bupropion

Bupropion may increase neuroexcitatory and/or seizure-potentiating effects of agents with seizure threshold-lowering potential such as caffeine.

• The exact mechanism of increased seizures risk is unknown, but it appears that the effects are mainly additive. 

Caution is recommended when prescribing bupropion to patients known to use caffeine, especially in large amounts or use of high-concentration sources (e.g. energy drinks, caffeine pills, or many shots of espresso).

a) Following inadvertent injection of a mixture of cocaine and bupropion into his vertebral artery, an emergency MRI showed that the man's brain stem and spinal cord were turning “to mush.” As the neurological havoc began to permanently shut down the patient’s body, he remained conscious and aware. The man was taken off life support, and died soon after. 

b) One case study of a male with a history of cocaine abuse developed paroxysms of psychosis following a 150 mg dose of bupropion. 

Another case report describes a 67 year old man who developed paranoid ideations after starting bupropion 150 mg daily. His paranoia resolved after stopping bupropion. It was later discovered that he had a similar psychotic experience 8 years previously when he was taking bupropion and using cocaine concomitantly. 

c) The use of cocaine with bupropion increases the risk of seizures. 

d) Two previous cocaine users reported experiencing cocaine-like sensations after taking bupropion. This did not cause any cravings for cocaine. 

e) Bupropion was effective in treating depressed bipolar disorder type 1 patients with comorbid cocaine dependence without increasing scores on the Young mania rating scale (YMRS).

f) A large retrospective cohort (n = 161,544) found that bupropion use was associated with higher remission rates from cocaine use disorder compared to other antidepressants (HR 1.57, 95% CI 1.27–1.94).

a) Bupropion appears to have the typical stimulant action of causing blood vessels to spasm and clamp shut, and heightens the same effects in cocaine, potentially causing anoxic injury to the brain (stroke) and other parts of the body. Tissue destruction may also occur following injection of the non-medicinal ingredients contained in the tablets. 

b) Cocaine binds to dopaminergic transporter at higher levels but with shorter occupancy (>50% for less than 20 minutes) than bupropion (25% for more than 24 hours). These cases  show the temporal relationship between emergence of psychotic symptoms with expected peak plasma levels of bupropion (about 2-3 hours). In addition, the paroxysms stopped upon discontinuation of bupropion. Similar to cocaine, chronically administered bupropion given to rats results in sensitization of behavioral and dopaminergic response. Cocaine psychosis, characterized by acute fear, paranoid delusions, and a lack of major perceptual disturbances has been studied in the context of sensitization. 

c) Cocaine and bupropion can both lower the seizure threshold or cause seizures.

f) Both drugs act on dopaminergic and serotonergic systems. Cocaine blocks monoamine reuptake, while bupropion may stabilize dopamine tone by inhibiting dopamine and norepinephrine reuptake and modulating related genes.

a) As the neurological havoc began to permanently shut down the patient’s body, he remained conscious and aware. The man was taken off life support, and died soon after. 

b) Some patients with a history of cocaine use may be unable to use bupropion without becoming paranoid. Use bupropion with caution in individuals with a history of cocaine abuse associated with psychosis. 

c) The manufacturer recommends extreme caution when prescribing bupropion to patients known to use cocaine.

f) Evidence remains limited and inconsistent. Bupropion may help promote remission or reduce craving, but its overall therapeutic benefit for cocaine use disorder is unclear.

OPIOIDS: a) There is some concern that smoking cessation therapies may be less effective in patients taking opioids. A study found that in patients stabilized on buprenorphine or methadone, bupropion did not result in significantly greater abstinence rates than placebo. 

CODEINE: Concomitant administration of bupropion with codeine may result in decreased analgesia. 

