Norepinephrine Dopamine Reuptake Inhibitors (NDRIs) are drugs that function by inhibiting the reuptake of the neurotransmitters norepinephrine and dopamine. This leads to increased neural concentrations of these activating neurotransmitters, resulting in increased stimulation of the central nervous system. Certain NDRIs inhibit reuptake of norepinephrine to a greater extent than dopamine (and vice versa).
Others may have relatively equalized affinities for norepinephrine and dopamine transporters. NDRI drugs are commonly utilized to increase cognitive function such as among those who have been diagnosed with ADHD, energy levels among individuals with fatigue, as well as to improve symptoms of depression. Although some NDRIs have been withdrawn from markets due to abuse potential, many are considered safe and well-tolerated.
Norepinephrine-Dopamine Reuptake Inhibitors (NDRI) List
Below is a comprehensive list of NDRIs with a brief description of each drug. Understand that these drugs differ from NRIs in that they also affect dopamine reuptake.
- Bupropion (Wellbutrin / Zyban): This is a drug (initially approved in 1989) that is commonly prescribed for the treatment of depression, but can also be utilized to aid in smoking cessation. It is considered an atypical antidepressant due to the fact that it works different than most SSRIs. It acts primarily as an NDRI, affecting norepinephrine significantly more than dopamine. Due to the stimulating nature of this drug, it is considered the best antidepressant for weight loss, but among the worst for anxiety. It also has been investigated off-label for the treatment of ADHD. (Read: Wellbutrin for ADHD).
- Dexmethylphenidate (Focalin): This drug consists of the D-stereoisomer of methylphenidate (Ritalin) and was developed by the company Novartis as an ADHD medication. It functions by preventing reuptake of norepinephrine and dopamine and elicits a stimulant effect on the CNS. It is known to be well-tolerated and effective when used for attentional deficits and has also been considered as an adjunct strategy for treating certain cases of depression. Various formulations of the drug differ in their length of action; some function for just 4-6 hours, while others function for 10-12 hours.
- Diphenylprolinol (D2PM): This is considered a “designer drug” that elicits minor effects as a norepinephrine-dopamine reuptake inhibitor. Upon administration, it is considered to produce minor stimulation which can be beneficial for cognitively-demanding tasks. Since it doesn’t generally produce significant euphoria, it wouldn’t be considered a recreational or party drug. Although euphoria is less common at low doses, when taken with the intention of getting “high” it can still become addictive due to its dopmainergic effects.
- Ethylphenidate (EPH): This is a drug that functions as a psychostimulant and is considered relatively similar to methylphenidate (Ritalin) in its effects. It functions as a norepinephrine-dopamine reuptake inhibitor, with a stronger affinity for dopamine. In comparison to methylphenidate, it elicits greater action on the dopamine transporter with less action on the norepinpehrine transporter. The fact that it significantly affects dopamine can lead to mood-elevating euphoria upon administration. Its legality differs based on the country, some countries like the U.S. it is uncontrolled, but in European countries like Germany and Denmark it is illegal.
- MDPV (Methylenedioxypyrovalerone): This is considered a designer drug that functions as a norepinpehrine-dopamine reuptake inhibitor. It was originally created in the 1960s by a group of researchers in Germany. It didn’t gain popularity until approximately 2004 in which it was being developed and sold recreationally as a designer drug. The substance MDPV was sold in many small shops, convenience stores, and gas stations in the United States. Due to the fact that it isn’t approved by the FDA for medical purposes and there is potential for psychological harm, it is illegal to use and/or possess in most countries. It tends to produce similar euphoria as resulting from cocaine and amphetamines.
- Methylphenidate (Concerta / Ritalin): This is a stimulant drug that has been approved by the FDA for the treatment of ADHD. It has been utilized for nearly half a century in medical practices and is considered very safe and well-tolerated. It is manufactured under a variety of trade names including Ritalin and Concerta. It has been approved since 1955 for the treatment of ADHD and is known to act as a DNRI dopamine-norepinephrine reuptake inhibitor. In other words, it acts on dopamine more than norepinephrine.
