Dopamine Reuptake Inhibitors (DRIs) are drugs that function by preventing the reuptake of the neurotransmitter dopamine. The fact that they prevent dopamine reuptake leads to increased concentrations of dopamine between synapses. This increases stimulation of the central nervous system and tends to improve cognitive function, alertness, and performance.
These medications are most often utilized for the treatment of ADHD, wakefulness disorders like narcolepsy, and in some cases to help treat obesity. In other cases they may be used as an antidepressant augmentation strategy if a psychiatrist believes a patient would benefit from increased dopamine. Although they are quite effective and well-tolerated when used for FDA approved conditions, many people use them recreationally as party drugs due to the fact that they can produce feelings of short-term euphoria.
As a result of their abuse potential and tendency to evoke dependence, they are considered “controlled substances” in the United States. Other conditions that DRIs may be used to help treat include: Alzheimer’s disease, dementia, hypothyroidism, and abnormally elevated levels of vitamin D. Unfortunately, long-term usage of many DRIs can lead to a gradual depletion of natural dopamine production. Fortunately dopamine levels will eventually return to homeostatic levels following withdrawal.
Dopamine Reuptake Inhibitors (DRIs) List
Below is a list of dopamine reuptake inhibitors and brief descriptions of each drug. Realize that there may be some overlap with the drugs listed below and NDRIs. That being said, it is important to distinguish DRIs from NRIs, or drugs that solely target norepinephrine. Due to poor tolerability and potential for abuse, many DRIs have been withdrawn from global markets and clinical development.
- Amineptine (Survector): This drug was originally approved in the late 1970s throughout France to treat depression. It is considered a tricyclic antidepressant that acts on primarily dopamine to elicit its antidepressant effect. Due to the fact that it increased dopamine levels, it was considered to have a high potential for abuse. People would take it to get “high” but the initial sense of euphoria wasn’t considered the same as the actual “antidepressant effect” which took over a week to establish. Some professionals classify this drug as an NDRI due to the fact that it inhibits reuptake of norepinephrine to a small degree. It was eventually withdrawn from the market due to cases of liver damage and abuse potential.
- Altropane (O-587): This is a powerful reuptake inhibitor of the neurotansmitter dopamine and is considered to have long-acting effects. It is typically used for scientific purposes to identify dopamine transporters in the brain. The substance is also considered to be an investigational treatment for ADHD and in diagnosing Parkinson’s disease.
- Amfonelic acid (AFA): This is a chemical that is strictly utilized for scientific research that possesses notable dopamine reuptake inhibition properties. It is considered a highly selective drug and has a fairly lengthy half-life of nearly 12 hours. Although the drug doesn’t tend to indirectly influence norepinephrine, in rodent studies it did have indirect effects on serotonin levels. It is considered to be nearly 150% as potent as the popular stimulant dextroamphetamine. Unlike many other DRIs, it is not considered a “controlled substance” in the United States.
- Benocyclidine (BTPC): This is considered a recreational drug that functions as a dopamine reuptake inhibitor with selective properties. It elicits a psychostimulant effect and is sometimes used by researchers to help identify dopamine transporters. In some types of MDMA, trace levels of BTPC are found. Since it is not considered a “controlled substance” is legal to have in the United States; the only exception is the state of Florida in which it is considered a “Schedule I” drug.
- DBL-58: This drug is derived from the piperazine class and acts as a dopamine reuptake inhibitor with selective action. It is administered as injections and tends to take a long period before it is filtered out of the body. Some evidence indicates that the drug can be found in the body for up to 30 days following just a single injection.
- Difluoropine (O-620): This is a drug that was derived from tropinone and acts as a DRI with selectivity. Its stereoisomer profile is notably unique in that it functions conversely to that of cocaine. Rather than the R-stereoisomer being active, the dopamine reuptake inhibition is brought upon by the S-stereoisomer. In animal models it is considered to have potential in improving various symptoms of Parkinson’s disease. Although it is not technically classified as a “controlled substance” some speculate that it may be illegal due to the fact that it is similar to cocaine.
- Fluorenol: This is a substance that was initially created as an insecticide in the late 1930s. It is considered to be derived from fluorene and is considered safe in humans. It is classified by some as a eugeroic drug and in studies it was nearly 40% more effective than Modafinil (Provigil) at keeping rodents awake. Although it does have dopamine reuptake inhibition properties, they are considered minimal. Of all the DRIs on this list, this one should be considered the weakest.
- GBR-12935: This is a drug with dopamine-reuptake inhibition effects that is a derivative of piperazine. It has been used in scientific research to help map out and label various dopamine transporters in the brain. It is believed that this drug is capable of helping diagnose Parkinson’s disease in animal models.
- GYKI-52895: This substance functions as a DRI with stimulant effects. As of now it is likely only utilized for scientific research. Not much information regarding this particular substance is documented or known other than it is a derivative of the anxiolytic drug 2,3-benzodiazepine.
- Modafinil (Provigil): This is considered a eugeroic drug that is approved by the FDA to treat wakefulness disorders like narcolepsy. Although its exact mechanism of action is unknown, it is believed to act on a variety of neurotransmitter systems. It is believed to act as a dopamine reuptake inhibitor to a very limited extent. It does tend to influence dopamine, but is thought to have less potential for abuse compared to amphetamines. It is sold by the company Cephalon Inc. and has been around since 1998 in the United States. Due to its ability to improve alertness and enhance cognition, many believe it is a pharmaceutical nootropic.
- RTI-229: This is a drug that was created in the 1990s and functions as a dopamine-reuptake inhibitor with selective properties. It is generally only used for research to help scientists identify and distinguish the dopamine transporter from the norepinephrine transporter. It is considered a legal drug in many countries, but may be considered a “controlled substance” in the United States due to the fact that it is similar to cocaine in structure.
