Restless Legs Syndrome (RLS) — RepurpOS

Disease overview

Alterations

109

Molecular (A)

100

Clinical (B–E)

Direct drugs

Via biomarker

153

Natural agents

Natural products

Merged ranked

200

With trial/literature evidence

Sources: Open Targets, HPO, ClinicalTrials.gov, DGIdb, ChEMBL, PubMed Literature, Seeds, Examine.com · Pipeline phase 7 · Updated 2026-07-06

Remission & chronicity

Spontaneous remission

Primary RLS is chronic; spontaneous remission in mild cases ~30-40% over 5 years; pregnancy-induced RLS remits post-delivery; augmentation on dopaminergic drugs worsens symptoms in 60-80% at 10 years

Best-intervention remission

Iron IV supplementation in iron-deficient RLS: 57% responders vs 35% placebo (ferric carboxymaltose — Phase 3 positive); alpha-2-delta ligands (gabapentin enacarbil, pregabalin): 53-55% RLS responders; dopamine agonists (pramipexole, ropinirole): 70-80% initial response but augmentation in 60-80% at 10 years

Drug-free remission

—

Relapse after remission

—

Chronicity

—

Gap size

Moderate — iron deficiency treatment is underused as primary intervention; dopamine agonists chronically overused despite augmentation risk

Primary barrier

framing/practice

Barrier detail: IV iron therapy for iron-deficient RLS (<50 µg/L ferritin) is highly effective and underused; dopamine agonists are first-line in most practices despite augmentation being essentially inevitable in long-term use; augmentation causes 24-hour symptoms worse than original disease

Last SoC change: 2023 — updated AAN/AASM guidelines recommending alpha-2-delta ligands over dopamine agonists as first-line (augmentation concern); ferric carboxymaltose approved for iron-deficient RLS; dopamine agonists (ropinirole, pramipexole) as first-line since 2006

Remission data layers: disease_db_100 · source-locked manual data · confidence: high

Identifiers: MONDO: MONDO:0005391

Right to Try Relevance

Eligibility: This disease meets the federal and state right-to-try legal standard (21 U.S.C. § 360bbb-0a and Montana SB 535): it lacks disease-modifying therapy with indication-specific FDA approval. Patients with Restless Legs Syndrome may be eligible to access investigational therapies outside of clinical trials under right-to-try frameworks.

Investigational Agents

Phase 3: 11, Phase 2: 20, Phase 1: 3

Most Advanced Phase

Phase 3

Highest dev. stage

Gene Targets

109

Actionable

Pipeline Compounds (Top 6)

Benserazide, Cabergoline, Carbidopa, Entacapone, Ferric Carboxymaltose, Levodopa

Legal Standard: Right-to-try requires the disease lacks "adequate approved therapy for that specific disease" (not symptom-management drugs). This distinction means a disease with antidepressants available still qualifies if no FDA approval exists for THAT disease indication.

View Right-to-Try Compendium

Alterations

Showing 80 of 109 · Types A (molecular) through E (functional)

