About

Misty D. Smith is a professor associated with the College of Pharmacy, specifically involved in the Pharmacology and Toxicology Department. Her research is closely linked with the Anticonvulsant Drug Development (ADD) Program, which has been at the forefront of epilepsy and seizure disorder research for over five decades. The program, founded in 1975, is recognized as the longest-running NIH-funded initiative of its kind and serves as a national model for impactful research in this field. The ADD Lab, under her affiliation, focuses on developing and testing anticonvulsant drugs, understanding seizure mechanisms, and exploring pharmacoresistance in epilepsy. The program has contributed significantly to the discovery and development of therapies that help millions of people living with epilepsy. Dr. Smith's leadership and the lab's ongoing projects continue to advance the understanding of seizure dynamics, drug effects, and mechanisms underlying pharmacoresistance, making substantial contributions to the field of neuropharmacology and epilepsy research.

Research topics

• Internal medicine
• Pharmacology
• Medicine
• Anesthesia
• Psychology
• Pediatrics
• Chemistry
• Neuroscience
• Psychiatry

Selected publications

• Epilepsy Therapy Screening From 1975 to 2026 and Beyond: Merging Established and New Approaches to Develop Novel Therapies

  Epiliepsy currents/Epilepsy currents · 2026-04-20

  articleOpen access

  Antiepileptic Drug Development: II. Anticonvulsant Drug Screening Krall RL, Penry JK, White BG, Kupferberg HJ, Swinyard EA. Epilepsia . 1978 Aug;19(4):409-28. doi:10.1111/j.1528-1157.1978.tb04507.x. PMID: 699894 By means of the maximal electroshock seizure test, the subcutaneous pentylenetetrazol seizure threshold test, and the Rotorod minimal neurotoxicity test, the Anticonvulsant Screening Project has evaluated the activity of 1,495 experimental compounds accessioned in the first 2 years. A three-screen protocol for appraising these compounds has proved reliable, fast, and inexpensive. Preliminary data show that 430 of these compounds have good anticonvulsant activity. Completed evaluations of 352 identified 16 that have anticonvulsant activity at doses less than 75 mg/kg and protective indices greater than 5.0.

  PublisherDOI

• Differential Effects of Neurotensin NTS1 and NTS2 Receptors on Locomotion

  Brain and Behavior · 2025-11-01

  articleOpen access1st authorCorresponding

  INTRODUCTION: Neurotensin (NT) is an endogenous neuropeptide with diverse central and peripheral effects, particularly as related to modulation of central nervous system dopaminergic activity. For example, interactions between dopamine and NT have been associated with the motivation to use, and the motor consequences of drugs abuse, including nicotine. However, the relative contribution of the two subtypes of cell surface G-protein coupled NT receptors (NTS1 and NTS2) to dopamine-related drug-induced effects is unclear. METHODS: We investigated the locomotor behavior and exploratory drive of C57BL/6J mice deficient in either NTS1 (NTS1 -/-) or NTS2 (NTS2 -/-) compared to wild-type C57BL/6J (WT +/+) mice in an open-field. In addition, the effect of nicotine on locomotion and intra-session habituation to a novel open field was compared in each of these genetic strains. RESULTS: When compared to WT (+/+) mice, the results demonstrated less intra-session habituation across time (i.e., less accommodation (as assessed by distanced travelled, horizontal activity, and vertical activity) in mice deficient in the NTS1 receptor. In contrast, mice deficient in the NTS2 receptor accommodated more rapidly. Nicotine injection reduced all three parameters of locomotor activity in WT (+/+) and NTS1 (-/-) mice. In contrast to effects in both WT (+/+) and NTS1 (-/-) mice, NIC exposure had a negligible effect on TD in the NTS2 (-/-) mice. CONCLUSION: These results suggest opposing effects of the NTS1 and NTS2 receptor subtypes in modulating natural and nicotine-induced dopaminergic transmission and consequent locomotor behavior.

