficacy
    • Co-administration should be avoided ^[3]
• Bupropion and its metabolites may increase levels of CYP2D6 substrates, including:
  • Antidepressants (venlafaxine, duloxetine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, sertraline)
    • Vortioxetine dose should be reduced by 50% when used with bupropion. Consider alternative options.
  • Antipsychotics (haloperidol, risperidone, aripiprazole)
    • Combined use with iloperidone lowers seizure threshold and augments QT-prolongation risk. Consider alternative options.
  • Beta-blockers (metoprolol)
  • Type 1C antiarrhythmics (propafenone, flecainide)
  • Consider dose reduction of CYP2D6 substrates when used concomitantly
  • Conversely, drugs that require CYP2D6 for activation (e.g., tamoxifen) may have reduced efficacy

Pharmacodynamic Interactions

• MAOIs
  • Contraindicated due to high risk of hypertensive crisis and serotonin syndrome
  • A 14-day washout period is required when switching to or from an MAOI ^[3]
• Serotonergic drugs (e.g., SSRIs, SNRIs, TCAs, triptans)
  • Concomitant use increases the risk of serotonin syndrome
  • Monitor closely for symptoms. If serotonin syndrome occurs, discontinue ^[3]
• Drugs that lower seizure threshold (e.g., other antidepressants, antipsychotics, theophylline, systemic corticosteroids)
  • Additive risk of seizures due to the bupropion component
  • Use with extreme caution. If a seizure occurs, Dextromethorphan/Bupropion must be permanently discontinued ^[3]
• Dopaminergic drugs (e.g., levodopa, amantadine)
  • May increase the risk of CNS toxicity (restlessness, agitation, tremor)
  • Use with caution and monitor for adverse effects ^[3]
• Digoxin
  • Bupropion may decrease plasma digoxin levels.
  • Monitor digoxin levels upon initiation of co-administration ^[3]
• Alcohol
  • May increase the risk of neuropsychiatric adverse events or reduce alcohol tolerance
  • Alcohol consumption should be minimized or avoided ^[3]
• False-positive drug screens
  • Bupropion can cause false-positive urine immunoassay tests for amphetamines ^[12,13]
  • Confirmatory tests (e.g., GC/MS) will distinguish bupropion from amphetamines

Half-life

• After reaching steady state (within 8 days), the mean elimination half-life is:
  • Dextromethorphan: ~22 hours ^[3]
  • Bupropion: ~15 hours ^[3]
• Bupropion’s active metabolites have longer half-lives (threohydrobupropion: ~33 hours; erythrohydrobupropion: ~44 hours)

Dosage forms

• Extended-release:
  • Tablets
    • 45 mg dextromethorphan hydrobromide/105 mg bupropion hydrochloride
    • Auvelity
• Generic substitution considerations:
  • Dextromethorphan:
    • Available as prescription or over-the-counter generic syrup (7.5 mL typically equals 45 mg dose)
    • Significantly lower cost (~$20/month vs $1,200/month for branded combination)
  • Bupropion:
    • Generic immediate-release: 100 mg twice daily or 200 mg once daily provides similar dosing to the 105 mg component in branded combination
• Formulation considerations:
  • May be taken with or without meals
  • Tablets must be swallowed whole
  • Cannot be crushed, divided, or chewed

Indications

FDA-Approved Indications

Major Depressive Disorder (MDD)

