Diazepam, globally recognized under the brand name Valium, stands as a landmark pharmaceutical with a rich history dating back to the psychopharmacological revolution of the 1950s. Its effectiveness in managing a broad spectrum of central nervous system (CNS) disorders, notably anxiety and epilepsy, has established it as a gold standard in pharmacotherapy. Valium is celebrated for its potency, rapid onset of action, and a safety profile that, while requiring careful consideration, has significantly impacted the landscape of mental health treatment. This article delves into the comprehensive profile of diazepam, exploring its synthesis, pharmacology, metabolism, potential adverse effects, clinical applications, regulatory context, and its enduring legacy in chemical neuroscience.
Anxiety and the Need for Anxiolytics: Setting the Stage for Valium
Anxiety disorders represent the most widespread category of psychiatric conditions. In the United States alone, over 40 million adults grapple with generalized anxiety disorder (GAD) and other debilitating forms of anxiety, including panic disorder, agoraphobia, post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD).[1] The global impact is equally significant, with anxiety disorders and limited access to treatment posing major health challenges across both developed and developing nations.[2]
Historically, the approach to treating anxiety relied on general depressants and sedatives. Substances such as alcohol, opiates, lithium bromide, and chloral hydrate were among the earliest remedies. By the mid-20th century, carbamates like meprobamate 3 and barbiturates such as phenobarbital 4 (Figure 1) gained prominence, superseding these earlier treatments. However, these options came with significant drawbacks, primarily a narrow therapeutic window and a high risk of adverse effects.
The year 1960 marked a turning point with the introduction of chlordiazepoxide 2 (Librium). This benzodiazepine heralded a new era of anxiety pharmacotherapy, offering a substantially improved safety profile compared to traditional sedatives and hypnotics. Benzodiazepines demonstrated potent anxiolytic effects with a reduced risk of fatal outcomes in overdose. Diazepam 1 (Valium) followed in 1963, proving to be an even more potent benzodiazepine. Valium distinguished itself by offering “a greater dissociation between its sedative and anxiolytic properties,”[2] making it highly effective for anxiety, epilepsy, muscle spasms, and alcohol withdrawal symptoms.[3]
Valium rapidly ascended to become one of the best-selling drugs globally, achieving this status even before its precise mechanism of action was fully understood. Its impact on medical practice and popular culture is undeniable, yet it also brought forth challenges related to dependence and misuse, highlighting the complex nature of potent psychotherapeutic drugs.
Delving into Diazepam: Properties and Chemical Synthesis
Diazepam, identified by its CAS No: [439-14-5], is a classic aryl 1,4-benzodiazepine. Its molecular characteristics include the absence of hydrogen bond donors, the presence of three hydrogen bond acceptors, a low molecular weight (MW = 284.7), a ClogP of 3, and a Topological Polar Surface Area (TPSA) of 32.7.[7] These physicochemical properties are now recognized as indicative of good CNS penetration and favorable drug metabolism. In fact, diazepam and its related compounds played a pivotal role in establishing these criteria, influencing numerous databases used for drug design and development guidelines.[7]
The Sternbach Synthesis: Pioneering the Benzodiazepine Route
The synthesis of diazepam was first achieved by Leo Sternbach at Hoffman-La Roche in the late 1950s (Scheme 1). This breakthrough originated from observations on quinazoline-3-oxides, such as compound 7.[8] Sternbach discovered that these compounds, when treated with hydroxide, ammonia, or primary amines, underwent ring-expansion reactions. This occurred via an initial nucleophilic attack at the 2-position of the quinoxaline ring, rather than a simple chloride displacement.[9]
Chlordiazepoxide (Librium 2), the first clinically approved benzodiazepine, was synthesized through the reaction of methylamine with compound 7.[10] The promising pharmacological profile of chlordiazepoxide spurred further investigation into benzodiazepine chemistry.[11] Acidic hydrolysis of chlordiazepoxide yielded N-oxide 8, which could be alkylated at the secondary amide nitrogen using methyl iodide. Subsequently, reduction of the N-oxide with either PCl3 or Raney nickel led to the creation of diazepam.[12] However, this initial synthetic route was complex and not conducive to rapid analog development.[13]
Streamlined Synthesis and Alternative Routes
Sternbach and his colleagues developed an alternative, more efficient route to diazepam, again starting from the amino-benzophenone 5, which was also used to synthesize compound 7. This improved synthesis involved cyclo-condensation with glycine ethyl ester hydrochloride to form the benzodiazepine core (10). Alkylation at the 1-position nitrogen was then achieved using dimethyl sulfate in sodium methoxide and methanol under reflux. Although converting 5 to 10 in one step was straightforward, reacting 5 with chloroacetyl chloride followed by ammonia and heat proved to be a higher-yielding and easier-to-purify method for obtaining 10.[14]
The original patent also described a synthesis involving initial alkylation. This was accomplished by tosylation of the 2-amino group, followed by selective amino methylation, deprotection, and cyclo-condensation with glycine ethyl ester in heated pyridine.[15] Since Sternbach’s pioneering work, other notable synthetic methods have emerged. Gates et al. reported a method using 7-chloro-1-methyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione, derived from 5-chloro-N-methylisatoic anhydride and glycine, achieving an overall yield of approximately 50% from the starting material.[16] Ishikura and colleagues developed a palladium-catalyzed carbonylation method to insert CO into aryl halides and cyclize into the seven-membered benzodiazepine ring via a concerted mechanism.[17] These advancements underscore the ongoing innovation in synthesizing diazepam and related benzodiazepines.