  PublisherOA PDFDOI

• Development of an antiseizure drug screening platform for Dravet syndrome at the NINDS contract site for the Epilepsy Therapy Screening Program

  Epilepsia · 2021 · 46 citations

  • Medicine
  • Anesthesia
  • Pharmacology

  OBJECTIVE: mouse. METHODS: mice had seizures. RESULTS: survive to adulthood and all have hyperthermia-induced seizures. The results suggest that hyperthermia-induced seizures in this model of DS are highly refractory to a battery of ASDs. Exceptions were clobazam, tiagabine, levetiracetam, and the combination of clobazam and valproic acid with add-on stiripentol, which elevated seizure thresholds. SIGNIFICANCE: Overall, the data demonstrate that the proposed model for DS is suitable for screening novel compounds for the ability to block hyperthermia-induced seizures and that heterozygous mice can be evaluated repeatedly over the course of several weeks, allowing for higher throughput screening.

  PublisherDOI

• Spontaneous recurrent seizures in an intra-amygdala kainate microinjection model of temporal lobe epilepsy are differentially sensitive to antiseizure drugs

  Experimental Neurology · 2021 · 34 citations

  • Medicine
  • Pharmacology
  • Neuroscience

  The discovery and development of novel antiseizure drugs (ASDs) that are effective in controlling pharmacoresistant spontaneous recurrent seizures (SRSs) continues to represent a significant unmet clinical need. The Epilepsy Therapy Screening Program (ETSP) has undertaken efforts to address this need by adopting animal models that represent the salient features of human pharmacoresistant epilepsy and employing these models for preclinical testing of investigational ASDs. One such model that has garnered increased interest in recent years is the mouse variant of the Intra-Amygdala Kainate (IAK) microinjection model of mesial temporal lobe epilepsy (MTLE). In establishing a version of this model, several methodological variables were evaluated for their effect(s) on pertinent quantitative endpoints. Although administration of a benzodiazepine 40 min after kainate (KA) induced status epilepticus (SE) is commonly used to improve survival, data presented here demonstrates similar outcomes (mortality, hippocampal damage, latency periods, and 90-day SRS natural history) between mice given midazolam and those that were not. Using a version of this model that did not interrupt SE with a benzodiazepine, a 90-day natural history study was performed and survival, latency periods, SRS frequencies and durations, and SRS clustering data were quantified. Finally, an important step towards model adoption is to assess the sensitivities or resistances of SRSs to a panel of approved and clinically used ASDs. Accordingly, the following ASDs were evaluated for their effects on SRSs in these mice: phenytoin (20 mg/kg, b.i.d.), carbamazepine (30 mg/kg, t.i.d.), valproate (240 mg/kg, t.i.d.), diazepam (4 mg/kg, b.i.d.), and phenobarbital (25 and 50 mg/kg, b.i.d.). Valproate, diazepam, and phenobarbital significantly attenuated SRS frequency relative to vehicle controls at doses devoid of observable adverse behavioral effects. Only diazepam significantly increased seizure freedom. Neither phenytoin nor carbamazepine significantly altered SRS frequency or freedom under these experimental conditions. These data demonstrate that SRSs in this IAK model of MTLE are pharmacoresistant to two representative sodium channel-inhibiting ASDs (phenytoin and carbamazepine) and partially sensitive to GABA receptor modulating ASDs (diazepam and phenobarbital) or a mixed-mechanism ASD (valproate). Accordingly, this model is being incorporated into the NINDS-funded ETSP testing platform for treatment resistant epilepsy.

  PublisherDOI

• Screening of prototype antiseizure and anti‐inflammatory compounds in the Theiler's murine encephalomyelitis virus model of epilepsy

  Epilepsia Open · 2021-10-20 · 28 citations

  articleOpen access

  OBJECTIVE: Infection with Theiler's murine encephalomyelitis virus (TMEV) in C57Bl/6J mice results in handling-induced seizures and is useful for evaluating compounds effective against infection-induced seizures. However, to date only a few compounds have been evaluated in this model, and a comprehensive study of antiseizure medications (ASMs) has not yet been performed. Furthermore, as the TMEV infection produces marked neuroinflammation, an evaluation of prototype anti-inflammatory compounds is needed as well. METHODS: Male C57Bl/6J mice were inoculated with TMEV (day 0) followed by daily administrations of test compounds (day 3-7) and subsequent handling sessions (day 3-7). Doses of ASMs, comprising several mechanistic classes, were selected based on previously published data demonstrating the effect of these compounds in reducing seizures in the 6 Hz model of pharmacoresistant seizures. Doses of anti-inflammatory compounds, comprising several mechanistic classes, were selected based on published evidence of reduction of inflammation or inflammation-related endpoints. RESULTS: Several prototype ASMs reduced acute seizures following TMEV infection: lacosamide, phenytoin, ezogabine, phenobarbital, tiagabine, gabapentin, levetiracetam, topiramate, and sodium valproate. Of these, phenobarbital and sodium valproate had the greatest effect (>95% seizure burden reduction). Prototype anti-inflammatory drugs celecoxib, dexamethasone, and prednisone also moderately reduced seizure burden. SIGNIFICANCE: The TMEV model is utilized by the Epilepsy Therapy Screening Program (ETSP) as a tool for evaluation of novel compounds. Compounds reducing seizures in the TMEV comprise distinct mechanistic classes, some with mechanisms of action that extend beyond traditional ASMs.