Name	Type	Subtype	Direction	Frequency	Evidence	Sources	Links
ACP1 acid phosphatase 1	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
ACTN1 actinin alpha 1	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
ADCYAP1 adenylate cyclase activating polypeptide 1	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
ALCAM activated leukocyte cell adhesion molecule	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
ARL4C ARF like GTPase 4C	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
ASPSCR1 ASPSCR1 tether for SLC2A4, UBX domain containing	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
ASTN2 astrotactin 2	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
ATP2C1 ATPase secretory pathway Ca2+ transporting 1	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
ATRNL1 attractin like 1	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
BCL11B BCL11 transcription factor B	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
BDNF brain derived neurotrophic factor	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
BTBD9 BTB domain containing 9	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
CA10 carbonic anhydrase 10 (inactive)	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
CACNA1A calcium voltage-gated channel subunit alpha1 A	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
CACNA1B calcium voltage-gated channel subunit alpha1 B	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
CACNA1C calcium voltage-gated channel subunit alpha1 C	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
CACNA1D calcium voltage-gated channel subunit alpha1 D	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
CACNA1E calcium voltage-gated channel subunit alpha1 E	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
CACNA1F calcium voltage-gated channel subunit alpha1 F	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
CACNA1G calcium voltage-gated channel subunit alpha1 G	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
CACNA1H calcium voltage-gated channel subunit alpha1 H	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
CACNA1I calcium voltage-gated channel subunit alpha1 I	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
CACNA1S calcium voltage-gated channel subunit alpha1 S	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
CACNA2D1 calcium voltage-gated channel auxiliary subunit alpha2delta 1	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
CACNA2D2 calcium voltage-gated channel auxiliary subunit alpha2delta 2	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
CACNA2D3 calcium voltage-gated channel auxiliary subunit alpha2delta 3	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
CACNA2D4 calcium voltage-gated channel auxiliary subunit alpha2delta 4	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
CACNB1 calcium voltage-gated channel auxiliary subunit beta 1	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
CACNB2 calcium voltage-gated channel auxiliary subunit beta 2	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
CACNB3 calcium voltage-gated channel auxiliary subunit beta 3	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
CACNB4 calcium voltage-gated channel auxiliary subunit beta 4	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
CACNG1 calcium voltage-gated channel auxiliary subunit gamma 1	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
CACNG2 calcium voltage-gated channel auxiliary subunit gamma 2	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
CACNG3 calcium voltage-gated channel auxiliary subunit gamma 3	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
CACNG4 calcium voltage-gated channel auxiliary subunit gamma 4	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
CACNG5 calcium voltage-gated channel auxiliary subunit gamma 5	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
CACNG6 calcium voltage-gated channel auxiliary subunit gamma 6	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
CACNG7 calcium voltage-gated channel auxiliary subunit gamma 7	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
CACNG8 calcium voltage-gated channel auxiliary subunit gamma 8	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
CADM1 cell adhesion molecule 1	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
CAMK1G calcium/calmodulin dependent protein kinase IG	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
CAMTA1 calmodulin binding transcription activator 1	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
CCDC148 coiled-coil domain containing 148	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
CCDC167 coiled-coil domain containing 167	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