Manufacturing and Market Presence of Valium
Diazepam, the generic name for compound 1, was originally marketed by Hoffman-La Roche under the brand name Valium. First synthesized in 1959, it was introduced to the market in 1963.[18] Valium quickly rose to prominence, becoming the top-selling pharmaceutical in the United States from 1968 to 1982. Its peak sales occurred in 1978, with an astounding 2.3 billion tablets sold.[19] Currently, Roche offers Valium in 2 mg, 5 mg, and 10 mg tablets in the United States.[20]
Upon patent expiration in 1985, the market opened to generic formulations. Today, over 500 different brands of generic diazepam are available worldwide, offered in various forms including tablets, suppositories, suspensions, gels, and injectable solutions.[21] In 2011, over 14 million prescriptions for diazepam were reported in the United States alone, highlighting its continued widespread use.[22] This extensive availability and diverse formulations underscore diazepam’s enduring role in medical therapeutics.
Drug Metabolism and Pharmacokinetics of Diazepam
Diazepam exhibits favorable pharmacokinetic properties, contributing to its clinical effectiveness. It is highly bioavailable, widely distributed throughout the body (Vd 0.95–2.0 L/kg), and readily penetrates the central nervous system due to its lipid solubility.[23] Oral bioavailability ranges from 93% to 100%, while rectal administration achieves approximately 90% bioavailability. Diazepam also demonstrates high plasma protein binding, ranging from 96% to 99%.[24]
Peak plasma concentrations are typically reached within 30–90 minutes following oral administration, 30–60 minutes after intramuscular injection, and 10–45 minutes after rectal administration. Steady-state levels during chronic dosing are attained after 5–14 days. Elimination follows a biphasic process, involving initial distribution into muscle and adipose tissue, with a prolonged half-life of 24–48 hours.[23] It is important to note that drug half-life and the free fraction of diazepam can increase in elderly populations due to reduced serum albumin levels and polypharmacy.[25]
Metabolic Pathways and Active Metabolites
Diazepam undergoes extensive metabolism in the liver, primarily mediated by CYP450 enzymes, followed by glucuronidation for excretion (Scheme 2). The primary metabolic pathway involves demethylation (via CYP 2C9, 2C19, 2B6, 3A4, and 3A5), yielding desmethyldiazepam (10, nordiazepam), which is equipotent to diazepam.[64] Desmethyldiazepam is further metabolized by 3′-hydroxylation (CYP 3A4, 3A5, and 2C19) to temazepam (12), although minor amounts of oxazepam (11, via CYP 3A4/3A5) are also formed. Only negligible amounts of unchanged diazepam are excreted in the urine, with the majority of the administered dose eliminated as metabolites.[26]
Notably, each of the major metabolites—nordiazepam (10), temazepam (11), and oxazepam (12)—has been independently developed and marketed as pharmaceutical drugs. Nordiazepam, with a longer half-life (50–120 hours), accumulates during daily diazepam administration and becomes the predominant circulating metabolite, requiring over 3 weeks to reach steady state.[27]
Cytochrome P450 Enzyme Interactions
The principal CYP enzymes involved in diazepam metabolism are CYP2C19 and CYP 3A isoforms. In vitro studies suggest that CYP2C19 and CYP 3A enzymes contribute approximately 33% and 44%, respectively, to total demethylation activity. Some reports indicate CYP2C19 may be a more efficient demethylator of diazepam.[26d] CYP 3A isoforms are primarily responsible for hydroxylation to temazepam (11), accounting for about 83% of this metabolic step, while CYP2C19 contributes a minor 9%.
