Newer, receptor-specific strategies offer hope for RLS augmentation, but no guarantees.
By Lisa Spear
When clinicians first began prescribing dopaminergic medications for restless legs syndrome (RLS), the results seemed miraculous. The relief that patients felt from dopamine agonists, medications that upregulate the D2/D3 dopamine receptors, was often immediate. However, years later, many patients experienced significant increases in their symptoms, leaving them worse off than they were at diagnosis.
New research shows that the phenomenon of worsening symptoms, eventually linked to dopamine agonist medications—known as RLS augmentation—could be a result of the downstream stimulation of the D1 receptor.1 Not everyone agrees, but some clinicians and scientists are cautiously optimistic that targeting a different part of the dopamine system, the D1 receptor, holds promise for RLS treatment.
“I don’t want to say that it is the golden ticket, but I think it is the best new shot that is out there if you want to use pharmacology,” says Stefan Clemens, PhD, (pictured) a professor in the department of physiology at East Carolina University and the principal investigator of the Clemens Lab, where his research is focused on investigating the role of dopamine in the spinal cord. He is excited, in particular, about drug candidate ecopipam (EBS-101), an investigational D1 antagonist.
In 2022, East Carolina University and Emalex Biosciences Inc entered into an agreement in which Emalex licensed the patent rights of ecopipam—which blocks the actions of the neurotransmitter dopamine at the D1 receptor—to potentially advance clinical studies for the treatment of RLS with augmentation. If approved by the US Food and Drug Administration (FDA), ecopipam could be available by late 2026 for the indication of Tourette syndrome, for which the compound is now in phase III trials. Emalex’s RLS augmentation trials are still in early stages, which means adding an FDA-approved RLS indication could come years later, at best.
Dopamine is a neurotransmitter in the central nervous system whose receptors have been classified into two “families” based on their genetic structure: D1 (including subtypes D1 and D5) and D2 (including subtypes D2, D3, and D4).2 Drugs that tend to bind to the D2 receptor also tend to bind to receptors D3 and D4. Drugs that tend to bind to the D1 receptor tend to bind to D5, with different affinities. D1 and D5 tend to be activators, while D1, D3, and D4 tend to be inhibitory. They can work together to counter each other.
If augmentation is caused by an overactive D1 receptor, but a drug such as ecopipam blocks the D1 receptor, then patients could be restored to their baselines, theoretically.
Still, some experts express concern about any medication that modulates dopamine, given the roller coaster history of dopamine agonists in RLS.
“When you screw around with the dopamine system, all kinds of things can happen, and it is not as simple as you may want to realize,” says Mark Buchfuhrer, MD, a clinical associate professor of psychiatry and behavioral sciences in sleep medicine at Stanford University.
Over the last 10 to 15 years, Buchfuhrer, who also works at Stanford Health Care’s Sleep Medicine Center, has tried to avoid prescribing dopaminergic medications for RLS, preferring gabapentinoids and opioids for patients experiencing augmentation. “Most patients are significantly worse, permanently worse, than they would have been if they had never been given the dopamine agonist drugs in the first place,” Buchfuhrer says.
Buchfuhrer does not find the limited research on ecopipam to be compelling. A study of 10 patients, published in the International Journal of Neuroscience, showed ecopipam was safe and well-tolerated, but there was no statistically significant improvement.3 “The ecopipam has only a modest effect on the D1 receptor,” says Buchfuhrer, who is not affiliated with the study.
However, the study authors from Methodist Neurological Institute at the University of Texas, Houston, wrote that RLS diaries and global impressions favored ecopipam, and given the lack of alternative options, larger efficacy studies for augmented RLS, and potentially de novo RLS would be justified.3
On the other hand, Buchfuhrer cautions that after seeing the fallout of other dopaminergic drugs, like pramipexole and ropinirole, he has reservations. “If tomorrow a drug came out and they said, ‘Look at this great study; it works fantastic,’ I personally would wait a while to see what happens. I have developed an unbelievable respect for the potential issues of using dopamine drugs,” he says.
Dopaminergic medications, he says, can lead to impulse control disorders, augmentation, and dopamine agonist withdrawal syndrome. “All kinds of funny stuff that we never knew existed” appeared after prescribers treated RLS patients with dopaminergic medicines, Buchfuhrer says.
Also, the American Academy of Sleep Medicine recently recommended against the use of D3 receptor agonists as first-line treatments for RLS and instead strongly recommends the alpha-2-delta ligand medications gabapentin enacarbil, gabapentin, and pregabalin, and intravenous iron in patients with low iron stores.4
“If you are going to use a dopamine agonist, keep it at a low dose, and never increase the dose. If a dose increase is necessary, it is clearly indicated at this point in time, that you need to move on to an alternative drug, and that means discontinuing the agonists,” says Christopher Earley, MBBCh, PhD, a professor of neurology at Johns Hopkins School of Medicine and the director of the Johns Hopkins Center for Restless Legs Syndrome.
Joseph Andrew “Andy” Berkowski, MD, who specializes in treating RLS at ReLACS Health, agrees that stimulating any one dopamine receptor could cause unintended downstream consequences.
If it weren’t complex enough, he says, dopamine receptors may have different functions in different parts of the nervous system. For instance, “you may want to block the D1 receptor in the spinal cord, but not in the brain. You might want to stimulate D3 in the spinal cord, but not in the brain,” says Berkowski, who is board-certified by the American Board of Psychiatry and Neurology in adult neurology and sleep medicine. “The dopamine system is so complex that if you hit one area, it might have an opposite effect in another area and be counterproductive,” he says.
Dopamine-modulating medications, in Berkowski’s opinion, should not be a first-line target. The root cause of the dopamine system not functioning properly in RLS could be low iron, a worthwhile target to look at long before dopaminergic medications, he says.
Still, as many clinicians lower their prescriptions of dopaminergic medications, some sleep scientists continue to study dopamine as a viable pharmacological pathway to both treat and understand the mechanisms behind RLS—only using receptor-specific pathways this time.
Image: Stefan Clemens, PhD, along with Kori Brewer, PhD, examine a mouse’s spinal column at East Carolina University’s Brody School of Medicine. Clemens’ work with mouse models was essential in helping him develop an investigational D1 antagonist that could potentially treat RLS augmentation. Credit: Cliff Hollis/East Carolina University
References
1. Clemens S, Ondo WG, Paulus W. Dopamine receptors in restless legs syndrome and augmentation: A novel perspective focused on D1 and D3 receptor dynamics. Mov Disord. 2025 Aug;40(8):1534-8.
2. Jones-Tabah J, Mohammad H, Paulus EG, et al. The signaling and pharmacology of the dopamine D1 receptor. Front Cell Neurosci. 2022 Jan 17;15:806618.
3. Ondo WG, Olubajo T. Exploratory cross-over, trial of augmented RLS with the dopamine receptor 1/5 antagonist ecopipam D1/D5 antagonist ecopipam for augmented RLS. Int J Neurosci. 2022 Aug;132(8):778-82.
4. Winkelman JW, Berkowski JA, DelRosso LM, et al. Treatment of restless legs syndrome and periodic limb movement disorder: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2025 Jan 1;21(1):137-52.