- Pipradrol (Meratran): This is considered a drug that functions as a norepinephrine-dopamine reuptake inhibitor that elicits minor stimulant effects. It is not typically utilized in most countries due to the fact that there is potential for abuse. However, based on its drug profile, its potential for abuse is likely less than many other stimulatory drugs. It was initially developed in the 1940s as an anorectic for the treatment of obesity and would later be used for conditions like ADHD, narcolepsy, and management of dementia symptoms. Due to the fact that it had relatively minor stimulant effects and a favorable safety profile, it was considered a beneficial drug. For unknown reasons, the drug eventually became less popularized and is seldom used these days other than for research purposes.
- Prolintane (Catovit / Promotil): This drug acts as a stimulant with noradrenergic and dopaminergic influence. It is relatively similar to the designer drug MDPV and contains a similar mechanism of function. Prolintane was created in the 1950s as a stimulatory medication for a variety of conditions, but was most notably used to combat motivational deficits associated with dementia. Although it has been banned throughout various countries in Europe, it is regarded as a nootropic with a favorable safety profile.
Below is a list of NDRI drugs that were either withdrawn from the market or are still used in scientific research. Understand that many of the drugs listed below were utilized throughout the latter half of the 20th century, but were eventually discontinued for various reasons.
- Amineptine (Survector): This is a drug that was created in the 1960s by French researchers and was sold by the company Servier. It was initially marketed as “Survector” and is classified as a tricyclic antidepressant. It functions primarily by inhibiting the reuptake of dopamine, and to a lesser degree the reuptake of norepinephrine. It is known for producing a short-term euphoria as a result of increased dopamine. The short-term euphoric response is different from a sustained antidepressant effect that can be established after a week’s usage. The drug was never approved by the FDA for use in the U.S. and was eventually pulled from European markets due to cases of liver damage.
- Desoxypipradrol (2-DPMP): This is a drug that was developed in the 1950s by the company Novartis (formerly CIBA) that was investigated for the treatment of ADHD and narcolepsy. It is considered very similar to methylphenidate (Ritalin) with a related mechanism of action. In comparison to most stimulant drugs, 2-DPMP is considered longer-acting. Upon development of methylphenidate by the same company, the development of this drug was stopped.
- Difemetorex (Cleofil): This is an NDRI drug that functions as a stimulant and is documented as an anorectic due to its appetite suppressant effects. It was originally developed in France in the 1960s, but was eventually withdrawn from the market due to significant adverse effects. It is no longer available in any country for approved medical use.
- Fencamfamine (Glucoenergan / Reactivan): This is a stimulant drug created in the 1960s by the pharmaceutical company Merck. It is considered effective for treating fatigue, attentional deficits, and certain cases of depression. Although it is seldom used as a treatment these days, it is considered to be well-tolerated and safe. It functions as a norepinephrine-dopamine reuptake inhibitor which is why it works well for the management of fatigue.
- Lefetamine (Santenol): This is a drug that functions as a stimulant with pain-relieving effects (i.e. analgesic). Compounds related to this drug were created in the 1940s and demonstrated minor analgesic effects. In the 1950s the drug was investigated and it was discovered that it provided minor analgesic effects that were similar to codeine, but significantly less potent. The exact status of this drug is unknown in regards to medical uses.
- Nomifensine (Merital / Alival): This is a drug that acts as an NDRI and was created in the 1960s. It functioned by blocking reuptake transporters of stimulatory neurotransmitters and shared a similar mechanism of action to illicit stimulants like cocaine. It was considered an effective treatment option for individuals with depression with no sedation. Additionally it was regarded as having minimal withdrawal symptoms upon discontinuation after 6 months. Eventually the drug was reconsidered due to the fact that its stimulant properties increased agitation and manufacturers removed it from markets for various safety concerns. Later it was investigated for the treatment of ADHD and was found to be an effective option.