CDIN1 CDAN1 interacting nuclease 1	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
CITED1 Cbp/p300 interacting transactivator with ED-rich tail 1	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
CNTNAP5 contactin associated protein family member 5	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
CRBN cereblon	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
DAB1 DAB adaptor protein 1	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
DACH1 dachshund family transcription factor 1	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
DDC dopa decarboxylase	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
DIAPH3 diaphanous related formin 3	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
DPH6 diphthamine biosynthesis 6	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
DPT dermatopontin	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
DRD2 dopamine receptor D2	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
DRD3 dopamine receptor D3	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
DRD4 dopamine receptor D4	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
Daytime Sleepiness as measured by the Epworth Sleepiness Scale	Scales & PROs	Clinical scale	—	—	Emerging	ClinicalTrials.gov	—
EBF3 EBF transcription factor 3	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
ENOX1 ecto-NOX disulfide-thiol exchanger 1	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
FAM114A1 family with sequence similarity 114 member A1	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
FRMD4A FERM domain containing 4A	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
GPR139 G protein-coupled receptor 139	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
GRIA1 glutamate ionotropic receptor AMPA type subunit 1	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
GRIA4 glutamate ionotropic receptor AMPA type subunit 4	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
HOXB9 homeobox B9	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
KCNAB1 potassium voltage-gated channel subfamily A regulatory beta subunit 1	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
KCNK13 potassium two pore domain channel subfamily K member 13	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
KLF12 KLF transcription factor 12	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
LINC03051 long independently transcribed non-coding RNA 3051	Molecular	Gene	—	—	Emerging	Open Targets	Ensembl Open Targets
LINGO2 leucine rich repeat and Ig domain containing 2	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
LMO1 LIM domain only 1	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
MEIS1 Meis homeobox 1	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
MGMT O-6-methylguanine-DNA methyltransferase	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
MYT1 myelin transcription factor 1	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
NDST4 N-deacetylase and N-sulfotransferase 4	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
NLGN1 neuroligin 1	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
NRIP1 nuclear receptor interacting protein 1	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
OLFM4 olfactomedin 4	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets
OMA1 OMA1 zinc metallopeptidase	Molecular	Gene	—	—	Emerging	Open Targets	UniProt Ensembl Open Targets

FDA-Approved Therapies

Phase 4 agents with regulatory approval for this indication

Drug Name	Mechanism	Type
ACETAZOLAMIDE	None	Gene-targeted
ADAPALENE		Gene-targeted
AMITRIPTYLINE HYDROCHLORIDE		Gene-targeted
AMLODIPINE BESYLATE		Gene-targeted
AMPHETAMINE	None	Gene-targeted
ARGIPRESSIN		Gene-targeted
ARSENIC TRIOXIDE		Gene-targeted
BACLOFEN		Gene-targeted
BEPRIDIL		Gene-targeted
BEPRIDIL HYDROCHLORIDE	blocker	Gene-targeted
BICALUTAMIDE	None	Gene-targeted
BORTEZOMIB		Gene-targeted
CAMPTOTHECIN		Gene-targeted
CAPSAICIN		Gene-targeted
CARBACHOL	None	Gene-targeted
CEFDINIR		Gene-targeted
CELECOXIB		Gene-targeted
CETUXIMAB		Gene-targeted
CHLORPROMAZINE		Gene-targeted
CIPROFLOXACIN	None	Gene-targeted
CLEVIDIPINE		Gene-targeted
CLOMIPRAMINE		Gene-targeted
CLOMIPRAMINE	None	Gene-targeted
COLCHICINE		Gene-targeted
CORTICOTROPIN		Gene-targeted
DACTINOMYCIN		Gene-targeted
DESFLURANE		Gene-targeted
DESIPRAMINE		Gene-targeted
DIAZEPAM	None	Gene-targeted
DICHLORPHENAMIDE	None	Gene-targeted
DIDANOSINE		Gene-targeted
DIETHYLSTILBESTROL		Gene-targeted
DIETHYLSTILBESTROL	None	Gene-targeted
DONEPEZIL HYDROCHLORIDE		Gene-targeted
DOXORUBICIN HYDROCHLORIDE		Gene-targeted
DRONABINOL		Gene-targeted
DULOXETINE HYDROCHLORIDE		Gene-targeted
EMPAGLIFLOZIN		Gene-targeted
ENFLURANE		Gene-targeted
EPIRUBICIN	None	Gene-targeted

