Psychedelic Drugs Show Promise as Antidepressants

Scientists suggest that some psychedelics are remarkably good at treating disorders
like depressionµand may now have a clue as to why

By David Biello August 19, 2010 32

PSYCHEDELIC RESPONSE?: The anesthetic ketamine has several notable side

effects, including hallucinations and, according to new research, strengthening
synapses. The top synapse pictured here is untreated whereas the more connected
synapse below shows regeneration in a rat receiving ketamine. Image:

Ketamine—a powerful anesthetic for humans and animals that lists hallucinations
among its side effects and therefore is often abused under the name Special K—
delivers rapid relief to chronically depressed patients, and researchers may now have
discovered why. In fact, the latest evidence reinforces the idea that the psychedelic
drug could be the first new drug in decades to lift the fog of depression.

"We were trying to figure out what ketamine was doing to produce this rapid
response," which can take as little as two hours to begin to act, says neuroscientist
Ron Duman of the Yale University School of Medicine. So Duman and his colleagues
gave a small amount of ketamine (10 milligrams per kilogram of body weight) to rats
and watched the drug literally transform the animals' brains. "Ketamine… can induce
a rapid increase in connections in the brain, the synapses by which neurons interact
and communicate with each other, " Duman says. "You can visually see this response
that occurs in response to ketamine."

More specifically, as the researchers report in the August 20 issue of Science,

ketamine seems to stimulate a biochemical pathway in the brain (known as mTOR) to
strengthen synapses in a rat's prefrontal cortex—the region of the brain associated
with thinking and personality in humans. And the ketamine helped rats cope with the
depression analog experience brought on by forcing the rodents to swim or exposing
them to inescapable stress. "Preclinical and clinical studies show that repeated stress
or depression can cause a decrease in connections and an atrophy of connections in
the same region of the brain," Duman explains, noting that magnetic resonance
imaging shows that some depressed patients have a smaller prefrontal cortex as a
result. "Ketamine has the opposite effect and can oppose or reverse the effects of
depression" for roughly seven days per dose.

Rats and humans have similar biochemical pathways. "There's a fair amount of
similarity between the neurotransmitter systems and the way drugs act in the brains
of rodents and humans. Biochemically, there is good correlation," Duman notes.
"Behaviorally, it's much more difficult to know whether an animal is depressed and
the drug is making it less depressed."

But ketamine is not alone among psychedelics in having potentially therapeutic

effects. A review, published August 18 in Nature Reviews Neuroscience, of research
on this grouping of drugs generally—ranging from dissociative anesthetics such as
ketamine to naturally occurring hallucinogenic compounds such as the psilocybin in
"magic mushrooms"— shows their efficacy at treating obsessive-compulsive
disorders and addiction as well as depression and anxiety, among other disorders.
(Scientific American is part of the Nature Publishing Group.)

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In fact, ketamine has shown promise at reducing the risk of suicide and is currently
being tested in humans for effectiveness in treating bipolar disorder and addiction.
Psilocybin can decrease obsessive-compulsive behaviors, or even eliminate them
entirely, for as long as a full day after treatment and is being tested to reduce
anxiety and depression in terminal cancer patients. And even LSD—lysergic acid
diethylamide-25—can combat inflammation, among other potential therapeutic uses.
"The potency is about 300 times more potent than steroidal anti-inflammatories,"
says pharmacologist Charles Nichols of the Louisiana State University Health
Sciences Center, who is working with the drug. "My lab is currently studying the
ability of it to block or prevent inflammation in models of human inflammatory
disorders, and the results are very promising so far."

The August 18 review, by psychiatrist Franz Vollenweider and neuropsychologist

Michael Kometer of the University Hospital of Psychiatry in Zurich, proposes that
various psychedelics' interaction with the receptors for the neurotransmitter
serotonin may prove key to understanding their beneficial—and mind-bending—
effects. "Psychedelics activate neuronal networks and the glutamate system that are
implicated in the regulation of emotion," Vollenweider says, noting that their
hallucinogenic effects can be impeded by blocking specific serotonin receptors in the
brain (known as 5-HT2A). Psychedelics typically boost serotonin and may also boost
the release of glutamate, according to the review authors, another neurotransmitter
that has been linked to short-term but long-lasting brain functions such as learning
and memory. More glutamate also has an impact on synapses. "This might result in
an increased number and function of spine synapses in the prefrontal cortex,"
Vollenweider says.