- O-2172: This is a drug that was created to function as a stimulant with mostly dopaminergic effects. It is similar to the drug methylphenidate, but only carries approximately 30% the potency. It was manufactured by the company Organix Inc. and its current status remains unknown. It is also thought to carry noradrenergic effects, but it is considered to have a stronger affinity for dopamine.
- Oxolinic acid: This is a substance from the 1970s that was developed as an antibiotic in Japan. In rodent models, it was found to promote the reuptake inhibition of dopamine, and was thought to affect norepinephrine to a lesser extent. It is typically only utilized for scientific research purposes.
- Pyrovalerone (Centroton / Thymergix): This was a drug created in the 1960s that was generally prescribed for the treatment of obesity as a result of its anorectic properties. It functions as a norepinephrine-dopamine reuptake inhibitor and works quite well at reducing chronic fatigue. It was most commonly utilized throughout European countries, but is considered problematic in that it has potential for abuse. In the U.S. it is regulated as a “Schedule V” controlled drug.
- Tametraline (CP-24,441): This is a compound that was tested by the pharmaceutical company Pfizer. It functioned primarily as a norepinephrine-dopamine reuptake inhibitor with a higher affinity for norepinephrine than dopamine. Although it is was not approved to treat any medical conditions, it is perhaps best known as a compound that lead to the creation of the popular serotonergic antidepressant Sertraline (Zoloft).
- WY-46824: This was a compound utilized by a subsidiary of the pharmaceutical company Wyeth in 2007. It functioned as a norepinephrine-dopamine reuptake inhibitor and was considered an Effexor (Venlafaxine) analog. It affects norepinephrine slightly more than that of dopamine and not much is known about the compound due to the fact that it was rarely cited in publicly available research.
Note: There may be other NDRIs that were omitted from the list above. If you happen to know of any additional drugs that should be included on the list, feel free to mention them in the comments section below.
Conditions treated with NDRIs
Norepinephrine-Dopamine Reuptake Inhibitors are often utilized to treat conditions that often benefit from increased CNS stimulation. Depending on whether the drug acts as a mild, moderate or strong reuptake inhibitor and the degree to which it has an affinity for norepinephrine over dopamine (and vice versa) often determines the condition for which it is most useful.
- ADHD: Many people have successfully managed their ADHD with drugs like methylphenidate that act on both norepinephrine and dopamine. These drugs may be preferred over more potent amphetamines for certain individuals. These drugs increase cortical arousal, making it easier to concentrate and think abstractly.
- Chronic fatigue: Since these drugs are inherently stimulating, many work great at combating lethargy associated with chronic fatigue syndromes. Individuals with chronic fatigue typically lack adequate dopamine and/or norepinephrine production, which makes them tired. These drugs speed up the nervous system and help the person maintain alertness throughout waking hours.
- Depression: Individuals with depression may have low norepinephrine and in some cases, may even have low dopamine (as opposed to serotonin). For depression, many people respond well to NDRIs and find that these drugs have favorable side effect profiles over SSRIs due to the fact that they don’t cause sexual dysfunction or weight gain. In cases of depression, energy levels can typically be low, and NDRI drugs do a great job at increasing them. The only drawback is that these drugs can increase psychomotor agitation as well as anxiety in some individuals.
- Narcolepsy: Individuals with narcolepsy and other wakefulness disorders often benefit from stimulating drugs. Many NDRIs have potent stimulatory effects and are considered to have less potential for abuse and dependence than amphetamines. In some cases, an NDRI may be utilized to help offset excessive daytime sleepiness.
- Neurodegenerative disorders: In some cases, these drugs are used to combat certain symptoms associated with neurodegenerative disorders like senile dementia. In many neurodegenerative disorders, it is known that dopamine levels plummet, making it difficult to think clearly, remember things, and pay attention. These drugs often help increase energy levels and mental focus for those with neurodegeneration.