- RTI-55 (Iometopane): This is considered a drug that is being utilized for medical research. It functions as a dopamine reuptake inhibitor, but is non-selective in its function. It also elicits an effect on serotonergic function. In rodent studies, it was found to improve certain mental functions such as locomotor ability. Due to its potency, it is generally used for mapping of dopamine transporters as well as dopaminergic neuron degradation in the brain.
- Vanoxerine (GBR-12909): This is a dopamine reuptake inhibitor that is considered extremely potent and selective. It binds to the dopamine transporter target with approximately 500x the potency as cocaine. However since it inhibits the release of dopamine as well, it leads to mild elevations in dopamine throughout the brain, leading to subtle stimulant effects. Some research suggests that this drug may help in treating cocaine addictions as a “replacement therapy” option. There is also some evidence to suggest that the drug is beneficial in treating cardiac arrhythmias with a favorable side effect profile.
Note: It is important to mention that only drugs that function primarily as dopamine-reuptake inhibitors are listed above. This list does not include drugs that influence a variety of other neurotransmitters in addition to dopamine.
Other drugs with DRI properties
Below is a list of other substances that tend to produce dopamine reuptake inhibiting effects, but also influence other neurotransmitters.
- 3-MeO-PCP (3-Methoxyphencyclidine): This is considered an anesthetic drug with dissociative properties that is manufactured for scientific research purposes. It was initially created in the late 1970s, but its mechanism of action wasn’t accurately documented until the late 1990s. This drug functions similar to PCP in that it binds to the NDMA receptor and is believed to inhibit reuptake of dopamine and also elicit opioid effects.
- 4-MeO-PCP (4-Methoxyphencyclidine): This is another anesthetic drug with dissociative properties that is also sold strictly for scientific research. It was initially developed in the 1960s but wasn’t very well understood until the 1990s. It is considered similar to PCP and is roughly 70% as potent. It is believed to inhibit the reuptake of dopamine, but primarily acts upon the NMDA receptor.
- Chaenomeles speciosa: This is a flowery fruit-bearing plant that is sometimes used in traditional Chinese medicine. Its formulated extract functions as a dopamine reuptake inhibitor. The particular effects are relatively undocumented in humans. Some speculate that it may work well at providing stimulatory effects.
- Medifoxamine (Cledial / Gerdaxyl): This is an antidepressant drug that is no longer in existence due to reports of liver damage. It acted primarily as a dopamine reuptake inhibitor, but also altered functioning of various serotonin receptors. The degree to which this drug was considered effective is unknown due to lack of studies and safety concerns.
- Ketamine: Most people know the drug ketamine is often used for anesthetic purposes and tends to be sedating. Off label uses include: providing pain relief and for treatment-resistant depression. It functions primarily as an NMDA receptor antagonist, but is believed to have some mild influence over dopamine reuptake inhibition, which gives individuals a sense of euphoria when they use this drug. Due to its psychomimetic properties, other medications like GLYX-13 are preferred for the treatment of depression.
- Phencyclidine (PCP): This is a recreational drug that has anesthetic and dissociative properties. It was originally developed as an anesthetic in the 1950s, but was banned for medical usage in 1965 due to causing hallucinations. It functions primarily as an NMDA antagonist, but is believed to also act as a mild dopamine reuptake inhibitor.
- Sertraline (Zoloft): This is an antidepressant drug that functions primarily as an SSRI. It tends to primarily increase the amount of serotonin in the brain. However, it is unique compared to other SSRIs in that it also acts as a dopamine reuptake inhibitor. In fact, it influences dopamine reuptake to a greater extent than the NDRI drug Burpropion. Therefore it could be technically considered an SDRI or serotonin-dopamine reuptake inhibitor.
- St. John’s Wort: This is a supplement that contains both “hyperforin” and “adhyperforin” which are known to affect the reuptake of a variety of neurotransmitters, including dopamine. In addition to increasing dopamine, they also boost levels of serotonin, norepinephrine, GABA, and glutamate.
Conditions treated with Dopamine Reuptake Inhibitors (DRIs)
There are various conditions that are thought to be influenced by low dopamine, that often benefit from increasing extracellular concentrations of dopamine. Particularly, conditions caused by low arousal and/or dopamine levels such as ADHD, chronic fatigue, wakefulness disorders, and certain types of treatment-resistant depression are thought to benefit the most.
- ADHD: Individuals with ADHD are typically prescribed amphetamines that act primarily as dopamine releasing agents (DRAs). However, some dopamine reuptake inhibitors are also effective at increasing cognitive function and attentional abilities. Therefore certain DRIs like Modafinil are thought to be effective for ADHD.
- Depression: Although most cases of depression are treated with serotonergic drugs, some cases benefit from medications that influence dopamine. In cases of treatment-resistant depression, a psychiatrist may prescribe a drug that inhibits reuptake of dopamine. It should also be mentioned that the antidepressant Sertraline acts on serotonin and dopamine as a reuptake inhibitor.
- Drug addiction: Individuals with various addictions to stimulants may benefit from certain DRIs. While some DRIs certainly carry potential for abuse, other weaker agents like Modafinil may actually help individuals withdraw from illicit drugs like cocaine. Although none are approved for this particular usage, some are being investigated.
- Fatigue: Those with chronic fatigue are believed to be understimulated and may lack dopamine. Therefore increasing dopamine levels in the brain can speed up the CNS and lead to increased arousal. This tends to give the person taking a DRI greater levels of energy.
- Wakefulness disorders: Various wakefulness disorders like narcolepsy are believed to benefit from dopamine reuptake inhibitors. While “eugeroics” may be preferred for such conditions, it should be mentioned that some eugeroics also function as weak DRIs (e.g. Modafinil).