Norepinephrine Reuptake Inhibitors (NRIs) are drugs that function primarily by inhibiting the reuptake of the neurotransmitter norepinephrine (noradrenaline) and/or epinephrine (adrenaline). Inhibiting the reuptake of norepinephrine tends to elicit stimulating effects, thereby increasing both cortical arousal and energy levels. The NRI drugs are typically prescribed to individuals that may benefit from increased arousal such as in cases of ADHD, narcolepsy, and depression.
There are a variety of other uses for norepinephrine reuptake inhibitors including: aiding in weight loss as well as serving as a counterintuitive treatment for certain subtypes of anxiety disorders (as caused by low arousal). This classification of drugs is generally considered safe throughout the medical community due to them having minimal potential for abuse, favorable side effect profiles, and relatively minor withdrawal symptoms compared to other classes.
Norepinephrine Reuptake Inhibitors (NRIs) List
Below is a list of selective norepinephrine reuptake inhibitors. These drugs treat various conditions by inhibiting the reuptake of norepinephrine. The drugs listed below are considered “selective” in that they specifically target norepinephrine. These are not to be confused with SNRIs which affect both serotonin and norepinephrine to a significant extent.
- Atomoxetine (Strattera): This is an NRI drug that has been approved by the FDA for the treatment of ADHD. It is often preferred over dopaminergic drugs like Adderall due to the fact that it is considered safer and no potential for abuse. Although it may lack the potency of a dopaminergic agent, many find it highly effective for the management of their attentional deficits. Some have even used it as an off-label antidepressant with success (Read: Strattera for depression). The only drawbacks associated with this medication is that it can take several weeks to elicit its full stimulatory effects and for some individuals it can eventually stop working.
- Maprotiline (Ludiomil): This is a “tetracyclic antidepressant” that functions primarily via that reuptake inhibition of norepinephrine. It is sold by Novartis and is commonly known by its brand name of “Ludiomil.” In addition to its norepinephrine reuptake inhibition, it also elicits minor effects on serotonergic and dopaminergic reuptake. Like most NRIs, it increases activity in the central nervous system. Due to its effects on other neurotransmitter functions, it also can be prescribed for certain types of anxiety, neuropathic pain, and panic attacks.
- Reboxetine (Edronax / Vestra): This is a drug that has not been approved in the United States, but has been approved in Australia and the United Kingdom for the treatment of depression. It functions as a norepinephrine reuptake inhibitor with moderately selective properties and was developed by Pfizer. Whether the drug is actually effective at treating depression is considered debatable throughout the scientific community, but it remains a relatively popular drug nonetheless. In a 2009 meta-analysis, Reboxetine was found ineffective at treating depression and some would argue that studies promoting its efficacy may be skewed. The drug does seem to have some benefit in the treatment of ADHD in children, teens, and adults.
- Viloxazine (Vivalan): This is a drug that functions as a norepinephrine reuptake inhibitor with selective properties. It is considered a “bicyclic andidepressant” likely due to the fact that it is a compound consisting of two stereoisomers. It is approved to treat depression in European countries such as England, France, Germany, Italy, and Spain. The drug is considered to have potent stimulant effects that are akin to amphetamines, but unlike amphetamines it has no potential for dependence. It has also been investigated as a treatment for bedwetting, narcolepsy, and alcoholism – with varying results for each condition.
Below is a list of norepinephrine reuptake inhibitors (NRIs) that were either never approved or only used in animal models. Keep in mind that some of these medications may have had promise in treating various conditions, but due to lack of funding and/or efforts, some never made it through clinical trials.
- Amedalin (UK-3540-1): This is an antidepressant drug that was developed in the 1970s, but never actually hit the pharmaceutical market. It functioned solely as a norepinephrine reuptake inhibitor without any influence on serotonergic and dopaminergic neurotransmission. It can be speculated that either drug companies felt that the drug lacked promise compared to other antidepressants.
- CP-39,332: This is a compound that was investigated, but never made it through developmental stages. It has some effect as an SNRI, but there is significant lack of documentation on this particular drug. Due to lack of scientific studies with this compound, its tolerability and efficacy for the treatment of various conditions remains unknown.
- Daledalin (UK-3557-15): This is a drug that was developed in the 1970s for the treatment of depression. Although the drug was tested to a certain extent, it never actually made it to the pharmaceutical market. It was considered a norepinephrine reuptake inhibitor with selective properties, meaning it didn’t affect other neurotransmitters like serotonin or dopamine.