DEXTROMETHORPHAN: a) A 43-year-old patient with a history of depression and post-traumatic stress disorder (PTSD) developed serotonin syndrome during treatment with bupropion and dextromethorphan. 

b) Bupropion appears to reduce the metabolism of dextromethorphan, a CYP2D6 substrate. In one study, 13 patients who were CYP2D6 extensive metabolizers received bupropion 150 mg daily for 3 days then 150 mg twice daily x 14 days and a 30 mg dose of dextromethorphan. Six of these subjects had a metabolic ratio of dextromethorphan that resembled that of a poor metabolizer. The 8 subjects who received placebo did not show any such change. 

c) Combination therapy of bupropion with dextromethorphan may improve symptoms in MDD. Montogomery Asberg Depression Rating Scale (MADRS) scores improved from week 1 (P = 0.007) and week 2 (P < 0.001). At week 6, remission occurred in 39.5% vs. 17.3% with placebo (95% CI 11.7–32.7; P < 0.001), and response in 54.0% vs. 34.0% (95% CI 8.4–31.6; P < 0.001). 

d) Another study found a greater mean MADRS change with dextromethorphan-bupropion than with bupropion alone (–13.7 vs. –8.8; 95% CI –6.8 to –3.1), with higher remission (46.5% vs. 16.2%) and response (60.5% vs. 40.5%) rates at week 6.

TRAMADOL: a) Bupropion may reduce the therapeutic effects of tramadol. 

b) Concomitant use of bupropion and tramadol may increase the risk of developing serotonin syndrome. 

c) Taking tramadol with bupropion can increase your risk of having seizures.

CODEINE: Bupropion is a strong CYP2D6 inhibitor. Concomitant administration with codeine, a CYP2D6 substrate may result in decreased conversion of codeine to the active analgesic morphine. 

DEXTROMETHORPHAN: a) Serotonin syndrome is a dose-related response to the use of serotonergic drugs, often in combination. Genetic polymorphism in CYP2D6 function leads to differences in the ability to metabolize dextromethorphan which may explain the differences in clinical experiences reported by those who abuse dextromethorphan for its dissociative effects. While bupropion mainly inhibits noradrenaline and dopamine reuptake, dopaminergic neurons can have mild effects on serotonergic transmission. 

b)Bupropion inhibits CYP2D6 which metabolizes dextromethorphan. 

c,d) Dextromethorphan acts as an uncompetitive NMDA receptor antagonist and simga-1 receptor agonist, modulating glutamate signaling. Bupropion slows dextromethorphan metabolism, sustaining therapeutic plasma levels.

TRAMADOL: a) Concomitant administration of bupropion with tramadol (a CYP2D6 substrate) may result in decreased conversion of tramadol to the active metabolite (O-desmethyl-tramadol) responsible for its opioid-like effects. The analgesic effects of tramadol are due to two separate mechanisms - a) agonism of the opioid receptor and b) via inhibition of serotonin and norepinephrine reuptake. The (+) enantiomer of O-desmethyl-tramadol, formed via O-demethylation by CYP2D6, is the primary opioid agonist. If CYP2D6 is inhibited, this leads to reduced agonism at opioid receptors. However, some analgesic effect does remain due to inhibition of serotonin and norepinephrine reuptake. 

b) While bupropion mainly inhibits noradrenaline and dopamine reuptake, dopaminergic neurons can have mild effects on serotonergic transmission, with additive effects on serotonergic transmission, since tramadol has effects of inhibition of serotonin and norepinephrine reuptake.

CODEINE: Patients who are co-administering these two drugs are at increased risk of poor pain control. If used concurrently, it is recommended to monitor for decreased analgesic response. If an inadequate response is observed, consider an alternative analgesic that does not require metabolic activation via CYP2D6. 

DEXTROMETHORPHAN: a) Patients should be monitored for symptoms of serotonin syndrome when bupropion and dextromethorphan are used concurrently. 

b) Use caution when initiating, discontinuing, or changing the dose of bupropion when patients are taking dextromethorphan. 

c,d) Some evidence suggests that dextromethorphan and bupropion combination produces rapid and sustained antidepressant effects from week 1 onward. 

TRAMADOL: a) Patients who are co-administering these two drugs are at increased risk of poor pain control. If used concurrently, it is recommended to monitor for decreased analgesic response. If an inadequate response is observed, consider an alternative analgesic that does not require metabolic activation via CYP2D6. 

b) Patients should also be monitored for symptoms of serotonin syndrome when tramadol and bupropion are used concurrently. 

c) The manufacturer recommends caution when bupropion is used with any other drug that may lower the seizure threshold.

MDMA a) Bupropion may reduce the metabolism of methylenedioxymethamphetamine (MDMA). 

b) One study found that bupropion reduced MDMA-mediated heart rate increases and plasma norepinephrine elevations. However, plasma MDMA concentrations were increased and subjective effects of MDMA were prolonged. Bupropion concentrations were increased by MDMA. 