Therapeutics

Direct disease associations, biomarker-linked drugs, OSMF narrative-review natural agents, and merged ranking. Only agents with registry trials or published clinical literature are shown by default.

Show agents without direct trial evidence

Drug	Type	Phase	Evidence	Score	Trials & literature	Sources	Links
ACETAZOLAMIDE Repurposing	Small molecule	Approved	Strong	95	—	ChEMBL	ChEMBL Open Targets
ADAPALENE Repurposing	Small molecule	Approved	Strong	95	—	DGIdb	—
AMITRIPTYLINE HYDROCHLORIDE Repurposing	Small molecule	Approved	Strong	95	—	DGIdb	—
AMLODIPINE BESYLATE Repurposing	Small molecule	Approved	Strong	95	—	DGIdb	—
AMPHETAMINE Repurposing	Small molecule	Approved	Strong	95	—	ChEMBL	ChEMBL Open Targets
ARGIPRESSIN Repurposing	Small molecule	Approved	Strong	95	—	DGIdb	—
ARSENIC TRIOXIDE Repurposing	Small molecule	Approved	Strong	95	—	DGIdb	—
BACLOFEN Repurposing	Small molecule	Approved	Strong	95	—	DGIdb	—
BEPRIDIL Repurposing	Small molecule	Approved	Strong	95	—	DGIdb	—
BEPRIDIL HYDROCHLORIDE Repurposing	Small molecule	Approved	Strong	95	—	DGIdb	ChEMBL Open Targets
BICALUTAMIDE Repurposing	Small molecule	Approved	Strong	95	—	ChEMBL	ChEMBL Open Targets
BORTEZOMIB Repurposing	Small molecule	Approved	Strong	95	—	DGIdb	—
CAMPTOTHECIN Repurposing	Small molecule	Approved	Strong	95	—	DGIdb	—
CAPSAICIN Repurposing	Small molecule	Approved	Strong	95	—	DGIdb	—
CARBACHOL Repurposing	Small molecule	Approved	Strong	95	—	ChEMBL	ChEMBL Open Targets
CEFDINIR Repurposing	Small molecule	Approved	Strong	95	No indexed hits View evidence CT.gov search · Cochrane · PubMed	DGIdb	—
CELECOXIB Repurposing	Small molecule	Approved	Strong	95	—	DGIdb	—
CETUXIMAB Repurposing	Small molecule	Approved	Strong	95	No indexed hits View evidence CT.gov search · Cochrane · PubMed	DGIdb	—
CHLORPROMAZINE Repurposing	Small molecule	Approved	Strong	95	—	DGIdb	—
CIPROFLOXACIN Repurposing	Small molecule	Approved	Strong	95	—	ChEMBL	ChEMBL Open Targets
CLEVIDIPINE Repurposing	Small molecule	Approved	Strong	95	—	DGIdb	—
CLOMIPRAMINE Repurposing	Small molecule	Approved	Strong	95	3 pubs View evidence CT.gov search · Cochrane · PubMed	DGIdb	—
CLOMIPRAMINE Repurposing	Small molecule	Approved	Strong	95	—	ChEMBL	ChEMBL Open Targets
COLCHICINE Repurposing	Small molecule	Approved	Strong	95	—	DGIdb	—
CORTICOTROPIN Repurposing	Small molecule	Approved	Strong	95	—	DGIdb	—
DACTINOMYCIN Repurposing	Small molecule	Approved	Strong	95	—	DGIdb	—
DESFLURANE Repurposing	Small molecule	Approved	Strong	95	No indexed hits View evidence CT.gov search · Cochrane · PubMed	DGIdb	—
DESIPRAMINE Repurposing	Small molecule	Approved	Strong	95	—	DGIdb	—
DIAZEPAM Repurposing	Small molecule	Approved	Strong	95	—	ChEMBL	ChEMBL Open Targets
DICHLORPHENAMIDE Repurposing	Small molecule	Approved	Strong	95	—	ChEMBL	ChEMBL Open Targets
DIDANOSINE Repurposing	Small molecule	Approved	Strong	95	—	DGIdb	—
DIETHYLSTILBESTROL Repurposing	Small molecule	Approved	Strong	95	—	DGIdb	—
DIETHYLSTILBESTROL Repurposing	Small molecule	Approved	Strong	95	—	ChEMBL	ChEMBL Open Targets
DONEPEZIL HYDROCHLORIDE Repurposing	Small molecule	Approved	Strong	95	1 trials View evidence Registry trials NCT02670161 — Quality Improvement and Practice Based Research in Neurology Using the EMR (ENROLLING_BY_INVITATION) PHASE4 CT.gov search · Cochrane · PubMed	DGIdb	—
DOXORUBICIN HYDROCHLORIDE Repurposing	Small molecule	Approved	Strong	95	No indexed hits View evidence CT.gov search · Cochrane · PubMed	DGIdb	—
DRONABINOL Repurposing	Small molecule	Approved	Strong	95	—	DGIdb	—
DULOXETINE HYDROCHLORIDE Repurposing	Small molecule	Approved	Strong	95	—	DGIdb	—
EMPAGLIFLOZIN Repurposing	Small molecule	Approved	Strong	95	—	DGIdb	—
ENFLURANE Repurposing	Small molecule	Approved	Strong	95	No indexed hits View evidence CT.gov search · Cochrane · PubMed	DGIdb	—
EPIRUBICIN Repurposing	Small molecule	Approved	Strong	95	—	ChEMBL	ChEMBL Open Targets
EPOETIN ALFA Repurposing	Small molecule	Approved	Strong	95	—	DGIdb	—
ESTRADIOL 3-BENZOATE Repurposing	Small molecule	Approved	Strong	95	—	DGIdb	—
ETHOXZOLAMIDE Repurposing	Small molecule	Approved	Strong	95	—	ChEMBL	ChEMBL Open Targets
FENTANYL CITRATE Repurposing	Small molecule	Approved	Strong	95	—	DGIdb	—
FLUMAZENIL Repurposing	Small molecule	Approved	Strong	95	—	ChEMBL	ChEMBL Open Targets
FLUOROURACIL Repurposing	Small molecule	Approved	Strong	95	No indexed hits View evidence CT.gov search · Cochrane · PubMed	DGIdb	—
FLUOXETINE HYDROCHLORIDE Repurposing	Small molecule	Approved	Strong	95	—	DGIdb	—
FLURBIPROFEN Repurposing	Small molecule	Approved	Strong	95	No indexed hits View evidence CT.gov search · Cochrane · PubMed	DGIdb	—
FLUTICASONE Repurposing	Small molecule	Approved	Strong	95	—	DGIdb	—
FLUVOXAMINE Repurposing	Small molecule	Approved	Strong	95	—	DGIdb	—