  PublisherOA PDFDOI

• Spontaneous recurrent seizures in an intra-amygdala kainate microinjection model of temporal lobe epilepsy are differentially sensitive to antiseizure drugs

  bioRxiv (Cold Spring Harbor Laboratory) · 2020-12-03 · 2 citations

  preprintOpen access

  Abstract The discovery and development of novel antiseizure drugs (ASDs) that are effective in controlling pharmacoresistant spontaneous recurrent seizures (SRSs) continues to represent a significant unmet clinical need. The Epilepsy Therapy Screening Program (ETSP) has undertaken efforts to address this need by adopting animal models that represent the salient features of human pharmacoresistant epilepsy and employing these models for preclinical testing of investigational ASDs. One such model that has garnered increased interest in recent years is the mouse variant of the Intra-Amygdala Kainate (IAK) microinjection model of mesial temporal lobe epilepsy (MTLE). In establishing a version of this model, several methodological variables were evaluated for their effect(s) on pertinent quantitative endpoints. Although administration of a benzodiazepine 40 minutes after kainate (KA) induced status epilepticus (SE) is commonly used to improve survival, data presented here demonstrates similar outcomes (mortality, hippocampal damage, latency periods, and 90-day SRS natural history) between mice given midazolam and those that were not. Using a version of this model that did not interrupt SE with a benzodiazepine, a 90-day natural history study was performed and survival, latency periods, SRS frequencies and durations, and SRS clustering data were quantified. Finally, an important step towards model adoption is to assess the sensitivities or resistances of SRSs to a panel of approved and clinically used ASDs. Accordingly, the following ASDs were evaluated for their effects on SRSs in these mice: phenytoin (20 mg/kg, b.i.d.), carbamazepine (30 mg/kg, t.i.d.), valproate (240 mg/kg, t.i.d.), diazepam (4 mg/kg, b.i.d.), and phenobarbital (25 and 50 mg/kg, b.i.d.). Valproate, diazepam, and phenobarbital significantly attenuated SRS frequency relative to vehicle controls at doses devoid of observable adverse behavioral effects. Only diazepam significantly increased seizure freedom. Neither phenytoin nor carbamazepine significantly altered SRS frequency or freedom under these experimental conditions. These data demonstrate that SRSs in this IAK model of MTLE are pharmacoresistant to two representative sodium channel-inhibiting ASDs (phenytoin and carbamazepine) but not to GABA receptor modulating ASDs (diazepam and phenobarbital) or a mixed-mechanism ASD (valproate). Accordingly, this model is being incorporated into the NINDS-funded ETSP testing platform for treatment resistant epilepsy. Highlights An intra-amygdala kainate model of TLE was evaluated for pharmacoresistant seizures Administration of midazolam during status epilepticus did not affect mortality Model characteristics were evaluated over a 90-day natural history study Spontaneous seizures were resistant to phenytoin and carbamazepine Spontaneous seizures were sensitive to valproic acid, diazepam, and phenobarbital

  PublisherOA PDFDOI

• Development of an Antiseizure Drug Screening Platform for Dravet Syndrome at the NINDS contract site for the Epilepsy Therapy Screening Program

