Norepinephrine and Dopamine Reuptake Inhibitors (NDRIs)

Norepinephrine and dopamine reuptake inhibitors (NDRIs) are antidepressant medications that block the action of specific transporter proteins, increasing the amount of active norepinephrine and dopamine neurotransmitters throughout the brain. Bupropion (Wellbutrin) is the major drug of this type used to treat depression in the United States.
prescription medication
In addition to depression, NDRIs may be used to help with smoking cessation and to treat seasonal affective disorder. Additional, off-label indications include bipolar disorder and adult attention-deficit hyperactivity disorder.

While these drugs are effective in treating depression, their use is associated with certain side effects, withdrawal, and some risk of overdose. Though the risk is far lower than that of certain other drugs of abuse, there is potential for misuse of these drugs, which could increase the risk of seizures, heart problems, and other health concerns.

What Are NDRIs?

NDRIs block the transport of norepinephrine and dopamine back into the brain cells that released them. In turn, a greater number of active neurotransmitters remains available in the brain, which may over time lead to changes that help relieve the symptoms of depression.1

NDRIs block the transport of norepinephrine and dopamine back into the brain cells that released them.

Norepinephrine is thought to play a role in the body’s stress response and helps to regulate sleep, alertness, and blood pressure. Dopamine plays a key role in movement and affects motivation, perception of reality, and the ability to experience pleasure.1

These medications are sometimes referred to as atypical antidepressants because their mechanism of action differs from that of the other known antidepressant classes (e.g., MAOIs, SSRIs, SNRIs, etc.).2

NDRIs are used to treat the following conditions:3,4

  • Major depressive disorder, particularly in people who do not respond well to selective serotonin reuptake inhibitors (SSRIs) or cannot tolerate SSRI side effects
  • Seasonal affective disorder
  • Nicotine addiction/smoking cessation
  • SSRI-associated sexual dysfunction
  • Bipolar depression
  • Attention-deficit hyperactivity disorder

It may take 2 to 4 weeks after people start on an NDRI before experiencing an improvement in their symptoms.4

Which Drugs Are NDRIs?

Bupropion (Wellbutrin, Zyban, Aplenzin) is currently the only NDRI used to treat depression in the United States. Amineptine, a drug with a similar mechanism of action, had its marketing authorization suspended in the United States in 1999 and was withdrawn from the French market in 2005.3,4,5

Methylphenidate (Ritalin), a stimulant drug used to treat attention-deficit hyperactivity disorder (ADHD) and narcolepsy, also inhibits the reuptake of dopamine and norepinephrine but is generally not used to treat depression.6

Side Effects and Interactions

Side effects of NDRIs can include:3,4,7

  • Insomnia.
  • Agitation.
  • Anxiety.
  • Headache.
  • Dizziness.
  • Ringing in the ears.
  • Sweating.
  • Dry mouth.
  • Nausea.
  • Abdominal pain.
  • Weight loss.
  • Constipation.
  • High blood pressure.
  • Tremors.
  • Rash.
  • Higher-than-normal energy levels and mood (hypomania – rare).

Bupropion may increase the risk of seizures. There is a greater risk with higher doses. Since the medication can cause insomnia, it should not be used with people who have severe insomnia.2,4

Additionally, bupropion may interact with the following drugs:4,7

  • Tricyclic antidepressants – can increase the levels of these drugs in a person’s system and increase the risk of toxicity
  • Monoamine oxidase inhibitors – may cause serotonin syndrome (a potentially life-threatening condition) if combined with these medications
  • Levodopa and amantadine – may increase the risk of negative side effects
  • Antipsychotics, theophylline, systematic steroids – can increase the risk of seizures
  • Beta blockers and antiarrhythmics – can increase the concentrations of these drugs in the blood

Overdose

unconscious man drug overdose
It is possible to overdose on bupropion. Some signs and symptoms of bupropion toxicity include:7

  • Hallucinations.
  • Seizures.
  • Loss of consciousness.
  • Severe tachycardia/bradycardia.
  • Cardiac conduction disturbances/arrhythmias.
  • Cardiac failure.

Someone who has overdosed needs immediate medical attention. Call 911 if you recognize these signs in yourself or another person. If you’re with someone who has overdosed, try to determine when the person took the medication and how much, and collect the pill bottle if you can find it.

In the emergency room, medical staff will likely ensure adequate breathing through oxygenation or ventilation. They will monitor the person’s cardiac and vital signs and may use activated charcoal to help prevent the medication from being absorbed from the digestive tract into the body.7

Most people recover from an overdose, but deaths have been reported due to catastrophic cardiac events and repeated, uncontrolled seizures.7

NDRI Withdrawal

Some degree of physical dependence and withdrawal is possible with prolonged use of norepinephrine and dopamine reuptake inhibitors.