Drug	Type	Phase	Evidence	Score	Sources	Links
BENSERAZIDE	Small molecule	Phase III	Moderate	80	Open Targets	ChEMBL Open Targets
CABERGOLINE	Small molecule	Phase III	Moderate	80	Open Targets	ChEMBL Open Targets
CARBIDOPA	Small molecule	Phase III	Moderate	80	Open Targets	ChEMBL Open Targets
ENTACAPONE	Small molecule	Phase III	Moderate	80	Open Targets	ChEMBL Open Targets
FERRIC CARBOXYMALTOSE	Small molecule	Phase III	Moderate	80	Open Targets	ChEMBL Open Targets
LEVODOPA	Small molecule	Phase III	Moderate	80	Open Targets	ChEMBL Open Targets
LISURIDE	Small molecule	Phase III	Moderate	80	Open Targets	ChEMBL Open Targets
NALOXONE	Small molecule	Phase III	Moderate	80	Open Targets	ChEMBL Open Targets
OXYCODONE	Small molecule	Phase III	Moderate	80	Open Targets	ChEMBL Open Targets
PREGABALIN	Small molecule	Phase III	Moderate	80	Open Targets	ChEMBL Open Targets
ROPINIROLE	Small molecule	Phase III	Moderate	80	Open Targets	ChEMBL Open Targets
APLINDORE	Small molecule	Phase II	Emerging	60	Open Targets	ChEMBL Open Targets
ASCORBIC ACID	Small molecule	Phase II	Emerging	60	Open Targets	ChEMBL Open Targets
BOTULINUM TOXIN TYPE A	Biologic	Phase II	Emerging	60	Open Targets	ChEMBL Open Targets
BP-14979	Small molecule	Phase II	Emerging	60	Open Targets	ChEMBL Open Targets
BUPROPION	Small molecule	Phase II	Emerging	60	Open Targets	ChEMBL Open Targets
CANNABIDIOL	Small molecule	Phase II	Emerging	60	Open Targets	ChEMBL Open Targets
DIPHENHYDRAMINE	Small molecule	Phase II	Emerging	60	Open Targets	ChEMBL Open Targets
DIPYRIDAMOLE	Small molecule	Phase II	Emerging	60	Open Targets	ChEMBL Open Targets
ERGOCALCIFEROL	Small molecule	Phase II	Emerging	60	Open Targets	ChEMBL Open Targets
FERROUS SULFATE	Small molecule	Phase II	Emerging	60	Open Targets	ChEMBL Open Targets
FERUMOXYTOL	Small molecule	Phase II	Emerging	60	Open Targets	ChEMBL Open Targets
IRON ISOMALTOSIDE 1000	Small molecule	Phase II	Emerging	60	Open Targets	ChEMBL Open Targets
IRON SUCROSE	Small molecule	Phase II	Emerging	60	Open Targets	ChEMBL Open Targets
ISTRADEFYLLINE	Small molecule	Phase II	Emerging	60	Open Targets	ChEMBL Open Targets
LEVETIRACETAM	Small molecule	Phase II	Emerging	60	Open Targets	ChEMBL Open Targets
METHADONE	Small molecule	Phase II	Emerging	60	Open Targets	ChEMBL Open Targets
RASAGILINE	Small molecule	Phase II	Emerging	60	Open Targets	ChEMBL Open Targets
SUVOREXANT	Small molecule	Phase II	Emerging	60	Open Targets	ChEMBL Open Targets
VITAMIN E	Small molecule	Phase II	Emerging	60	Open Targets	ChEMBL Open Targets
ZURETINOL ACETATE	Small molecule	Phase II	Emerging	60	Open Targets	ChEMBL Open Targets
CRISUGABALIN	Small molecule	Phase I	Emerging	35	Open Targets	ChEMBL Open Targets
ECOPIPAM	Small molecule	Phase I	Emerging	35	Open Targets	ChEMBL Open Targets
PREDNISONE	Small molecule	Phase I	Emerging	35	Open Targets	ChEMBL Open Targets
ALCOHOL	Small molecule	Preclinical	Emerging	15	Open Targets	ChEMBL Open Targets
BUPIVACAINE HYDROCHLORIDE	Small molecule	Preclinical	Emerging	15	Open Targets	ChEMBL Open Targets
DRONABINOL	Small molecule	Preclinical	Emerging	15	Open Targets	ChEMBL Open Targets
FERRIC OXYHYDROXIDE	Small molecule	Preclinical	Emerging	15	Open Targets	ChEMBL Open Targets
GABAPENTIN	Small molecule	Preclinical	Emerging	15	Open Targets	ChEMBL Open Targets
GABAPENTIN ENACARBIL	Small molecule	Preclinical	Emerging	15	Open Targets	ChEMBL Open Targets