• Only oral NMDA receptor antagonist combination approved for adults with MDD ^[3]
• Rapid onset of action: separation from placebo on MADRS by week 1 and sustained superiority at week 6 in the pivotal GEMINI trial ^[3,5]
• Superiority over bupropion SR alone at week 6 was reported in the ASCEND study, supporting the specific contribution of dextromethorphan to overall efficacy ^[14]
• May be considered for patients requiring faster symptom relief or those with inadequate response to first-line antidepressants
  • However, limited long-term comparative data, high cost, and dextromethorphan’s diversion potential can temper routine use. ^[1]
  • Durability question: An unpublished TRD trial showed early separation from bupropion at weeks 1–2, but this advantage was not maintained at week 6, highlighting the need for confirmatory results ^[1,2]
• Dosing:
  • Starting dose: One tablet (45 mg dextromethorphan/105 mg bupropion) once daily in the morning ^[3].
  • Target dose: After 3 days, increase to the maximum recommended dosage of one tablet twice daily, with doses separated by at least 8 hours ^[3]
  • Maximum dose: 90 mg dextromethorphan/210 mg bupropion (two tablets per day) ^[3]
  • Strong CYP2D6 inhibitors or known CYP2D6 poor metabolizers: 1 tablet once daily ^[3]

Off-label Uses

• Treatment-resistant depression and cognitive/anxiety symptoms in MDD are being explored in open-label and extension studies (e.g., COMET-TRD, EVOLVE); evidence is preliminary and not guideline-endorsed. ^[1]
• There are currently no well-established off-label uses for the dextromethorphan-bupropion combination.

Side effects

Most common side effects

Neurological

• Dizziness (16% incidence)
  • Most common side effect ^[3,5]
  • Take precautions to reduce fall risk, particularly in patients with motor impairment or a history of falls
  • Caution patients about operating machinery and driving until they know how Auvelity affects them
• Headache (8% incidence) ^[3,14]
• Somnolence (7% incidence)
  • Despite containing bupropion, which is typically activating
  • Consider morning dosing if sedation persists

Gastrointestinal

• Nausea (13% incidence)
  • Less likely to lead to discontinuation compared to SSRIs ^[5]
  • Can be minimized by taking with food
  • Generally improves within the first week of treatment
• Diarrhea (7% incidence)
  • Usually mild and self-limiting ^[14]
  • Ensure adequate hydration if persistent
• Dry mouth (6% incidence)
  • Sugar-free gum or lozenges may help
• Constipation (4% incidence)

Other common side effects

• Sexual dysfunction (6% incidence)
  • Significantly lower than SSRIs/SNRIs
  • Bupropion component may actually mitigate sexual side effects ^[15]
  • Consider Dextromethorphan/Bupropion for patients with SSRI-induced sexual dysfunction
• Hyperhidrosis (5% incidence) ^[3].
  • May require dose adjustment if bothersome
• Anxiety (4% incidence)
  • Leading adverse reaction causing study discontinuation (2% of patients) in clinical trials ^[3].
  • Monitor during the initial titration period
• Insomnia (4% incidence)
  • Ensure doses are separated by at least 8 hours
  • Avoid evening doses

Severe side effects

• Seizures
  • Dose-related risk inherent to bupropion ^[3]
  • Contraindicated in patients with seizure disorder, eating disorders (especially bulimia), or undergoing abrupt discontinuation of alcohol/benzodiazepines
  • Risk factors include: head trauma, CNS tumors, metabolic disorders, concomitant medications lowering seizure threshold ^[3]
  • Do not exceed the maximum dose of 2 tablets daily. Screen patients for use of other bupropion-containing products before initiating treatment.
• Hypertension and cardiovascular effects
  • Risk increased with MAOIs, nicotine replacement, or drugs that increase dopaminergic/noradrenergic activity ^[3]
  • Monitor blood pressure before initiation and periodically during treatment
  • Use caution in patients with pre-existing hypertension or cardiovascular disease
• Activation of mania/hypomania
  • As with other antidepressants, there is a risk of precipitating a manic or hypomanic episode. Screen for bipolar disorder before initiation ^[3]
  • Case report described dextromethorphan-induced manic symptoms in a bipolar patient on lithium ^[16]
  • Interestingly, the combination of dextromethorphan and memantine was assessed in a clinical trial for treating bipolar disorder ^[17]
  • Monitor for the emergence of manic symptoms, especially in the first few weeks
• Serotonin syndrome
  • Risk with concomitant SSRIs, SNRIs, tricyclics, triptans, or other serotonergic agents ^[3]
  • Contraindicated with MAOIs (14-day washout required) ^[3]
  • Monitor for symptoms: hyperthermia, muscle rigidity, autonomic instability, mental status changes
• Psychosis and neuropsychiatric reactions
  • Bupropion can cause delusions, hallucinations, paranoia, confusion ^[3,18]
  • Dextromethorphan overdose can cause toxic psychosis ^[19]
  • Risk increased with higher doses or in predisposed individuals
  • Discontinue if psychotic symptoms emerge
• Angle-closure glaucoma
  • Pupilary dilation induced by bupropion may trigger angle-closure attack in patients with anatomically narrow angles ^[3,20]
  • Screen patients with narrow angles who have not had iridectomy
  • Educate about symptoms: eye pain, vision changes, eye redness/swelling

