From nose to brain: New route for chemical incapacitation?

I first realized the power of intranasal drug delivery after reading a 2005 paper in Nature entitled “Oxytocin Increases Trust in Humans.” In it, the authors–several psychologists, neuroscientists, and economists–reported on a study based on a game that pitted two players against each other–an investor and a trustee. (You may be wondering what this has to do with oxytocin, a neuropeptide involved in mammalian social behaviour, but bear with me!) The investor has the option of donating his money to the trustee. If he does so, the experimenters add to that amount by a known multiple. The trustee then can turn around and share the rewards (from the original investment and the experimenter’s donation) with the investor or just keep the money for himself.

The possibility that the intranasal route would allow other drugs or other chemical agents to bypass the protective blood-brain barrier and allow direct access to the brain for malign purposes is deeply worrying.”

The investor, therefore, faces a dilemma–will the trustee share the money or leave him high and dry? Most people put in this situation are rather averse to placing too much trust in the trustee. However–and here is where oxytocin comes in–the experimenters were able to show that administration of oxytocin within the nose (known as intranasal administration) significantly increased the amount of trust an investor displayed when playing the game.

The initial publication led other experimenters to further investigate what was causing the extra-trusting behavior of the investor. For example, in a 2008 Neuron journal study, “Oxytocin Shapes Neural Circuitry of Trust and Trust Adaptation in Humans,” the impact of the drug on the investor’s behavior was shown to persist even after trust between the two players had been breached several times.

While there are positive implications of these discoveries–intranasal administration of oxytocin might just be helpful in decreasing anxiety–the possibility that the intranasal route would allow other drugs or chemical agents to bypass the protective blood-brain barrier and allow direct access to the brain for malign purposes is deeply worrisome. Even more troubling is that it has long been understood that such bioregulators–naturally occurring chemicals in the body that control regulatory functions such as heart rate, temperature, sleep, and mood–can exert their effects at very low concentrations in the brain. A 2006 Institute of Medicine and National Research Council joint-committee (the so-called Lemon-Relman committee) warned of the impact of bioregulators on immune, neurological, and endocrine systems. The committee also warned in their final report, Globalization, Biosecurity, and the Future of the Life Sciences, about the potential use aerosol technology, microencapsulation, nanotechnology, and gene therapy to maximize the impact of such bioregulators on the human body. Advances in the field since the report’s publication four years ago have only heightened these concerns.

Although the way in which drugs pass from the nose to brain isn’t yet entirely understood, given the beneficial medical possibilities, the potential routes have been subject to careful investigation. The most obvious possibility is that there is direct transport to the brain along the olfactory nerve. There are numerous other potential routes to the brain following intranasal drug administration. One such mechanism arises because the olfactory receptor neurons regenerate every 3-4 weeks (due to their regular contact with toxins in the environment), and as a result, nasal barriers to the central nervous system may be rather porous. The special cells that ensheath the olfactory receptor neurons don’t decay but remain intact to guide the regrowth of the olfactory receptor neurons. Thus they could provide another direct route to the brain via fluid-filled extracellular channels–during neuron regeneration. In other words, these channels could allow for extracellular transport of drugs in addition to travelling along the axons of the neurons themselves.

Indeed, it appears likely, given the rapid onset of effects after intranasal drug administration that the extracellular channels allow drugs to be delivered to the brain faster than other pathways, such as the trigeminal nerve in the nasal passage or the various blood systems that supply the nose. It may well be that different drugs in different carriers travel from the nasal passage to the brain via a variety of routes.

What perhaps matters more in relation to the concerns raised in the Lemon-Relman report is that there are clearly also ways in which the efficiency of drug or chemical agent delivery through the intranasal route could be improved. Drugs can be encapsulated in carriers so that they are more soluble at the nasal epithelium–a soft membranous tissue–and thus more likely to be transported into the brain. The permeability of this nasal tissue also may be increased through the addition of chemicals known as permeation enhancers (for example cyclodextrins, which are used to increase the solubility of compounds). Finally, it may be possible to reduce the speed at which drugs or chemical agents are removed from the nasal epithelium by adding chemicals (vasoconstrictors) that narrow the blood vessels and thus allow the drug more time to be transported to the brain.

So could any benign civilian work in this area really be of much concern? Certainly. One example: a 2007 Journal of Neuroscience study “Systemic and Nasal Delivery of Orexin-A (Hypocretin-1) Reduces the Effect of Sleep Deprivation on Cognitive Performance in Nonhuman Primates.” It was only in the late 1990s that orexin/hypocretin was discovered and its dramatic role in sleep regulation revealed. In particular, it’s now understood that disruption of the orexin/hypocretin transmitter-receptor system is a major cause of narcolepsy. This 2007 study showed that primates that were deprived of sleep and not performing well on cognitive tasks improved their performance when administered both intravenous and intranasal dosages of orexin/hypocretin. The study’s investigators also found that the intranasal drug route was much more effective than intravenous pathways. To see the dual-use potential, I only need to add that effective orexin antagonists–drugs that have the opposite effect to orexin–could be powerful sleep-inducing chemicals and thus attractive to those seeking new incapacitants.

It is little wonder then that neuroscientists are asking their colleagues to sign a pledge to prevent the malign misuse of their discipline. This is a welcome move. The next step: neuroscientists and neuroethicists must incorporate dual-use considerations into their awareness of potential misuse and work out rules, guidelines, and regulations to prevent such potential malign uses in the future. For guidance, I would recommend looking at the 2008 final declaration of the Biological Weapons Convention States Parties. The initiatives outlined there–codes of conduct, increased awareness and education, and government oversight–could be very useful in such an effort.