  bioRxiv (Cold Spring Harbor Laboratory) · 2020-12-02 · 4 citations

  preprintOpen access

  Summary Objective Dravet syndrome (DS) is a rare, but catastrophic genetic epilepsy, with 80% of patients with carrying a mutation in the SCN1A gene. Currently, no anti-seizure drug (ASD) exists that adequately controls seizures. Patients with DS often present clinically with a febrile seizure and generalized tonic-clonic seizures that continue throughout life. To facilitate the development of ASDs for DS, the contract site of the NINDS Epilepsy Therapy Screening Program (ETSP) has evaluated a mouse model of DS using the conditional knock-in Scn1a A1783V/WT mouse. Methods Survival rates and temperature thresholds for Scn1a A1783V/WT were determined. Prototype ASDs were administered via intraperitoneal injections at the time-to-peak effect, which was previously determined, prior to the induction of hyperthermia-induced seizures. Protection was determined if ASDs significantly increased the temperature at which Scn1a A1783V/WT mice seized. Results Approximately 50% of Scn1a A1783V/WT survive to adulthood and all have hyperthermia-induce seizures. The results suggest that hyperthermia-induced seizures in this model of DS are highly refractory to a battery of ASDs. Exceptions were clobazam, tiagabine, and the combination of clobazam and valproic acid with add-on stiripentol, which elevated seizure thresholds Significance Overall, the data demonstrate the proposed model for DS is suitable for screening novel compounds for the ability to block hyperthermia-induced seizures and heterozygous mice can be evaluated repeatedly over the course of several weeks, allowing for higher throughput screening. Key Points Scn1a A1783V/WT mice have a 50% survival rate and all have hyperthermia-induced seizures. Common DS treatments such as CLB and combinatorial therapy of CLB, VPA, and STP increase temperature thresholds in Scn1a A1783V/WT mice. Sodium channel blockers, such as CBZ and LTG, decrease temperature thresholds of Scn1a A1783V/WT mice as predicted. S cn1a A1783V/WT mice are highly pharmacoresitant to common ASDs The Scn1a A1783V/WT may be a useful preclinical drug screening platform for the treatment of DS.

  PublisherOA PDFDOI

• Cannabidiolic acid exhibits entourage-like improvements of anticonvulsant activity in an acute rat model of seizures

  Epilepsy Research · 2020 · 33 citations

  • Pharmacology
  • Chemistry
  • Medicine

  OBJECTIVES: Cannabidiolic acid (CBDa) is pharmacologically unique from cannabidiol (CBD), but its chemical instability poses challenges for potential clinical utility. Here, we used magnesium ions to stabilize two cannabidiolic acid-enriched hemp extracts (Mg-CBDa and Chylobinoid, the latter of which also contains minor cannabinoid constituents) and compared their anticonvulsant activities with CBD in the maximal electroshock seizure test (MES) in rats. METHODS: Sprague-Dawley rats received intraperitoneal (i.p.) injections of Chylobinoid, Mg-CBDa, or CBD at varying doses at discrete time points. Rats were challenged with a 0.2 s, 60 Hz, 150 mA corneal stimulation and evaluated for resultant hindlimb tonic extension. Dose-response relationships were calculated using Probit analysis and statistical significance was assessed with a two-sample z-test. RESULTS: ) and 95 % confidence intervals were calculated for each compound and adjusted according to percentage of CBDa (w/w): Chylobinoid: 76.7 (51.7-109.2) mg/kg. Mg-CBDa: 115.4 (98.8-140.9) mg/kg. CBD: 68.8 (56.6-80.0) mg/kg. SIGNIFICANCE: CBDa-enriched hemp extracts exhibited dose-dependent protection in the MES model at doses comparable, but not more effective than, CBD. Chylobinoid was more effective than Mg-CBDa despite lower CBDa content. Test compounds should be compared by sub-chronic dosing in the MES test in order to assess safety and pharmacokinetic profiles. CBDa should be evaluated in pharmacoresistant and chronic animal models of epilepsy.

  PublisherDOI

• Music-Enhanced Analgesia and Antiseizure Activities in Animal Models of Pain and Epilepsy: Toward Preclinical Studies Supporting Development of Digital Therapeutics and Their Combinations With Pharmaceutical Drugs