That's exactly what Yale's Duman and his colleagues have now found, at least in the
case of ketamine, though Duman is skeptical of a shared mechanism, given that
ketamine and other hallucinogens affect different biochemical pathways. "There is
evidence that the psychedelic agents enhance glutamate," he says. "I don't think the
evidence is all that strong."

Regardless, it is unlikely that ketamine, psilocybin or any of these psychedelics would

be used directly, because of their hallucinogenic and other side effects. According to
Duman, several pharmaceutical companies have already begun the search for
alternative compounds that target the same biochemistry or brain function, including
some that his lab is testing. "We are testing other targets that we identified that we
now know are potentially related and could impact pathways we have found to try to
come up with novel targets and treatments that produce a ketamine-like effect with a
better safety profile." In other words, a drug that treats depression the same basic
way as a psychedelic but without any of the hallucinations and other mind-bending
effects.

http://www.scientificamerican.com/article.cfm?id=psychedelics-may-help-treat-
depression

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Changing Minds: Has Selective Breeding Restructured Some Dog Brains?

A new study suggests dog breeding by humans has altered brain structure and
position in short-skulled canines, possibly diminishing their olfactory abilities

By Ferris Jabr August 13, 2010 20

BREEDING THE BRAIN: Selective breeding may have altered canine brain structure
in addition to body shape. Image: Keith Pomakis, Wikimedia Commons

Compare the petite Chihuahua with the daunting Great Dane, or the lithe greyhound
to the poofy Pomeranian. Many scientists agree that the domestic dog displays more
morphological variation than any other known species, thanks to selective breeding
by humans. But dog breeds differ in more than their outward appearances. A new
study suggests that human preferences have dramatically altered the structure and
position of the brain in certain dog breeds, potentially modifying their sense of smell
and behavior as well.

In a study published online July 26 in PLoS ONE, neuroscientist Michael Valenzuela of

the University of New South Wales in Australia investigated an aspect of canine
anatomy that has not received much attention from earlier research: the position of
the brain within the skull. All dogs, no matter what the breed, belong to the same
subspecies (Canis lupus familiaris) of the gray wolf (Canis lupus) from which they
were domesticated. Gray wolves have relatively long skulls and one gray wolf skull is
more or less the same as another (age and gender differences notwithstanding). In
contrast, the skulls of domestic dogs range from one extreme to another: from the
long-snouted German shepherd and Russian wolfhound to the stubby-snouted Boston
terrier and flat-faced pug, whose wrinkled muzzle resembles a collapsed accordion.
Valenzuela and his colleagues wanted to determine whether the artificially selected

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differences in skull length between dog breeds also reorganized the canine brain.

The researchers used magnetic resonance imaging (MRI) to scan the brains of 11
recently euthanized dogs from a local Australian pound, along with two living English
springer spaniels. The euthanized dogs made up a diverse group, including an Akita
cross, a mastiff cross, a Maltese, a Staffordshire bull terrier, a shih tzu cross, a
greyhound, an Australian cattle dog cross, a Jack Russell terrier and a pit bull cross.
Once they acquired the brain images, the researchers analyzed the overall position of
the brain in the skull and estimated the relative volumes of the olfactory lobe—a bulb
of neural tissue responsible for processing scents that is approximately 40 times
larger in dogs than in humans, relative to total brain size. The experimenters also
calculated a cephalic index (CI) by dividing skull width by skull length and multiplying
by 100. The higher the CI, the shorter the skull length and vice versa.

The dogs with the shortest skulls—such as the pit bull, Akita and shih tzu cross—
demonstrated significant brain reorganization. In short-snouted dogs, not only had
the brain's cerebral hemispheres rotated forward by as much as 15 degrees, the
olfactory lobes had shifted position from the front of the brain toward the base of the
skull. The brains of puglike dogs did not sit inside the skull in the same way as brains
of long-snouted dogs, whose skulls and brains more closely match those of the
domestic dog's wolf ancestor. In other words, the findings imply that when selective
breeding by humans squashed the snouts of certain dog breeds, it also morphed
their brains.

"The whole brain had rotated in more puglike dogs," Valenzuela says, "and the
olfactory lobe had shifted to the bottom of the skull. There was quite a high
correlation, a linear relationship, between short-skulledness and forward rotation of
brain. And although there were no differences between breeds in the volume of the
olfactory lobe, the position of the olfactory lobe changed in short-skulled dogs."

