Norepinephrine and Dopamine Reuptake Inhibitors (NDRIs)

Many people live with depression and may take medication to manage their symptoms. There are several medications that are effective for treating depression, including NDRIs.

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?

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.

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

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

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.

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 of NDRIs

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

Is There a Risk of Overdosing on NDRIs?

While uncommon, 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.

NDRI Withdrawal

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

Upon abruptly 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

Can NDRIs Be Misused?

Bupropion, and antidepressants in general, have a relatively low potential for misuse. 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.

Getting Help for Addiction

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 addiction or co-occurring disorders, there is effective help that can get you on the road to recovery and living the life you deserve. American Addiction Centers’ nationwide network of treatment centers have helped thousands of individuals find hope and healing in lives of sobriety. To learn more about your treatment options, give us a call at . Our navigators can answer your questions, help verify your insurance, and help you begin your recovery journey.