CYP2C19 exhibits genetic polymorphism, with approximately 5% of Caucasians and 15–20% of Asian populations classified as poor metabolizers.[28] Inhibitors of CYP2C19, such as fluvoxamine (a selective serotonin reuptake inhibitor, SSRI), can decrease diazepam clearance and increase peak plasma concentrations, half-life, and exposure to both diazepam and its primary metabolite, nordiazepam. Conversely, CYP2C19 inducers, including carbamazepine and phenytoin (anticonvulsants and mood stabilizers), can enhance diazepam clearance.[29]
Clinical Significance of Diazepam Metabolites
The metabolites of diazepam have distinct pharmacological profiles and clinical applications. Oxazepam (12) has a slower onset of action and does not require hepatic oxidation for clearance, making it a preferred option for elderly patients or those with hepatic impairment.[30] Temazepam (11), with a shorter overall half-life due to bypassing the long-lived nordiazepam, is often favored for treating insomnia.[31] These metabolic considerations are crucial in tailoring benzodiazepine therapy to individual patient needs and conditions.
Pharmacology, Medicinal Chemistry, and Structure-Activity Relationships of Diazepam
Diazepam and its active metabolite nordiazepam were instrumental in defining the “benzodiazepine receptor,” which was later identified as the ionotropic GABAA chloride channel through receptor binding studies.[32] Beyond the GABAA receptor, evidence suggests diazepam interacts with voltage-gated sodium channels, potentially contributing to its anticonvulsant properties.[33] Diazepam has also demonstrated activity as a neuronal voltage-gated calcium channel blocker in rat models.[34] Furthermore, it binds to a unique benzodiazepine receptor, initially termed the “peripheral benzodiazepine receptor” and subsequently characterized as the “translocator protein (18 kDa),” localized on the mitochondrial membrane.[35] Additional studies have shown diazepam to inhibit acetylcholine release in the mouse hippocampus,[36] reduce histamine recycling in the mouse brain,[37] and suppress prolactin release in rats.[38]
GABAA Receptor Modulation: The Primary Mechanism
Despite these multiple binding sites, the majority of diazepam’s pharmacological actions are mediated through the GABAA chloride channel, where it acts as a positive allosteric modulator. Diazepam does not directly affect GABA levels but binds to a distinct allosteric site (BZ site) on the GABAA receptor complex, separate from the binding sites of GABA, barbiturates, and channel blockers. The GABAA receptor is a heteropentameric channel composed of two α, two β, and one γ subunits. The BZ site is located at the interface of the γ and α subunits.
Upon diazepam binding, the GABAA complex undergoes a conformational change, increasing its affinity for the endogenous GABA ligand. This potentiation enhances GABA’s inhibitory effects on CNS activity by increasing postsynaptic chloride-ion influx, leading to hyperpolarization and reduced neuronal excitability.[4, 39, 40] These GABA-potentiating actions are observed in brain regions such as the limbic system, thalamus, hypothalamus, and cerebral cortex, resulting in anxiolytic and antiepileptic effects.[5] Diazepam’s clinical efficacy and commercial success are attributed to its targeted mechanism, potency, high bioavailability, and rapid onset of action.
Receptor Subtype Selectivity and Clinical Effects
The GABAA receptor family includes six known α subunit isoforms, with subtypes containing α4 and α6 subunits being “benzodiazepine-insensitive.” The “benzodiazepine-sensitive” subtypes can be broadly categorized based on their associated clinical effects: α2/α3 subtypes are linked to anxiolytic effects, while α1/α5 subtypes are associated with sedation, ataxia, and amnesia. The most prevalent GABAA receptor subtype in the brain is α1,β2,γ2.
