Does Botox get into the brain? Troubling research contradicts
earlier findings about the treatment.
The way it usually works is, the rats and mice die first. Or at
least get sick first. Or at the very least, show some adverse
effect first—as in, before people do. The reason countless lab
animals have given their lives during the testing of experimental
drugs is to allow manufacturers and regulators to see that a
compound might be toxic, even deadly, before millions of people use
it. And if the compound does look a little dodgy, the lab-animal
tests uncover the reason—how the compound affects the liver, say,
or reaches the brain. Not surprisingly, these "preclinical tests"
(that is, those performed before testing on humans) were especially
rigorous for botulinum. One of the deadliest poisons in nature and
a possible bioterrorism agent, this neurotoxin reached the market,
in very dilute doses, starting in 1989 as Botox. A big reason Botox
and its cousins, such as Myobloc, were OK'd was that preclinical
testing showed that after being injected, they did not travel along
the body's highways—nerve cells—to the brain and spinal cord. Yes,
there was some evidence the toxin slipped into the bloodstream or
the lymph system, but Botox in the bloodstream cannot enter the
brain, says its manufacturer.
Oops. In a reversal of the usual sequence in science,
researchers have discovered, after millions of people have received
the drug, something fundamental about how Botox can act. Contrary
to what turned up in preclinical testing, botulinum toxin can
travel along neurons from the injection site into the brain, at
least in lab animals. Researchers at Italy's Institute of
Neuroscience injected rats and mice with botulinum neurotoxin A in
doses comparable to those used in people. (Strains are named A, B
and E, depending on where the common soil bacteria that produce
them live; A is Botox, B is Myobloc, which is used for severe back
pain.) Neurons at the injection site—the whisker muscles—absorbed
some of the toxin and passed it along to other neurons they
connected to, the researchers report this month in The Journal of
Neuroscience. Within three days, the toxin had migrated from the
whisker muscles to the brainstem, where it disrupted neuronal
activity. "The discovery was quite serendipitous ... and
surprising," Matteo Caleo, who led the study, told the journal
Science. "A significant portion of the toxin is active where it's
not intended to be."
That stands in contrast to the findings of earlier studies,
which suggested that the neurotoxin is completely broken down at
the injection site into innocuous compounds and does not migrate
beyond it—or if it does, only into the bloodstream or lymph system.
Botox's manufacturer, Allergan, thinks those older studies are more
credible. "This study is not conclusive," says spokesperson Cathy
Taylor, "and other published studies using botulinum toxin type A
contradict these findings." Contrary to Allergan's statement that
the Italian scientists "injected the material directly into the
brain," however, they injected the neurotoxin into facial
muscles—and from there it found its way to the brainstem. "This is
a new pathway, and we need to think about the implications of
this," says Edgar Salazar-Grueso, chief medical officer of Solstice
Neurosciences, which makes Myobloc. The new study, he says, means
the original preclinical testing of Botox and its cousins "can be
interpreted in a different light."
Something else that can be seen in a different light is the
hospitalizations and deaths that have been reported following Botox
injections. In 2005 scientists at the U.S. Food and Drug
Administration analyzed 1,437 such "adverse events" between 1989,
when Botox was approved for eye spasms, and 2003. Most came from
people who got Botox to erase their wrinkles, but the 28 deaths
occurred in people who had received it for medical purposes. The
FDA didn't do much in response, but since then it has been getting
new reports of serious adverse reactions in people receiving Botox,
and launched a safety review. An analysis of the FDA's database by
the advocacy group Public Citizen found 16 deaths from Botox or
Myobloc. Most involved children with serious diseases like cerebral
palsy, who got the injections for muscle spasms (an unapproved,
though legal, use). But the agency has "evidence that [serious
reactions and even death] can happen in a broader population," said
the FDA's Russell Katz. "Is it possible with cosmetic use?
Possibly."
Those unapproved uses are another concern of the agency. Last
month Allergan revealed that federal prosecutors were investigating
it for promoting the non-FDA-approved use of Botox for headaches,
though doctors are free to prescribe a drug as they see fit.
Allergan says it's cooperating.
Botox and Myobloc carry labels warning of possible adverse
reactions near the injection site such as drooping eyelids, and of
severe difficulty swallowing in patients with neuromuscular
disorders. The FDA's Katz said that people getting Botox for
cosmetic reasons should "make their own personal best judgment
about this" and "be aware that there's the potential for" the
neurotoxin to spread. With the new evidence that Botox can spread
to the brain in ways that preclinical tests failed to turn up, it's
enough to bring back those Botox-erased frown lines.