Riluzole Original Trials — Bensimon 1994 and Lacomblez 1996
Riluzole has been the standard pharmacological treatment for ALS since 1995, when the FDA approved it based on two randomized controlled trials published in the New England Journal of Medicine (1994) and The Lancet (1996). It modestly slows ALS progression by inhibiting glutamate excitotoxicity — one of the mechanisms by which motor neurons die in ALS. Riluzole has never been tested in a randomized controlled trial specifically for PLS. It is prescribed off-label to some PLS patients, but there is no evidence that it benefits — or does not benefit — people with PLS. Understanding riluzole's evidence base requires understanding both what it demonstrated in ALS and what was never tested in PLS.
Mechanism of action: glutamate excitotoxicity
Glutamate is the primary excitatory neurotransmitter in the central nervous system. In ALS — and potentially in PLS — motor neurons are thought to be susceptible to excitotoxicity: a process in which excessive glutamate signaling triggers calcium influx, mitochondrial dysfunction, and ultimately cell death. Evidence for glutamate excitotoxicity in ALS includes elevated glutamate levels in CSF and plasma of ALS patients, and the finding that patients with ALS have reduced glutamate transporter expression in motor cortex and spinal cord.
Riluzole works through several complementary mechanisms, all related to reducing glutamate excitotoxicity. It inhibits glutamate release at presynaptic terminals, blocks certain subtypes of voltage-gated sodium channels (reducing neuronal excitability), and has some effect on NMDA receptors. The net result is reduced excitatory drive on motor neurons — potentially reducing the rate at which already-vulnerable neurons are pushed toward cell death.
The Bensimon 1994 trial
The pivotal early riluzole trial was conducted by Bensimon and colleagues and published in the New England Journal of Medicine in 1994. It enrolled 155 patients with ALS, randomizing them to riluzole 100 mg daily or placebo for 18 months. The primary endpoint was survival.
At 18 months, the riluzole group showed improved survival compared to placebo: 74% of patients in the riluzole group were alive versus 58% in the placebo group — a statistically significant difference. For limb-onset ALS, the benefit was particularly pronounced. The rate of deterioration in muscle strength and the ALS severity scale score was also slower in the riluzole group, though the absolute differences were modest.
Side effects were manageable. Asthenia (fatigue) and nausea were more common with riluzole, and elevated liver enzymes (ALT/AST) required monitoring. These findings established riluzole's basic safety and tolerability profile that continues to inform current prescribing.
The Lacomblez 1996 dose-ranging trial
A larger dose-ranging trial by Lacomblez and colleagues, published in The Lancet in 1996, enrolled 959 ALS patients and tested three doses of riluzole (50 mg, 100 mg, 200 mg daily) versus placebo. The 100 mg dose was confirmed as optimal — providing survival benefit while minimizing the risk of adverse effects that increased at the 200 mg dose.
The Lacomblez trial established the 50 mg twice-daily (100 mg total daily) dosing that remains the standard riluzole prescription today. Survival benefit was modest: riluzole extended median survival by approximately 2–3 months across the trial population. For a disease typically measured in months from diagnosis, a 2–3 month survival extension is clinically real but not transformative. The authors were clear about the modest magnitude of benefit.
Together, the Bensimon and Lacomblez trials provided sufficient evidence for the FDA to approve riluzole for ALS in December 1995 — the first disease-modifying therapy approved for the condition.
Riluzole in PLS: the evidence gap
No randomized controlled trial of riluzole has been conducted specifically in PLS patients. PLS has been treated with riluzole off-label based on biological plausibility — the UMN pathophysiology in PLS involves glutamate excitotoxicity at the corticospinal tract level, and if riluzole reduces that excitotoxic burden in ALS, it might do the same in PLS.
This extrapolation has been made by neurologists for years, but it is extrapolation, not evidence. PLS is not ALS with slower progression. The 2020 PLS consensus criteria emphasize that PLS involves purely upper motor neuron degeneration without lower motor neuron involvement — a fundamentally different distribution of pathology than in ALS, where lower motor neurons are also progressively lost. Whether the glutamate excitotoxicity mechanism in ALS, which involves both UMN and LMN pathways, translates to the purely UMN context of PLS is not known.
The 2025 Scirocco review of PLS management explicitly notes that no disease-modifying therapies are available for PLS — a statement that implicitly includes riluzole among the therapies without demonstrated PLS efficacy. Some PLS neurologists prescribe riluzole; others do not, reasoning that prescribing a drug with unproven benefit in PLS exposes patients to side effects (liver enzyme monitoring, fatigue, nausea) without established benefit. This remains a matter of clinical judgment in the absence of PLS-specific trial data.
Why the riluzole situation illustrates a broader problem
The history of riluzole in PLS is a case study in the fundamental challenge of rare disease drug development. When a drug is approved for a more common condition (ALS), it gets applied to closely related but distinct rare conditions (PLS) by extrapolation, without the rigorous testing needed to know whether it works in the different population.
This pattern is not unique to riluzole. Edaravone (FDA-approved for ALS in 2017) has also been used off-label in some PLS patients without a PLS-specific trial. The same will likely be true of future ALS approvals unless PLS advocates and researchers successfully build the trial infrastructure needed to test drugs specifically in PLS.
Current status
Riluzole is widely available in generic form and is inexpensive compared to newer ALS therapies. The primary branded formulation (Rilutek) has been joined by extended-release and oral suspension formulations (Tiglutik, Exservan) that may improve tolerability. Riluzole remains standard of care in ALS. Its status in PLS remains off-label, without established efficacy, and without an agreed clinical consensus on whether to prescribe it.
How this connects
Riluzole's foundational position in ALS provides the baseline against which all subsequent ALS therapies are compared. For a later approved targeted therapy, see the Tofersen VALOR Trial. For a full picture of why PLS has no equivalent approved therapies and what the field is doing to build that evidence base, see Drug Trial Research. The practical treatment options currently available — including riluzole's use in PLS — are discussed in Treatments.
Citation
Bensimon G, Lacomblez L, Meininger V; ALS/Riluzole Study Group. A controlled trial of riluzole
in amyotrophic lateral sclerosis. New England Journal of Medicine.
1994;330(9):585–591. doi:10.1056/NEJM199403033300901.
Lacomblez L, Bensimon G, Leigh PN, Guillet P, Meininger V; Amyotrophic Lateral Sclerosis/
Riluzole Study Group II. Dose-ranging study of riluzole in amyotrophic lateral sclerosis.
Lancet. 1996;347(9013):1425–1431. doi:10.1016/S0140-6736(96)91680-3.