Drug	Type	Phase	Evidence	Score	Trials & literature	Sources	Links
ACETAZOLAMIDE Repurposing via ACP1	Small molecule	Approved	Strong	95	—	ChEMBL	ChEMBL Open Targets
ADAPALENE Repurposing via BDNF	Small molecule	Approved	Strong	95	—	DGIdb	—
AMITRIPTYLINE HYDROCHLORIDE Repurposing via BDNF	Small molecule	Approved	Strong	95	—	DGIdb	—
AMLODIPINE BESYLATE Repurposing via CACNA1B	Small molecule	Approved	Strong	95	—	DGIdb	—
AMPHETAMINE Repurposing via ACP1	Small molecule	Approved	Strong	95	—	ChEMBL	ChEMBL Open Targets
ARGIPRESSIN Repurposing via BDNF	Small molecule	Approved	Strong	95	—	DGIdb	—
ARSENIC TRIOXIDE Repurposing via BDNF	Small molecule	Approved	Strong	95	—	DGIdb	—
BACLOFEN Repurposing via BDNF	Small molecule	Approved	Strong	95	—	DGIdb	—
BEPRIDIL Repurposing via CACNA1A	Small molecule	Approved	Strong	95	—	DGIdb	—
BEPRIDIL HYDROCHLORIDE Repurposing via CACNA1B	Small molecule	Approved	Strong	95	—	DGIdb	ChEMBL Open Targets
BICALUTAMIDE Repurposing via ACP1	Small molecule	Approved	Strong	95	—	ChEMBL	ChEMBL Open Targets
BORTEZOMIB Repurposing via BDNF	Small molecule	Approved	Strong	95	—	DGIdb	—
CAMPTOTHECIN Repurposing via BDNF	Small molecule	Approved	Strong	95	—	DGIdb	—
CAPSAICIN Repurposing via BDNF	Small molecule	Approved	Strong	95	—	DGIdb	—
CARBACHOL Repurposing via ACP1	Small molecule	Approved	Strong	95	—	ChEMBL	ChEMBL Open Targets
CEFDINIR Repurposing via ACP1	Small molecule	Approved	Strong	95	No indexed hits View evidence CT.gov search · Cochrane · PubMed	DGIdb	—
CELECOXIB Repurposing via CACNA1B	Small molecule	Approved	Strong	95	—	DGIdb	—
CETUXIMAB Repurposing via BDNF	Small molecule	Approved	Strong	95	No indexed hits View evidence CT.gov search · Cochrane · PubMed	DGIdb	—
CHLORPROMAZINE Repurposing via BDNF	Small molecule	Approved	Strong	95	—	DGIdb	—
CIPROFLOXACIN Repurposing via ACP1	Small molecule	Approved	Strong	95	—	ChEMBL	ChEMBL Open Targets
CLEVIDIPINE Repurposing via CACNA1B	Small molecule	Approved	Strong	95	—	DGIdb	—
CLOMIPRAMINE Repurposing via BDNF	Small molecule	Approved	Strong	95	3 pubs View evidence CT.gov search · Cochrane · PubMed	DGIdb	—
CLOMIPRAMINE Repurposing via ACP1	Small molecule	Approved	Strong	95	—	ChEMBL	ChEMBL Open Targets
COLCHICINE Repurposing via BDNF	Small molecule	Approved	Strong	95	—	DGIdb	—
CORTICOTROPIN Repurposing via BDNF	Small molecule	Approved	Strong	95	—	DGIdb	—
DACTINOMYCIN Repurposing via BDNF	Small molecule	Approved	Strong	95	—	DGIdb	—
DESFLURANE Repurposing via ATP2C1	Small molecule	Approved	Strong	95	No indexed hits View evidence CT.gov search · Cochrane · PubMed	DGIdb	—
DESIPRAMINE Repurposing via BDNF	Small molecule	Approved	Strong	95	—	DGIdb	—
DIAZEPAM Repurposing via ACP1	Small molecule	Approved	Strong	95	—	ChEMBL	ChEMBL Open Targets
DICHLORPHENAMIDE Repurposing via ACP1	Small molecule	Approved	Strong	95	—	ChEMBL	ChEMBL Open Targets
DIDANOSINE Repurposing via BDNF	Small molecule	Approved	Strong	95	—	DGIdb	—
DIETHYLSTILBESTROL Repurposing via BDNF	Small molecule	Approved	Strong	95	—	DGIdb	—
DIETHYLSTILBESTROL Repurposing via ACP1	Small molecule	Approved	Strong	95	—	ChEMBL	ChEMBL Open Targets
DONEPEZIL HYDROCHLORIDE Repurposing via BDNF	Small molecule	Approved	Strong	95	1 trials View evidence Registry trials NCT02670161 — Quality Improvement and Practice Based Research in Neurology Using the EMR (ENROLLING_BY_INVITATION) PHASE4 CT.gov search · Cochrane · PubMed	DGIdb	—
DOXORUBICIN HYDROCHLORIDE Repurposing via BDNF	Small molecule	Approved	Strong	95	No indexed hits View evidence CT.gov search · Cochrane · PubMed	DGIdb	—
DRONABINOL Repurposing via BDNF	Small molecule	Approved	Strong	95	—	DGIdb	—
DULOXETINE HYDROCHLORIDE Repurposing via BDNF	Small molecule	Approved	Strong	95	—	DGIdb	—
EMPAGLIFLOZIN Repurposing via BDNF	Small molecule	Approved	Strong	95	—	DGIdb	—
ENFLURANE Repurposing via ATP2C1	Small molecule	Approved	Strong	95	No indexed hits View evidence CT.gov search · Cochrane · PubMed	DGIdb	—
EPIRUBICIN Repurposing via ACP1	Small molecule	Approved	Strong	95	—	ChEMBL	ChEMBL Open Targets