- Edivoxetine (LY-2216684): This is a drug that functions as a norepinephrine reuptake inhibitor with selective properties. It is was developed by the pharmaceutical heavyweight Eli Lilly for the treatment of multiple conditions including depression and ADHD. It had reached Phase III clinical trials in 2013, and was supposed to already be approved, but it failed to meet study “endpoints” a.k.a. it didn’t establish significant efficacy. Research demonstrated that it was actually far less effective than standard SSRIs. Despite all the investment in this medication for an adjunct depression treatment, it may never hit the market.
- Esreboxetine: This drug was created by Pfizer as a reuptake inhibitor of norepinephrine with selective properties. It was investigated for the treatment of fibromyalgia as well as neuropathic pain. Unfortunately in clinical trials it never showed superior efficacy to current medications and its development was halted. It is a variant of the drug Reboxetine, containing a stereoisomer with a more selective mechanism of action.
- Lortalamine (LM-1404): This drug is considered an antidepressant that functions as a norepinephrine reuptake inhibitor with highly selective properties. It was initially developed in the 1980s but never made it to clinical trials due to reports of toxicity in animals, leading to eye damage. Some researchers may still use this substance in animal studies involving PET scans because it helps identify the norepinephrine transporter (NET).
- Nisoxetine (LY-94,939): This drug is an extremely selective and very potent inhibitor of norepinephrine reuptake. Although it was initially created in the 1970s by researchers, it currently has no acceptable uses among humans. Despite originally being developed as an antidepressant and showing significant promise, Eli Lilly decided to invest efforts into creating the SSRI that is Prozac instead. There was some evidence to suggest it may have been beneficial for treating obesity and providing minor pain relief.
- Talopram (Lu 3-010): This is a drug that was developed in the 1960s and is considered related in structure to the drug Celexa (an SSRI). Unlike Celexa though, this drug functions as a selective norepinephrine reuptake inhibitor and was researched as an antidepressant throughout the 1970s. The company Lundbeck had originally hired a medicinal chemist to develop a non-SSRI antidepressant and came up with two compounds; Talopram was one of those compounds. In studies, it was found that activating noradrenergic drugs like Talopram increased suicidality, which prompted Lundbeck to discontinue its development. However, this chemist eventually converted Talopram into “Citalopram” a.k.a. Celexa – which became a highly successful SSRI.
- Talsupram (Lu 5-005): Like Talopram, this drug functioned as a selective norepinephrine reuptake inhibitor and was studied throughout the 1970s as an antidepressant. Additionally, just like Talopram, it is considered to have similar structure to the SSRI that is Celexa. Although the drug was investigated, the reports that noradrenergic drugs increased suicidality lead to discontinued development.
- Tandamine (AY-23,946): This is another drug that was investigated throughout the 1970s as a norepinephrine reuptake inhibiting antidepressant. Like many other noradrenergic agents at this time, it never made it through clinical trials. It is extremely similar to the investigational serotonergic compound that is pirandamine.
These are drugs that tend to primarily elicit norepinephrine reuptake inhibition properties, but also act on the functioning of other neurotransmitters. It should be noted that most effects on other neurotransmitters are considered minimal.
- Bupropion (Wellbutrin / Zyban): This is an atypical antidepressant medication that is also commonly used as an aid in the process of smoking cessation. It functions primarily as a norepinephrine reuptake inhibitor, but elicits minor effects on dopaminergic processes. It is considered to be the best antidepressant for weight loss but unfortunately can also increase anxiety due to the fact that it is stimulating.
- Ciclazindol (Wy-23,409): This was an investigational drug developed in the 1970s for the treatment of depression. It also was found to be an appetite suppressant, but never ended up hitting the market. It functioned mostly as a norepinephrine reuptake inhibitor, but also had minor effects on the reuptake inhibition of dopamine. Some evidence suggested that the drug may have blocked sodium and potassium channels in the brain due to its anesthetic properties.
- Manifaxine (GW-320,659): This was a drug that was created by GSK (GlaxoSmithKline) that acted primarily as a norepinephrine reuptake inhibitor with lesser effects on dopamine reuptake inhibition. It contained the active metabolite of the medication Wellbutrin and was suggested as being beneficial for treating ADHD and obesity. Preliminary evidence suggests that the drug is safe and tolerable, but its current developmental status remains unknown.
