Epilepsy is distinct among neurological conditions in that it has enjoyed a relatively high degree of translational success advancing preclinical agents to effective clinical treatments for symptomatic seizures. Early 20th century treatment of people with epilepsy using, first, bromide and then later phenobarbital gave way to a relative explosion in the number of drugs available for the management of symptomatic seizures following the identification of phenytoin in the maximal electroshock (MES) test in 1937 (Loscher et al., 2013). Based on its efficacy in this test, phenytoin was approved for people with epilepsy in 1938. The MES model provided a predictive platform on which many later new and impactful antiseizure medicines (ASMs) were initially identified in laboratory animals the 20th century. In spite of this high degree of success, treatment-resistant epilepsy continues to affect roughly 30% of individuals (Chen et al., 2018). No agent has yet been FDA-approved for the prevention of disease in at-risk individuals. Thus, much of the 21st century epilepsy drug discovery for epilepsy strategy is now shifting to prioritize agents that address the remaining unmet medical needs of specific patient groups; e.g., precision medicine strategies for developmental epileptic encephalopathies – DEE (Vasquez et al., 2022)) – and the discovery of disease-modifying agents (Barker-Haliski et al., 2021; Barker-Haliski et al., 2015; Loscher, 2017a).

Cannabidiol (CBD), a non-euphorigenic phytocannabinoid, was approved in 2018 as the first medical treatment derived from the marijuana plant (Patra et al., 2019). It is currently indicated for seizures associated with Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS) or Tuberous Sclerosis (TSC) in patients 1 years of age and older (Devinsky et al., 2017a; Thiele et al., 2018). Since the approval of CBD for DS in 2018, the number of studies that have investigated the antiseizure and disease-modifying potential of this agent for epilepsy has grown exponentially (Fig. 1). However, prior to that FDA approval, only a few studies existed to define the therapeutic potential of this agent for epilepsy, largely due to local and international regulations restricting access to marijuana plant-derived components for basic biological research, as well as the social stigmas associated with use of marijuana plant-derived compounds. Nonetheless, the preceding preclinical and clinical research with CBD that was available painted a promising therapeutic picture. In this commentary, we discuss how a few critical preclinical studies reported in the 2010s, coupled with dramatic changes in public perception of medical marijuana plant use (OFFICE, 2021) and a groundswell of parental and advocate support provided the impetus to advance a mechanistically unique agent for difficult to treat patients. There have been a few key points in the history of ASM discovery that have led to expansive growth in the number of therapies available to patients. In this commentary, we discuss how CBD likely represents another critical node in the discovery and development of invaluable epilepsy therapies. The clinical approval of CBD revealed a new, disruptive strategy to fundamentally transform the way epilepsy therapies are brought to clinical populations. We are now likely poised on the next horizon of therapeutic innovation that will shift how 21st century treatments are identified.

Over 30 ASMs are currently on the market. The mechanisms of action of these ASMs are diverse but largely focus on modulation of the excitatory/inhibitory imbalance synonymous with epilepsy. While a discussion of these mechanisms is largely beyond the scope of this commentary, the reader is referred to work summarizing the predominate mechanisms of currently approved ASMs (Barker-Haliski et al., 2014; Sills and Rogawski, 2020). Further, many new agents are in active development and some exhibit extensive mechanistic differentiation from available ASMs (Bialer et al., 2020a, Bialer et al., 2020b). Epilepsy drug discovery is clearly a prolific endeavor with many agents in various stages of development.

Two areas of consistent therapeutic focus in recent decades include modulation of the excitatory/inhibitory imbalance through as-yet untapped molecular targets and attenuation of the epilepsy-induced neuroinflammation. New targets associated with the excitatory/inhibitory imbalance are essential to epilepsy therapy discovery to differentiate from ASM standards-of-care. For example, agents are in development to target neuronal excitability at untapped presynaptic sites, including allosteric modulators of type 2 metabotropic glutamate receptors, and positive allosteric modulators of neuronal Kv7.2–7.5 (KCNQ2–5) potassium channels (Bialer et al., 2020a). Further, neuroinflammation is gaining traction as a tractable therapeutic target in epilepsy and agents are in development to address these processes (Iori et al., 2017; Pauletti et al., 2017).