Because these effects were consistent across a wide range of skull shapes and were
independent of body weight and brain size, the researchers determined that brain
organization is most strongly linked to skull length as opposed to other anatomical
variables. The researchers hypothesized that the olfactory lobe may have scooted
into a new location to allow for proper development of the frontal cortex, but they did
not test for this directly.

The research team also speculated as to the implications of morphed brains for smell
—regulated by the olfactory lobe—and behavior, which is largely orchestrated by the
frontal cortex. Selective breeding may have robbed short-snouted dogs of their keen
sense of smell when it relocated their olfactory lobes. The researchers note that
puglike dogs are rarely if ever recruited to track down scents. Instead, olfactory
orienteering commonly falls to the long-snouted hounds.

"This is the next step of our work," Valenzuela says. "At the moment we don't have
any direct correlations or linkages, but we have circumstantial evidence that puglike
dogs don't seem to have very good olfactory abilities—they're never used in scent
work. Breeding may have a consequence for their olfactory ability and general
behavior, but we need to do more research."

http://www.scientificamerican.com/article.cfm?id=breeding-dog-brains

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Dopamine Determines Impulsive Behavior

Brain scans illuminate the internal connection among the neurotransmitter,

impulsiveness and addiction

By Katherine Harmon July 29, 2010 7

REGULATING THE RASH: Some people spend longer considering the ramifications
of their decisions than others. A new model of the human brain's dopamine circuit
might help explain this difference--and how it might inform drug addiction as well.
Image: GREGORY R. SAMANEZ-LARKIN/JOSHUA W. BUCKHOLTZ

Binge-shoppers and serial daters might perpetually be living at the whim of their
latest impulse, and now research is getting to the biological basis of their seemingly
random behavior.

"Individuals vary widely in their capacity to deliberate on the potential consequences

of their choices before they act," note the authors of a new study on the impulsive
tendency. "Highly impulsive people frequently make rash, destructive decisions."

Impulsivity has long been linked to the neurotransmitter dopamine, which is involved
in learning and reward. And a new model helps to illuminate the connection between
the two. The work is described in a study published online July 29 in Science.

A team of researchers led by Joshua Buckholtz, a PhD candidate in neuroscience at

Vanderbilt University, proposed that people who were more impulsive might have
less active dopamine receptors in their midbrain but their brains would be more likely
to fire off large quantities of the neurotransmitter when stimulated.

To verify their hypothesis, the researchers used PET scans to watch the brains of 32

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healthy and psychiatrically normal test subjects ages 18 to 35 (who had no history of
substance abuse) while they were taking a classic test to measure impulsivity. Before
the first testing round, subjects had taken a placebo pill, but before the second, they
were given an oral dose of amphetamine, which can stimulate the brain's reward
pathways, mobilizing dopamine.

People who had the higher impulsivity scores had the lowest activity in the midbrain
D2/D3 autoreceptors, which are in charge of receiving dopamine. But under the
influence of the amphetamine, these impulsive individuals released much more
dopamine than those who were less impulsive.

To see how these changes might be related to substance abuse—which has also
been linked to dopamine abnormalities—the researchers polled the subjects about
how much they wanted more of the amphetamine after the experiment ended.

"The people who had the highest levels of dopamine release reported subjectively
stronger cravings after we gave them the drug," Buckholtz says. These findings
"suggest a neurobiological link between human impulsiveness and drug abuse
vulnerability," the researchers noted in their paper.

But what causes these individual differences? "Our best guess is that perhaps there's
some inherited or environmentally mediated predisposition to having lower midbrain
dopamine autoreceptor availability," Buckholtz says.

The evidence for genetic inheritance is strong, and another recent study, published
earlier this month in Psychological Science, found people with a certain dopamine
receptor type—known as DRD4—had different drinking habits than those without it.
Specifically, test subjects with this variant were more likely to drink heavily if they
had seen others doing the same while those without that variant kept their drinking
moderate even when surrounded by heavier boozers.

The new results also suggest the potential for pharmacological interventions,
Buckholtz notes. Some drugs for psychiatric conditions related to dopamine
dysfunction, such as schizophrenia, work in broad strokes with "kind of a
sledgehammer approach," he explains. Homing in on particular receptors and firing
patterns might help develop drugs that could modulate in a "more targeted and
perhaps nuanced way," he says, helping people with a broad range of dopamine-
related ailments.

http://www.scientificamerican.com/article.cfm?id=dopamine-impulsive-addiction