Natural Products

15 natural products with the same evidence schema as repurposed drugs — registry trials, PubMed literature, and reference links (pipeline-ranked). Only agents with direct clinical evidence are shown by default.

Reference lookups: Examine.com

Show agents without direct trial evidence

Drug	Type	Phase	Evidence	Score	Trials & literature	Links
Folate Natural product Human Study Restless leg syndrome may be associated with a deficiency of folic acid. Commentary Iron and folate deficiencies may be associated with restless leg syndro…	Nutraceutical	Preclinical	Emerging	10	1 trials View evidence Registry trials NCT06324760 — Alpha-lipoic Acid Combined With B Vitamins Shows Promise for Treating Restless Legs Syndrome (COMPLETED) CT.gov search · Cochrane · PubMed	PubChem
Vitamin D3 Natural product Human Study The effect of vitamin D on restless legs syndrome: prospective self-con… Human Study Therapeutic effects of magnesium and vitamin B6 in alleviating the symp…	Nutraceutical	Approved	Emerging	10	2 trials View evidence Registry trials NCT03063190 — Cholecalciferol Supplementation in Restless Leg Syndrome in Patients With Chronic Kidney Disease (WITHDRAWN) PHASE4 NCT02256215 — Vitamin D in the Treatment of Primary Restless Legs Syndrome (UNKNOWN) PHASE2, PHASE3 CT.gov search · Cochrane · PubMed	PubChem
Magnesium Natural product Systematic review Effects of Dietary Supplementation in Patients with Restless Legs Syndr… Systematic review Magnesium supplementation for the treatment of restless legs syndrome a… Clinical trial publication Magnesium citrate monotherapy improves restless legs syndrome symptoms…	Nutraceutical	Phase III	Emerging	10	2 trials 3 Trial pubs 1 RCT View evidence Registry trials NCT04462796 — The Effect of Magnesium Citrate Supplementation in Restless Legs Syndrome (RLS) (UNKNOWN) NA NCT02397057 — Placebo-Controlled Study to Investigate the Efficacy & Safety of Injectafer in the Treatment of RLS (COMPLETED) PHASE3 Published literature Systematic review Effects of Dietary Supplementation in Patients with Restless Legs Syndrome: A Systematic Review (Nutrients, 2024) Systematic review Magnesium supplementation for the treatment of restless legs syndrome and periodic limb movement disorder: A systematic review (Sleep medicine reviews, 2019) Clinical trial publication Magnesium citrate monotherapy improves restless legs syndrome symptoms and multiple suggested immobilization test scores in an open-label pilot study (Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine, 2024) Clinical trial publication Therapeutic effects of magnesium and vitamin B6 in alleviating the symptoms of restless legs syndrome: a randomized controlled clinical trial (BMC complementary medicine and therapies, 2022) Clinical trial publication Magnesium therapy for periodic leg movements-related insomnia and restless legs syndrome: an open pilot study (Sleep, 1998) CT.gov search · Cochrane · PubMed	PubChem
L-Arginine Natural product Human Study Arginine may have therapeutic value in restless leg syndrome.	Amino acid	Preclinical	Emerging	7	No indexed hits View evidence CT.gov search · Cochrane · PubMed	PubChem
Niacin Natural product Human Study Therapeutic effects of magnesium and vitamin B6 in alleviating the symp… Human Study The effect of vitamin D on restless legs syndrome: prospective self-con…	Nutraceutical	Preclinical	Emerging	7	No indexed hits View evidence CT.gov search · Cochrane · PubMed	PubChem
Valerian Natural product Systematic review Effects of Dietary Supplementation in Patients with Restless Legs Syndr… Clinical trial publication Comparison the effect of valerian and gabapentin on RLS and sleep quali… Clinical trial publication Does valerian improve sleepiness and symptom severity in people with re…	Botanical	Preclinical	Emerging	7	2 Trial pubs 2 RCT View evidence Published literature Systematic review Effects of Dietary Supplementation in Patients with Restless Legs Syndrome: A Systematic Review (Nutrients, 2024) Clinical trial publication Comparison the effect of valerian and gabapentin on RLS and sleep quality in hemodialysis patients: A randomized clinical trial (Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy, 2023) Clinical trial publication Does valerian improve sleepiness and symptom severity in people with restless legs syndrome? (Alternative therapies in health and medicine, 2009) CT.gov search · Cochrane · PubMed	—
Ashwagandha Natural product Human: Case Report Withania somnifera as an adjunctive treatment for refractory restless l…	Ayurvedic	Preclinical	Emerging	7	2 pubs View evidence CT.gov search · Cochrane · PubMed	PubChem