Diazepam exhibits relatively nonselective binding across the “benzodiazepine-sensitive” α subunit isoforms (Table 1),[40] contributing to its broad therapeutic efficacy and diverse range of clinical applications, in addition to its non-GABAA receptor interactions.[41] The binding potency of diazepam correlates well with its electrophysiological potency (Table 1).[42]
Table 1: Diazepam Binding Affinity and Potentiation at GABAA Receptor Subtypes
| Receptor Subtype | Ki (nM)a | EC50 (nM)b | Max Potentiationb |
|---|---|---|---|
| α1β1γ2 | 16 | 53 | 120% |
| α1β2γ2 | 16 | ||
| α1β3γ2 | 13 | ||
| α1β2γ3 | 670 | ||
| α2β1γ2 | 17 | 60 | 270% |
| α2β2γ2 | 17 | ||
| α3β1γ2 | 17 | 140 | 400% |
| α3β2γ2 | 8.6 | ||
| α3β3γ2 | 33 | ||
| α4β2γ2 | >10,000 | ||
| α5β1γ2 | – | 4,000 | 110% |
| α5β2γ2 | 15 | ||
| α5β3γ2 | 17 | ||
| α6β3γ2 | >10,000 |
a Ki data compiled from various sources in reference [40].
b GABA-evoked Cl– ion current in HEK293 cells expressing transfected receptors. Data from reference [42].
Structure-Activity Relationship and Analog Development
At therapeutic concentrations, only a small fraction (2–3%) of diazepam and its metabolite nordiazepam reaches the cerebrospinal fluid (CSF) relative to plasma concentrations, aligning with the plasma free-fraction.[43] Even at these concentrations, diazepam occupies approximately 20% of available GABAA receptors, which is sufficient to produce significant GABA-mediated Cl– ion potentiation and clinical anxiolytic effects. Higher doses, particularly in treating status epilepticus, lead to increased receptor occupancy, sedative effects, and anterograde amnesia.[44]
The success of diazepam spurred the development of thousands of analogs, with over 20 benzodiazepines approved for human use globally. Medicinal chemistry efforts, largely conducted before detailed understanding of GABAA receptor subtypes, revealed structure-activity relationships. Substitutions on the benzo-fused ring are modestly tolerated, with electron-withdrawing groups at the 7-position generally preferred. For the pendant phenyl ring, unsubstituted or ortho-halo phenyl groups are common in approved drugs. Flunitrazepam (13) represents an optimized analog identified by the Sternbach group. Various substituents are tolerated at the lactam nitrogen, such as the diethylamino group in flurazepam (14) (Figure 2).[18] Modifications in this region can also lead to 5-membered ring analogs like triazolam (16) and midazolam (17). Removing the pendant phenyl group results in compounds like flumazenil (15), which bind to the BZ site but act as neutral allosteric modulators, not potentiating GABA.[45] Flumazenil is clinically valuable as a GABAA receptor radiotracer and antidote for benzodiazepine overdose.[46] Most diazepam analogs exhibit similar activity across α1, α2, α3, and α5 containing receptors (Table 1).[40] Pharmacophore models of the GABAA receptor have been proposed to guide the design of subtype-selective benzodiazepines to dissociate sedative, anxiolytic, and cognitive effects.[47]
Approved and Off-Label Uses of Valium
Diazepam holds approvals for a range of clinical indications, including the treatment of anxiety disorders, acute alcohol withdrawal syndrome, skeletal muscle spasm, and convulsive disorders such as status epilepticus.[3] Beyond these approved uses, diazepam is frequently employed off-label for conditions such as insomnia, restless leg syndrome, and pre- and post-operative sedation. In the United States, diazepam is classified as a Schedule IV controlled substance, reflecting its potential for misuse and dependence.[2]
Dosage and Administration Guidelines
For anxiety and epilepsy management in adults, typical initial diazepam dosages range from 2 to 10 mg orally, administered two to four times daily. Maximum recommended doses can reach up to 30 mg every 8 hours. For hypnotic purposes, doses up to 30 mg orally are generally administered before bedtime. In the treatment of status epilepticus, intravenous or intramuscular doses of 5–10 mg every 10–15 minutes, up to a maximum of 30 mg, may be used, often in conjunction with other antiseizure medications.[20] Dosage adjustments are often necessary based on individual patient factors, including age, hepatic and renal function, and concurrent medications.