METHAMPHETAMINE: a) Bupropion does not appear to increase abstinence rates in methamphetamine-dependent patients who used methamphetamine less than daily. Adherence was a major limitation in this trial. 

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• b) Bupropion may be effective for methamphetamine withdrawal treatment. In a two-stage, placebo-controlled trial, the weighted average response which defined as at least three methamphetamine-negative urine samples was 13.6% with naltrexone-bupropion and 2.5% with placebo (p < 0.001). 
  
  METHYLPHENIDATE: a) A 16 year old boy taking methylphenidate 30 mg twice daily, bupropion 100 mg twice daily, and erythromycin 1000 mg/day experienced an acute MI. 
  
  b) a 14 year-old boy taking methylphenidate 60 mg daily had his bupropion dose increased from 200 mg to 300 mg. 4 weeks after the bupropion was increased the patient experienced a generalized tonic-clonic seizure. Bupropion was discontinued and he remained seizure-free.

MDMA a) Bupropion inhibits CYP2D6, which metabolizes MDMA. 

b) Reduced norepinephrine release may be responsible for reduced cardiostimulatory effects of MDMA. 

METHAMPHETAMINE: b) The exact mechanism is unknown. Bupropion inhibits dopamine and norepinephrine reuptake, helping restore neurotransmitter balance disrupted by chronic methamphetamine exposure, thereby improving dysphoria and craving linked to stimulant use.

METHYLPHENIDATE: a) Erythromycin may have resulted in increased bupropion levels, which may have combined with the sympathetic effects of methylphenidate to cause excessive vasospasm. However, erythromycin does not inhibit CYP2B6 so it is unclear how it would have increased bupropion concentrations. 
 

MDMA a) Patients may be more likely to experience an overdose of MDMA while taking bupropion. 

b) Taking MDMA while on bupropion may result in higher plasma concentrations of both, as well as increased subjective effects and decreased cardiac effects of MDMA. 

METHAMPHETAMINE: b) The significance remains uncertain. Among adults with methamphetamine use disorder, the response over 12 weeks with bupropion and naltrexone therapy was low but higher than that with placebo.

METHYLPHENIDATE: a) The significance of this case report is unclear. 

b) The combination of bupropion and stimulants may increase the risk of seizure.

Psilocybin: A retrospective anonymous survey of 611 participants who self-identified using a moderate or high dose of psilocybin during antidepressant treatment, found the probability of reporting weaker than expected psilocybin effects during treatment with bupropion was 0.29 with a 95% CI [0.20–0.39] compared with using the same dose without antidepressants or by individuals not taking antidepressants. The reduction in psilocybin effects was less pronounced with the NDRI bupropion than with SSRIs or SNRIs.

LSD: No information currently available.

Psilocybin: The mechanism of decreased psilocybin effects is likely to be 5-HT2A receptor downregulation due to long term use of antidepressant. Although bupropion does not directly act on 5-HT2A receptors, its inhibition of dopamine and norepinephrine reuptake can alter serotonergic tone indirectly. The subjective effects of psilocybin are known to correlate with 5-HT2A receptor occupancy.

• Psilocybin: The significance is uncertain, but concomitant use may reduce the psychoactive effects of psilocybin.

ALL BENZODIAZEPINES: Bupropion is contraindicated during abrupt withdrawal from benzodiazepines due to the risk of seizures. 

DIAZEPAM: A crossover study in 12 healthy subjects demonstrated that the combination of bupropion with diazepam resulted in similar function compared to bupropion alone. 

ZOLPIDEM: A case report describes a 17 year old boy taking bupropion 450 mg daily who increased his zolpidem dose from 5-10 mg daily to 60 mg daily and experienced visual hallucinations for 3-4 hours.

ZOLPIDEM: Bupropion is not a known inhibitor of CYP3A4, the major CYP enzyme that metabolizes zolpidem.

DIAZEPAM: The combination dose not appear to result in decreased psychomotor function. 

ZOLPIDEM: This patient took 6 times the recommended maximum daily dose of zolpidem, which can cause hallucinations on its own. Therefore, it is unclear if an interaction with bupropion is responsible for this case.