- Mazindol (Mazanor / Sanorex): This is a stimulatory medication that was developed as an anorectic in the 1960s. It functions similar to an amphetamine, by stimulating the central nervous system via norepinephrine reuptake inhibition. It also has minor effects on serotonin and dopamine reuptake inhibition. It is typically utilized over a short-term to help control obesity as an adjunct strategy along with exercise and dietary restrictions. Although it is beneficial for the treatment of obesity, its only accepted medical use is for the treatment of muscular dystrophy.
- Radafaxine (GW-353,162): This is a drug developed by GSK for the treatment of obesity and neuropathic pain. It was also being researched as a potential treatment for depression due to its norepinephrine and dopamine reuptake inhibition. Unfortunately, the development of this particular medication was halted due to the fact that it performed poorly in preliminary trials. It contained the active metabolite found in Wellbutrin, but comparatively was nearly 400% better at inhibiting norepinephrine reuptake.
- Tapentadol (Nucynta): This is a drug that is prescribed as an analgesic for the management of moderate and severe pain. It is believed to function as a norepinephrine reuptake inhibitor as well as a mu-opioid receptor agonist. Its properties suggest that it is more powerful than the popular drug Tramadol, but lesser so than Morphine. It is considered a controlled substance in the United States and has potential for abuse.
- Teniloxazine (Lucelan / Metatone): This is a drug that was developed in Japan for the treatment of arterial obstruction within the brain. Initial developments lead researchers to believe that it elicited nootropic and neuroprotective effects, but data is inconclusive to verify these speculations. It functions primarily as very potent norepinephrine reuptake inhibitor with some effects on serotonergic and dopaminergic functions.
Conditions treated with NRIs
Due to the fact that norepinephrine-reuptake inhibitors are typically stimulating, they often work well at treating conditions associated with low arousal such as ADHD, depression, and fatigue. In other cases they may work well for neuropathic pain and anxiety disorders.
- ADHD: Many NRIs are utilized for the treatment of attentional deficits. Although not all are approved to treat ADHD, many are utilized as off-label strategies especially in cases of comorbid depression. By increasing stimulation in the nervous system and levels of norepinephrine between synapses, many people experience improvements in cognitive function. While these drugs may not be as effective as dopaminergic agents, they are sometimes preferred as a result of their low abuse potential.
- Anxiety: Many individuals with anxiety would not benefit from taking a norepinephrine reuptake inhibitor. In fact, taking an NRI with anxiety will likely increase anxiety and overall discomfort. However, there are certain individuals with a subtype of anxiety caused by low arousal and slow thinking that may benefit from an NRI. Additionally some NRIs influence serotonin and histamine receptors, making them effective for some individuals in treating panic.
- Bedwetting: Children often struggle with a condition scientifically known as “nocturnal enuresis” or bedwetting. Although many NRIs have been developed for the treatment of depression, these same drugs have been found to work quite well at preventing children from wetting the bed at night.
- Chronic fatigue: The sympathomimetic effects of norepinephrine reuptake inhibitors make them viable options for treating chronic fatigue. Individuals who are tired all the time often have problems increasing their level of arousal and noradrenergic drugs can help. Although for some they may be less effective than dopaminergic drugs, they may be preferred due to having less potential for abuse.
- Chronic pain: In many cases of chronic pain, noradrenergic drugs are prescribed. They often help with the management of mild or moderate chronic pain. Although they may not work as well as an opioid, the norepinephrine reuptake inhibition is often associated with an increased tolerance for pain.
- Depression: NRIs are typically prescribed for the treatment of various types of depression. Some cases of depression are believed to be directly influenced by low norepinephrine. Whether there is truth to this hypothesis hasn’t been scientifically validated. However, some people with depression respond better to drugs that act on norepinephrine as opposed to other neurotransmitters like serotonin.
- Obesity: Certain NRIs were found to be great treatments for obesity when utilized over the short-term. They tend to act as anorectics or appetite suppressants due to the fact that they stimulate the sympathetic nervous system. The increased stimulation tends to speed up metabolism, reduce appetite, and increase self-control.
- Narcolepsy: It is known that individuals with narcolepsy often experience excessive daytime sleepiness. A doctor will often prescribe a eugeroic drug like Modafinil or a dopaminergic drug like Adderall to help combat the sleepiness. However, in some cases they may first test a norepinephrine reuptake inhibitor due to the fact that they have less potential of creating dependency and being abused.
- Neuropathic pain: There is evidence that norepinephrine reuptake inhibiting drugs can improve symptoms of neuropathic pain. Many have been granted FDA approval for this specific condition. Although they may not be as potent as an opioid, many practitioners favor them in certain cases due to their low abuse potential.