Abuse potential

• Dextromethorphan is available as an over-the-counter antitussive that produces intoxicating, hallucinogenic, and dissociative effects at supra-therapeutic doses ^[21]
• Recreational use of DXM is sometimes referred to in slang form as “robo-tripping” or “skittling”, whose prefix derives from the Robitussin brand name, or “Triple Cs”  ^[22]
• Fatal overdoses have been reported in cases where death was attributed to dextromethorphan toxicity ^[23]
• Known as “poor man’s cocaine” due to its stimulant-like effects, bupropion has earned this street name and is the most commonly misused antidepressant, with 75% increase in abuse between 2000-2012 ^[24–26]
• Monitor for signs of misuse, especially in patients with a substance use history

Use in special populations

Pregnancy

• Not recommended: Animal studies show fetal harm and neurotoxicity concerns.
  • Manufacturer recommends discontinuing treatment in pregnant females ^[3]
• Use alternative treatment for women who are planning to become pregnant.

Breastfeeding

• Breast-feeding is not recommended during therapy and for 5 days after the final dose because of potential neurotoxicity ^[3]
• Bupropion and active metabolites appear in human milk (≈ 2% of the weight-adjusted maternal dose). 
• Dextromethorphan levels in human milk are unknown. 

Hepatic Impairment

• Mild to moderate impairment (Child-Pugh A or B):
  • No dose adjustment needed ^[3]
• Severe hepatic impairment (Child-Pugh C):
  • Use is not recommended (has not been studied) ^[3]

Renal Impairment

• Mild impairment (eGFR ≥60 mL/minute/1.73 m²):
  • No dosage adjustment necessary
• Moderate impairment (eGFR 30-59 mL/minute/1.73 m²):
  • Reduce to one tablet once daily in the morning ^[3]
• Severe impairment/End-stage renal disease (eGFR <30 mL/minute/1.73 m²):
  • Use is not recommended (has not been studied) ^[3]

CYP2D6 Poor Metabolizers

• Dosage adjustment required: One tablet once daily in the morning ^[3]
• Poor metabolizers have approximately 3-fold higher dextromethorphan concentrations.

Elderly

• No patients ≥ 65 years were enrolled in pivotal trials; pharmacokinetics unstudied.

Brand names

• US: Auvelity

References

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2. Read, 18. M. (2020, March 30). Axsome Therapeutics Announces Topline Results of the STRIDE-1 Phase 3 Trial in Treatment Resistant Depression and Expert Call to Discuss Clinical Implications. BioSpace. https://www.biospace.com/axsome-therapeutics-announces-topline-results-of-the-stride-1-phase-3-trial-in-treatment-resistant-depression-and-expert-call-to-discuss-clinical-implications
3. Food, U. S., & Administration, D. (2024). AUVELITY® (dextromethorphan hydrobromide and bupropion hydrochloride) extended-release tablets, for oral use. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/215430s008lbl.pdf
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