Adverse Effects, Risks, and Dosage Considerations
Serious and fatal adverse events directly attributable to diazepam are rare and typically associated with interactions with other CNS depressants such as opioids or alcohol. Respiratory arrest and prolonged seizures, rather than acute overdose, are the more common causes of severe outcomes, often resulting from chronic, habitual use. Paradoxically, extremely high diazepam overdoses (up to 2000 mg) have been reported to induce temporary coma with subsequent recovery.
More common, moderate adverse effects associated with chronic diazepam use include amnesia, dizziness, ataxia, confusion, sedation, depression, and tachycardia. In some patients treated for epilepsy or anxiety disorders, paradoxical worsening of seizures or anxiety may occur.[48]
Tolerance, Dependence, and Withdrawal
Chronic diazepam use carries risks of tolerance, dependence, and withdrawal. While diazepam is considered to have a lower addiction and dependence potential compared to some other benzodiazepines, it is still crucial to exercise caution with dosage and duration, especially for long-term anxiety management. Diazepam is sometimes used to manage withdrawal symptoms from other benzodiazepines and alcohol due to its longer half-life and smoother withdrawal profile compared to shorter-acting benzodiazepines.
Benzodiazepine withdrawal symptoms can range from mild, such as headaches and muscle aches during gradual cessation, to severe and life-threatening, including psychosis, hallucinations, seizures, mania, and death from convulsions, particularly if high-dose chronic treatment is abruptly discontinued.[49]
Mechanisms of Tolerance and Dependence
Studies suggest that tolerance to and dependence on diazepam and other benzodiazepines develop through GABA-ergic neuronal desensitization, possibly involving receptor internalization and transcriptional regulation. Concurrently, the NMDA glutamate excitatory system may become hypersensitized, potentially leading to excitotoxicity. Benzodiazepines are also known to reduce levels of norepinephrine, serotonin, acetylcholine, and dopamine, further disrupting normal neuronal network balance. To mitigate dependence and withdrawal risks associated with chronic prescription, gradual dose tapering before complete discontinuation is recommended.[50]
Diazepam’s Historical Significance and Impact on Neuroscience
Diazepam and its analogs are indispensable pharmacological tools in translational neuroscience, largely due to their well-defined effects in humans across a spectrum of clinical indications. In rodent models of anxiety and sedation, diazepam is frequently used as a control to validate assay reliability, owing to its consistent effects and ease of administration (typically 1–10 mg/kg) in laboratory animals.[51]
Over its five-decade history, diazepam has undeniably become one of the most influential psychotropic compounds produced by the pharmaceutical industry. From its serendipitous discovery to its immense commercial success and subsequent controversies, the legacy of Valium embodies both therapeutic triumph and cautionary lessons.
Revolutionizing Anxiety Treatment: A Paradigm Shift
Prior to benzodiazepines, available treatments for anxiety, including chloral hydrate, barbiturates, and bromide salts, suffered from low therapeutic indices and prolonged half-lives, making precise dosing challenging. Habitual use of these earlier agents commonly induced tolerance. Overdoses frequently resulted in severe sedation, motor impairment, cognitive dysfunction, coma, respiratory depression, and even death. Furthermore, distinguishing adverse effects from intended therapeutic effects was often difficult. These earlier drugs primarily focused on generalized sedation rather than targeting the underlying neurobiological mechanisms of anxiety. In the absence of specific drugs and identified molecular targets, psychiatry largely emphasized Freudian psychoanalysis over pharmacological interventions, which were often associated with undesirable side effects. Even with the advent of the psychopharmacological revolution in the 1950s, first-line anxiolytics like meprobamate offered only marginal improvements in safety and efficacy compared to earlier treatments.[2, 49b, 52]
The introduction of benzodiazepines, spearheaded by diazepam, marked a watershed moment in psychotropic drug development. Diazepam proved effective in patients who had not responded to previous treatments, without carrying the high overdose risk associated with conventional sedatives. Accidental deaths from sleeping pills, a common occurrence previously, significantly decreased with the widespread use of benzodiazepines. Psychoanalysis, while still influential, was increasingly overshadowed by the convenience of prescribing drugs like diazepam. From a safety and therapeutic perspective, diazepam was initially hailed as a “worry-free panacea,” effective for anxiety, insomnia, epilepsy, alcohol and opioid withdrawal, panic attacks, and muscle spasms.[2]
Unraveling the Mechanism: From Clinical Success to Molecular Understanding