Iron Natural product Cochrane review Iron therapy & restless legs syndrome: a narrative review Cochrane review Efficacy of oral vs. intravenous iron for the treatment of iron deficie… Cochrane review Efficacy and safety of intravenous ferric carboxymaltose in the treatme…	Nutraceutical	Approved	Emerging	7	8 trials 11 Cochrane 17 Meta-analysis 34 Trial pubs 22 RCT View evidence Registry trials NCT07307482 — Study on the Mechanism of Gut Microbiota Mediating Restless Legs Syndrome Through Iron Metabolism (NOT_YET_RECRUITING) NCT07083492 — Non-invasive Detection of Iron Deficiency in Obstetrics (RECRUITING) NCT00685815 — Intravenous Iron Metabolism in Restless Legs Syndrome (COMPLETED) PHASE2 NCT03457571 — Clinical Observational Study: IBD Patients With Restless-legs-syndrome and Iron Deficiency Syndrome (COMPLETED) NCT04610827 — Oral Iron Frequency for Childhood Restless Leg Syndrome/Periodic Limb Movement Disorder (TERMINATED) PHASE4 NCT07061470 — A Clinical Trial of Iron Supplementation for Youth With ADHD and Restless Sleep (NOT_YET_RECRUITING) PHASE1, PHASE2 NCT01617044 — Probiotics in the Treatment of Iron Deficiency in Children With Restless Leg Syndrome (COMPLETED) PHASE2 NCT01245777 — Restless Legs Syndrome With Iron Deficiency or Anaemia in the 3rd Trimester of Pregnancy (COMPLETED) PHASE4 Published literature Cochrane review Iron therapy & restless legs syndrome: a narrative review (Sleep & breathing = Schlaf & Atmung, 2026) Cochrane review Efficacy of oral vs. intravenous iron for the treatment of iron deficiency anemia in different conditions: A systematic review and meta-analysis (Biomedical reports, 2026) Cochrane review Efficacy and safety of intravenous ferric carboxymaltose in the treatment of Restless Legs Syndrome: a systematic review and meta-analysis (Frontiers in neurology, 2024) Cochrane review Association of low serum ferritin levels with augmentation in patients with restless legs syndrome: A systematic review and meta-analysis (Sleep medicine, 2023) Cochrane review Restless Leg Syndrome in Hemodialysis Patients: A Narrative Review (The neurologist, 2022) Meta-analysis Restless legs syndrome among blood donors: A systematic review and meta-analysis (Vox sanguinis, 2025) Meta-analysis Clinical efficacy and safety of IV ferric carboxymaltose in restless legs syndrome: A meta-analysis of 537 patients (Sleep medicine, 2024) Meta-analysis Prevalence and clinical profile of patients with restless legs syndrome in Parkinson's disease: A meta-analysis (Sleep medicine, 2024) Meta-analysis Pharmacological responsiveness of periodic limb movements in patients with restless legs syndrome: a systematic review and meta-analysis (Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine, 2023) Systematic review Efficacy and safety of pharmacological treatments for restless legs syndrome in hemodialysis patients: a systematic review and meta-analysis (Frontiers in neurology, 2026) Systematic review Is the Juice Worth the Squeeze? Vitamin C Supplementation in Hemodialysis Patients: A Systematic Review (Nutrients, 2026) Systematic review Pharmacological impact on sleep architecture and polysomnographic measures in Restless Legs Syndrome: A systematic review (Sleep medicine reviews, 2025) CT.gov search · Cochrane · PubMed	PubChem
Peony Natural product Meta Analysis, Review Paeoniae Radix-containing herbal medicines might promote improvements i…	Nutraceutical	Preclinical	Emerging	0	No indexed hits View evidence CT.gov search · Cochrane · PubMed	—
Olive Oil: Topical Natural product Human Study Application of short-term massage with olive oil as a complementary met…	Nutraceutical	Preclinical	Emerging	0	No indexed hits View evidence CT.gov search · Cochrane · PubMed	—
B-Complex Natural product Human Study B complex is a safe and effective treatement of nocturnal leg cramps in…	Nutraceutical	Preclinical	Emerging	0	1 trials View evidence Registry trials NCT06324760 — Alpha-lipoic Acid Combined With B Vitamins Shows Promise for Treating Restless Legs Syndrome (COMPLETED) CT.gov search · Cochrane · PubMed	—
D-Ribose Natural product Human Study D-ribose improves quality of life and reduces the severity and onset of…	Food compound	Preclinical	Emerging	0	No indexed hits View evidence CT.gov search · Cochrane · PubMed	PubChem
Flavonoids Natural product Human Study Restless legs syndrome: prevention with Pycnogenol and improvement of t…	Nutraceutical	Preclinical	Emerging	0	No indexed hits View evidence CT.gov search · Cochrane · PubMed	—
Pycnogenol (Pine Bark) Natural product Human Study Restless legs syndrome: prevention with Pycnogenol and improvement of t…	Nutraceutical	Preclinical	Emerging	0	No indexed hits View evidence CT.gov search · Cochrane · PubMed	—
Palmitoylethanolamide Natural product Human: Case Report Palmitoylethanolamide (PEA) in the treatment of restless legs syndrome:…	Nutraceutical	Preclinical	Emerging	0	1 pubs View evidence CT.gov search · Cochrane · PubMed	—

Alterations and therapeutics are aggregated from public databases (Open Targets, HPO, ChEMBL, DGIdb, and others). Natural agents are candidates from OSMF narrative reviews on opensourcemed.info/chronic-disease.html — not approved treatments. This page is for research orientation only — not medical advice.