Upon stopping the medication or reducing the dose, individuals might experience:8,9

  • Headaches.
  • Irritability.
  • Anxiety.
  • Restlessness.
  • Dizziness.
  • Insomnia.
  • Tiredness.
  • Flu-like symptoms.
  • Nausea and vomiting.
  • Appetite changes.
  • Aches and pains.
  • “Electric shock” sensations.
  • Tingling or prickling sensation in the skin.

Withdrawal symptoms usually develop within 3-5 days of going off the medication and last 1 to 2 weeks. Most people’s withdrawal experience is mild. If your symptoms become severe, contact your doctor immediately.8,9

The severity of the symptoms may be influenced by how long the drug was used and the average dose taken. Someone who has been taking a large dose for years will likely experience a more severe withdrawal than someone who has been taking a small dose for a few months.

In some cases, physicians may taper their patients off the medication, gradually reducing the dose over a period of a few weeks. This method reduces the likelihood of experiencing withdrawal symptoms as the body is gradually eased off the medication.

Can NDRIs Be Abused?

Bupropion, and antidepressants in general, have a relatively low potential for abuse. But there are several documented cases of nonmedical bupropion use or misuse for the sake of intoxication or getting high.

  • Bupropion has been abused in correctional facilities due to the decreased availability of stimulants and benzodiazepines. Some facilities have removed bupropion from their pharmacies in response.10
  • Some athletes may abuse bupropion to enhance their motivation and achieve euphoria.10
  • Drug users in Canada have been injecting bupropion on the streets, where it has been dubbed by some as “poor man’s cocaine.”11

People who abuse the drug report cocaine-like effects and a euphoric high. Some people may swallow several pills to get high, but many people crush the pills and snort the powder. Rarely, people may also dissolve the crushed tablets in water and inject them intravenously.10

Risks of abusing bupropion include:10,11

  • Seizures.
  • Psychotic symptoms.
  • Cardiotoxicity.
  • More severe withdrawal symptoms.
  • Damage to tissue around the injection area.

If a person has been abusing bupropion—especially with other drugs or alcohol—medical detox may be the safest option for withdrawal management. This type of detox ensures 24-hour supervision and care during withdrawal. Medical professionals can monitor and manage uncomfortable withdrawal symptoms, and patients have support from staff members to best prevent relapse.

How Effective Are NDRIs?

Several studies have examined the effectiveness of bupropion:

  • A 2016 systematic review of bupropion, which examined 51 studies, supported its use as an antidepressant prescribed on its own or with another antidepressant.12
  • A 2005 review that compared bupropion to selective serotonin reuptake inhibitors (SSRIs) found that both medications were equally effective in treating depression. The major difference was that SSRIs were more likely to cause sexual dysfunction.13
  • A 2007 review of clinical trials examining the effectiveness of bupropion for smoking cessation found that the medication doubled the chances of quitting.2

Finding Help

In most cases, those who take NDRIs do not abuse their prescriptions. These medications can be a critical part of managing depression and other conditions when used in conjunction with therapy and healthy lifestyle choices.

If you are struggling with abuse of NDRIs or any substance, help is available. With medical detox and comprehensive addiction treatment, you can leave substance abuse in the past and embrace a balanced life in recovery.

Sources

[1]. Andrews, L. Encyclopedia of Depression. ABC-CLIO.

[2]. ScienceDirect. Dopamine Reuptake Inhibitors.

[3]. Tulane University School of Medicine. (2016). NDRI: Bupropion.

[4]. Behere, P. Das, A., and Behere, A. (2018). Clinical Pharmacology: An Update. Springer.

[5]. DrugBank. (2018). Amineptine.

[6]. DrugBank. (2018). Methylphenidate.

[7]. National Library of Medicine, DailyMed. (2010). Wellbutrin XL – bupropion hydrochloride tablet, extended release.

[8]. Berigan, T. and Harazin, J. (1999). Bupropion-Associated Withdrawal Symptoms: A Case Report. The Primary Care Companion, 1(2), 50-51.

[9]. Warner, C., Bobo, W., Reid, S., and Rachal, J. (2006). Antidepressant Discontinuation Syndrome. American Family Physician, 74(3), 449-456.

[10]. Evans, E. and Sullivan, M. (2014). Abuse and misuse of antidepressants. Substance Abuse and Rehabilitation, 5, 107-120.

[11]. Tyron, J. and Logan, N. (2013). Antidepressant Wellbutrin becomes ‘poor man’s cocaine’ on Toronto streets. Global News.

[12]. Patel et al. (2016). Bupropion: a systematic review and meta-analysis of effectiveness as an antidepressant. Psychopharmacology, 6(2), 99-144.

[13]. Thase, M. et al. (2005). Remission rates following antidepressant therapy with bupropion or selective serotonin reuptake inhibitors: a meta-analysis of original data from 7 randomized controlled trials. Journal of Clinical Psychiatry, 66(8), 974-981.

Last Updated on September 4, 2019
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Dan Wagener
Dan Wagener is a Senior Web Content Editor at American Addiction Centers.
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