  Frontiers in Neurology · 2019-03-27 · 20 citations

  articleOpen access

  Digital therapeutics (software as a medical device) and mobile health (mHealth) technologies offer a means to deliver behavioral, psychosocial, disease self-management and music-based interventions to improve therapy outcomes for chronic diseases, including pain and epilepsy. To explore new translational opportunities in developing digital therapeutics for neurological disorders, and their integration with pharmacotherapies, we examined analgesic and antiseizure effects of specific musical compositions in mouse models of pain and epilepsy. The music playlist was created based on the modular progression of Mozart compositions for which reduction of seizures and epileptiform discharges were previously reported in people with epilepsy. Our results indicated that music-treated mice exhibited significant analgesia and reduction of paw edema in the carrageenan model of inflammatory pain. Among analgesic drugs tested (ibuprofen, cannabidiol (CBD), levetiracetam, and the galanin analog NAX 5055), music intervention significantly decreased paw withdrawal latency difference in ibuprofen-treated mice and reduced paw edema in combination with CBD or NAX 5055. To the best of our knowledge, this is the first animal study on music-enhanced antinociceptive activity of analgesic drugs. In the plantar incision model of surgical pain, music-pretreated mice had significant reduction of mechanical allodynia. In the corneal kindling model of epilepsy, the cumulative seizure burden following kindling acquisition was lower in animals exposed to music. The music-treated group also exhibited significantly improved survival, warranting further research on music interventions for preventing Sudden Unexpected Death in Epilepsy (SUDEP). We propose a working model of how musical elements such as rhythm, sequences, phrases and punctuation found in K.448 and K.545 may exert responses via parasympathetic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis. Based on our findings, we discuss: (1) how enriched environment (EE) can serve as a preclinical surrogate for testing combinations of non-pharmacological modalities and drugs for the treatment of pain and other chronic diseases, and (2) a new paradigm for preclinical and clinical development of therapies leading to drug-device combination products for neurological disorders, depression and cancer. In summary, our present results encourage translational research on integrating non-pharmacological and pharmacological interventions for pain and epilepsy using digital therapeutics.

  PublisherOA PDFDOI

• Cannabidiol reduces seizures following CNS infection with Theiler's murine encephalomyelitis virus

  Epilepsia Open · 2019-07-04 · 32 citations

  articleOpen accessSenior authorCorresponding

  OBJECTIVE: C57BL/6J mice infected with Theiler's murine encephalomyelitis virus (TMEV) develop acute behavioral seizures in the first week of infection and later develop chronic epilepsy. The TMEV model provides a useful platform to test novel antiseizure therapeutics. The present study was designed to test the efficacy of cannabidiol (CBD) in reducing acute seizures induced by viral infection. METHODS: plaque-forming units of TMEV. Mice were divided into two treatment groups-1) CBD-treated mice and 2) vehicle-treated mice. Frequency and severity of acute seizures were evaluated by video-monitoring the mice four times daily by the experimenter blinded to the treatment group. RESULTS: Cannabidiol (180 mg/kg; 360 mg/kg/day) decreased both the frequency and severity of acute behavioral seizures following TMEV infection, but 150 mg/kg of CBD did not improve overall seizure outcome. The time to peak effect (TPE) of CBD in the 6 Hz 32 mA psychomotor seizure test using C57BL/6J mice was observed at 2 hours post-CBD treatment. Interestingly, CBD (150 mg/kg) significantly reduced frequency and severity of TMEV-induced acute seizures at 2 hours post-CBD treatment. These results suggest that CBD could be effective in decreasing TMEV-induced acute seizures when the seizure test is conducted at the TPE of CBD. SIGNIFICANCE: Cannabinoids are increasingly studied for their potential antiseizure effects. Several preclinical and clinical studies provide evidence that CBD could be an effective therapy for intractable epilepsies. The present study corroborates those previous findings and provides an opportunity to investigate pharmacokinetics, pharmacodynamics, and mechanism(s) of antiseizure effects of CBD in the TMEV model, which may help to design future clinical studies more effectively.

  PublisherOA PDFDOI

Frequent coauthors

• H. Steve White

  University of Washington

  27 shared

• Karen S. Wilcox

  University of Utah

  17 shared

• Cameron S. Metcalf

  University of Utah

  15 shared

• Grzegorz Bułaj

  University of Utah

  13 shared

• Peter J. West

  University of Utah

  10 shared

• Brian D. Klein

  National Institutes of Health

  8 shared

• Liuyin Zhang

  University of Utah

  7 shared

• Hee-Kyoung Lee

  University of Utah

  6 shared

Labs

• ADD LabPI

  The ADD Program Students page at the University of Utah showcases students involved in addiction, delirium, and CNS disorders research, highlighting their academic pursuits and contributions to the field.

Education

• Ph.D., Biomedical Sciences - Pharmacology, Physiology and Neuroscience

  University of South Carolina

• B.S., Biology

  Muskingum University