Valproic Acid for Perfect Pitch? Steady, Now…

FDA_seizure_drug_DepakoteFor the past few days, the internet has been abuzz with the announcement of the “perfect pitch miracle drug.” Let’s back up a bit, shall we?

Valproic acid has been used alone or in addition to other medications for nearly fifty years to treat epilepsy, and is the active ingredient in drugs such as Valproate and Depakon. It is also used in the prevention of migraines, mania in bipolar disorder and for the treatment of aggression exhibited in children with ADHD. It is in the class of anticonvulsants. To talk a little bit about how it works, our brain is made up of thousands of nerve cells that communicate back and forth via electrical signal, a very intricate and delicate process that need maintain a steady and stable balance for normative functioning. When repetitive and abnormally rapid electrical signals are released, this process becomes disturbed and over stimulated. Anticonvulsants such as Valproate function as a stabilizer by increasing the amount of the natural nerve-calming chemical GABA, (gamma-Aminobutyric acid), as an HDAC (histone deacetlyase) inhibitor (Monti et al., 2009). GABA is one of the brain’s chief inhibitory neurotransmitters, which many researchers believe to regulate anxiety. When the amount of GABA in the brain falls too low, Valproate prevents the breakdown of the chemical and works to stabilize the amount of electrical activity, which explains why the drug has been found effective as a treatment for periods of mania and epileptic seizures.

Unfortunately, valproic acid is far from the ideal end-all. Valproate has been known to potentially cause serious or life threatening damage to the liver, pancreas, and blood cells, and holds an alarmingly high statistic for weight gain. It is not approved for use during pregnancy and breastfeeding, and has recently been the target of a lawsuit due to unforeseen birth defects. It is also known to cause ataxia, thrombocytopenia and leucopenia, so before we all go rushing off to “increase our brain function,” it might be wise to spend a moment thinking critically.

This morning, Tom Ashbrook of On Point, NPR stated “Imagine a pill that could rewire your brain. Would make your brain young again. Able to learn and absorb like a five-year old. Music. Languages. Would you take it?”  Neuroplasticity has risen to near-celebrity status over the past few months, and recent study by Frontiers of Systems Neuroscience is certainly fanning the flame. Carried out by researchers from France, Canada, Maryland, Australia, Massachusetts and England, the study set out to discover whether such periods when enzymes “impose ‘brakes’ on neuroplasticity, might be able to “reopen critical periods of neuroplasticity” via a drug that blocks productions of those enzymes. Absolute pitch was thought to be a solid assessment of this possibility because there are “no known cases of an adult acquiring absolute pitch.”

Absolute pitch (AP) is the ability to identify or produce the pitch of a musical sound without any reference point. Individuals who possess AP, constituting about 0.01% of the general population, are able to identify the pitch class, i.e., one of the 12 notes of the Western musical system, e.g., C, D, G#, of a sound with great accuracy (varying between 70–99%, depending on the task, as compared to 10–40% for non-AP individuals, Takeuchi and Hulse, 1993). The study explains:

“Importantly, acquiring AP has a critical period (Levitin and Zatorre, 2003; Russo et al., 2003). A critical period is a fixed window of time, usually early in an organism’s lifespan, during which experience has lasting effects on the development of brain function and behavior. The principles of critical period phenomena and neural plasticity are increasingly well understood both at the behavioral/experiential (Kleim and Jones, 2008) and at the molecular/cellular level (Hensch, 2005). Specifically, behaviorally induced plasticity in the healthy brain, typically after the end of the relevant critical period, can lead to improvement beyond normal or average performance levels. However, for many tasks, this requires targeted training—simple routine use is often insufficient. The factors known to influence the efficiency of such targeted training include the number of repetitions involved, the intensity of the training as well as the relevance or saliency of the stimuli or task trained. Importantly, such training-induced learning is quite specific to the trained task and to the underlying brain networks, although some transfer to other, related domains of knowledge or skills is sometimes possible. At the cellular level, critical periods close when maturational processes and experiential events converge to cause neuoro-physiological and molecular changes that dampen or eliminate the potential for further change (Hensch, 2005Bavelier et al., 2010), thus imposing “brakes” on neuroplasticity. One of the epigenetic changes leading to decreased plasticity after the critical period involves the action of HDAC, an enzyme that acts as an epigenetic “brake” on critical-period learning (Morishita and Hensch, 2008Qing et al., 2008). Research has shown that inhibition of HDAC can reopen critical-period neuroplasticity in adult mice to enable recovery from amblyopia (Putignano et al., 2007Silingardi et al., 2010), and to facilitate new forms of auditory learning (Yang et al., 2012).” ( ).

The randomized, double blind study was conducted on twenty four men, half of which received Valproate and the other half, a placebo. The men who received Valproate showed advantage in pitch class identification. To come to the conclusion, it is imperative that we acknowledge the fact that these powerful pharmaceuticals were in no way developed for something so “trivial” of the acquisition of perfect pitch – the diagnostic simply was appropriate for a brief and extremely small study and subject pool. The researchers conclude:

If confirmed by future replications, our study will provide a behavioral paradigm for the assessment of the potential of psychiatric drugs to induce plasticity. In particular, the AP task may be useful as a behavioral correlate. If further studies continue to reveal specificity of VPA to the AP task (or to tasks on which training or intervention is provided), critical information will have been garnered concerning when systemic drug treatments may safely be used to reopen neural plasticity in a specific, targeted way.”

It is vital during this time of exponential and rapid advances in the realm of neuroscience that we keep the grounding measures of ethics and morality at the forefront of our minds. There is a reason performance enhancing drugs are strictly forbidden in competitive sports. While it is truly of great interest to deliberate over the implications of a drug altered to target neuroplasticity, with great power (all together now) comes great responsibility. 

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