One of the primary areas of active therapeutic development in recent years has focused on mitigating neuroinflammation associated with epilepsy (Barker-Haliski et al., 2017b; Devinsky et al., 2013; Galanopoulou and Moshe, 2015; Galanopoulou et al., 2016; Wilcox and Vezzani, 2014). Numerous targets have been implicated, including inflammatory cytokines, reactive oxygen species (McElroy et al., 2017), and glia-specific processes (Pauletti et al., 2017; Wilcox and Vezzani, 2014). Moreover, neuroinflammation is likely a major driver of the pathological cycle underlying epileptogenesis itself such that minimizing inflammatory states may produce the long-sought disease-modifying effects in managing clinical epilepsy.

Abnormal glial activation may increase neuronal excitability and inflammatory processes. The outcome of inflammation depends mainly on the number of cytokines and the length of time the CNS is exposed to this damage (Lach et al., 2022). The effect of neuroinflammation can also cause modifications of the blood-brain barrier (BBB). This phenomenon produced by the release of inflammatory mediators may reduce the threshold for epileptic seizures, altering the sensitivity of channels, the uptake and release of neurotransmitters, and the glia-related regulation of ion concentrations. Thus, controlling the inflammatory response and the immediate outcomes, such as the BBB breakdown, may be a potential strategy for attenuating the severity of seizures. Neuroinflammation is a critical and untapped target for epilepsy and may also represent a potential opportunity for disease-modifying intervention.

Novel agents with unique mechanisms of action represent an important therapeutic advance versus currently available “traditional” mechanisms, such as Na+ and Ca2+channel blockers, modulation of glutamate release, and GABAA receptor modulators. However, what is increasingly recognized as being more critical and commercially tractable is the advancement of agents that benefit specific patient demographics (i.e., DEE). Specifically, orphan disease indications with epilepsy as a clinical feature are adding pressure to shift how new ASMs are initially identified and differentiated in the preclinical arena. Orphan disease indications are defined by the US FDA as those conditions that affect fewer than 200,000 people nationwide. The US Orphan Drug Act (ODA) passage in 1983 created financial incentives for drug and biologics manufacturers, including tax credits for costs of clinical research, government grant funding, assistance for clinical research, and a seven-year period of exclusive marketing given to the first sponsor of an orphan-designated product who obtains market approval from the FDA for the same indication (Fig. 1). With the Rare Disease Act of 2002, the US increased the national investment in the development of diagnostics and treatments for patients with rare diseases and disorders (US Congress Rare Disease Act of 2002). This major legislation allowed for greater emphasis on addressing the treatment needs of specific patient populations with epilepsy.

The US FDA approved oral cannabidiol for both DS and LGS for patients 2 years and older in 2018. Importantly, in 2020 the label indication was updated by the FDA to include TSC (in addition to LGS and DS) and the age for use was updated to 1 year and older. These facts revealed the very real possibility that preclinical models of orphan disease indications could play an increasingly prominent role in frontline ASM discovery in the 21st century. No longer would ASM discovery merely rely on the convincing demonstration of efficacy in traditional seizure and epilepsy models evoked in wild-type, neurologically-intact animals, including the MES test, subcutaneous pentylenetetrazol (scPTZ) test, and kindling models (Barker-Haliski and White, 2020; Barker-Haliski et al., 2017a). The ability to identify genetic conditions more rapidly and accordingly prescribe precision medicines for specific patient populations has created a seismic shift in the approach to ASM identification and differentiation. While the traditional models have robustly identified numerous effective therapies for epilepsy and will likely continue to have an important position in ASM discovery (Barker-Haliski, 2019; Barker-Haliski and White, 2020; Barker-Haliski et al., 2017a; Klein et al., 2018), it is now likely that the market is at saturation to uncover new molecular targets exclusively relying on these models. As a result, models of orphan diseases and models recapitulating specific patient groups (e.g., infantile spasms models (Galanopoulou and Moshe, 2015), late-onset epilepsy models (Del Pozo et al., 2022)) will occupy an increasingly prominent position in the early discovery and differentiation of investigational agents that may ultimately proceed to clinical use. New ASMs will likely be identified, or the preclinical profile extended, in these models, which may effectively disrupt the clinical epilepsy treatment landscape in the 21st century.