The remarkable potency and perceived safety of benzodiazepines spurred intense research into their mechanism of action. Early findings in 1974 by Roche and other research groups demonstrated that diazepam specifically enhanced the effects of GABA.[53] In 1977, it was discovered that diazepam bound selectively to receptors in the CNS, which were subsequently identified as critical sites on the GABAA receptor complex.[32] Advances in molecular biology led to the identification, sequencing, cloning,[54] and structural analysis of the GABAA receptor complex using electron microscopy.[55] These breakthroughs structurally validated diazepam’s binding site and selectivity. This specificity for GABAA receptors and its indirect activation through allosteric modulation explained diazepam’s favorable safety profile and adjustable dosage for various clinical applications.[20]
The Shadow of Overprescription and Dependence
Diazepam’s rapid onset of action, low toxicity, and high potency not only established it as an effective medication but also transformed it into a pop-culture icon. However, this widespread popularity and blockbuster sales also brought to light the risks of overprescription and dependence, issues that were initially underestimated. While early assessments of benzodiazepines’ addictive potential downplayed concerns, the safety profile was often taken for granted, leading to inappropriate prescribing practices, with some patients receiving higher doses for longer durations than clinically necessary. More critical reviews of clinical and preclinical data highlighted that dependence was indeed a significant factor, particularly with higher dosages and prolonged use. Concerns about normal-dose dependence emerged in the 1970s, prominently voiced by groups in the United Kingdom, and were confirmed in the 1980s. By the 1990s, the scope of benzodiazepine dependence expanded to include even chronic low-dose administration.[52a, 56]
Regulatory Responses and Shifting Prescribing Patterns
Despite the majority of diazepam prescriptions being for legitimate medical needs and abuse often occurring in individuals with polysubstance abuse issues (particularly heroin and alcohol), diazepam and other benzodiazepines faced increasing scrutiny from the medical community and regulatory bodies. Public perception became increasingly negative, leading to stigmatization. While regulatory actions in the United States under the Controlled Substances Act (Schedule IV) have been relatively moderate, European countries and certain regions implemented stricter measures.[57] Triazolam (16), once widely prescribed in the US and UK, was suspended and subsequently withdrawn from the market in the Netherlands (1979), the UK (1991), and other Western European nations.[58] Several countries imposed stringent restrictions on other benzodiazepines with high abuse potential, especially those used intravenously, such as temazepam (11).[59] New York State introduced rigorous prescription regulations in 1989, notably requiring state-issued triplicate prescription forms, resulting in a 30–60% decrease in benzodiazepine prescriptions and a paradoxical increase in the use of less safe alternatives like chloral hydrate and meprobamate by over 100%.[60] In 1994, the World Health Organization expert committee on drug dependence identified flunitrazepam (13) abuse as a significant public health threat.[61] Flunitrazepam’s use as a “date rape” drug has led to even tighter regulations and scheduling compared to other benzodiazepines.[48a] While diazepam itself has not faced singular regulatory actions, it often serves as the archetype for benzodiazepine class regulations, particularly as Valium, the iconic “Mother’s Little Helper.” The advent of newer antidepressants like tricyclic antidepressants and SSRIs, combined with the lingering concerns from overuse in the 1970s and 1980s, contributed to a significant decline in diazepam prescriptions.[62]
Diazepam in Modern Medicine: Enduring Relevance
Despite the controversies and shifting prescribing trends, recent perspectives argue against declaring “the end of the benzodiazepine era.” While newer drug classes have become preferred for conditions like OCD, benzodiazepines, including diazepam, remain first-line treatments for many anxiety disorders and phobias. This is partly due to the significant side effect profiles of SSRIs, their limited efficacy for certain anxiety conditions, and their slower onset of action, despite ongoing advocacy for SSRIs as first-line treatments by many groups.[63]
Diazepam’s inclusion in the World Health Organization’s list of essential medicines underscores its continued critical role in modern medicine. Its 50-year history of raising the standard of care and revolutionizing the treatment of anxiety, epilepsy, and other conditions unequivocally solidifies its status as a classic in chemical neuroscience.
Declaration of Competing Financial Interest: The authors declare no competing financial interest.
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