are bits of writing from many sources such as personal correspondence,
posts to on-line discussion groups, notes, and occasionally even some journaling.
All of this is informal in nature, but contains some interesting and/or
to the Monkey House
[Posted to the neuroscience
group on MySpace.com]
>please make a drug
that permanently makes people less angry, so that I can distribute it in
the water supplies everywhere kthx
As for the original
question, the "heightened alertness" of this post 9/11/01 era made people
look more closely at this idea of drugging the water supply. My lab was
funded to research the idea of using cultured neuronal networks as broad
band biosensors with which to sample the water for neuroactive compounds,
so I tended to watch the reports on such a threat relatively closely.
However, the experts
almost universally doubted the possibility based on the typically tremendous
volume of reservoirs that supply our drinking water. The amount of any
drug that would have to be dumped into such a body in order for it to achieve
an effective concentration at your tap would be inconceivable, especially
since everyone drinks bottled water or soft drinks anyway.
Now, if you want
to have a significant effect on the population, get a job at Starbucks
and switch the coffee for decaf and see if the world doesn't chill out
On a more serious
note, Kurt Vonnegut famously tackled a question to this effect in his short
story "Welcome to the Monkey House" (found in the story collection of the
same name and probably in most freshman English short story anthologies).
I won't spoil it for anyone, but I will say it's worth reading if you're
interested in pharmacology, free will, and ethics.
An interesting effect
of SSRIs (and a good lesson on brain anatomy) is that you will be aware
of certain feelings, but no longer act on them or be affected by them while
on medication in the same manner as you were while unmedicated. My plethora
of OCD and other symptoms demonstrate this all the time. I have a compulsion,
but I just think I'm going to do it, and I don't. My frontal cortex is
unaffected (as I understand it there are no serotonin receptors in the
FC), but my limbic system is on track. The habits are present as memories,
but not the impetus for action.
[Posted to the neuroscience
group on MySpace.com]
have much of an effect on men. In fact, one of the differential effects
of the stuff was accidentally demonstrated during an fMRI study a year
or two ago. The study was designed to map the mental processes involved
in taste the way we have for other modalities such as hearing and vision,
so the subjects were given various foods while they were being scanned.
As you already guessed, one of these was chocolate. One of the "incidental
findings" of the study was that the male participants eventually reached
a satiation point beyond which they really couldn't eat any additional
chocolate without feeling sick. By contrast, the women in the study *never*
reached that point. So now we understand Valentine's Day... and maybe have
a little more insight into what happened to Anna Nicole Smith!
think Jon's original post was about people being less angry, not necessarily
that they had to be happy. There are a lot of cases of mental dysfunction
in which individuals engage in rages without any clinical depression (although
I should point out that anger/rages are somewhat typical of "low-grade"
depression in males whereas the expected lethargy is almost the norm in
females). Many in the population also suffer from lack of prefrontal control,
which results in impulsive (read: "thoughtless") outbursts in which they
act on their first thought and respond negatively. Conversely, a person
*with* control would still have the thought but would be better able to
mitigate the response such that it would come out more diplomatically,
if at all (e.g., some are great at holding their tongues; others are just
There's an excellent
lay article on the most extreme cases of such lack of control and the science
behind it by New Yorker magazine writer Malcolm Gladwell at:
This is a fairly
well-studied phenomenon among people with abnormal brain chemistries. Although
it sounds like some sort of holistic healing or anti-physician approach,
it isn’t. What people tend to do when they aren’t “right” is to find a
pharmacological treatment that brings them back to balance. People with
ADD, for example, tend to go for stimulants: everything from caffeine to
cocaine; anything with an amphetamine-like effect. Schizophrenics are smokers
in far greater numbers than the general population, largely because of
several chemical agents with anti-psychotic properties found among the
other 4,000 compounds in tobacco. Alcohol works on depression ironically
because it is a depressant. However, what it depresses is the inhibitory
components of the brain. Thus, people become “disinhibited,” the complete
opposite of when depressed. There are other examples (e.g. chocolate for
jilted women), but I’m not as familiar with their mechanisms.
[Posted to the neuroscience
group on MySpace.com]
>>What do u think
are going to be the greatest advancements in this area of neuro?
>the greatest developments
will come from research discovering new receptors and their natural ligands.
While new compounds
are constantly being discovered, they are only extending our ability to
influence things at the synaptic level. Essentially, we are compensating
for excesses and/or shortages in neurotransmitters when, in fact, the problem
is almost always more systemic (hence the effect on behavior that created
the need for the individual to seek aid in the first place).
developments in neuroscience and psychiatry will more likely come from
gene manipulations that will address the issues that lead to the problems
we presently "bandage" with pills. By that, I mean that medication is a
temporary treatment that only lasts until the next dosage whereas changes
at the genetic level would continually exert an influence. I don't claim
to know how this will be accomplished or I would be at the patent office
right now, but the end result will be larger and more permanent changes
at the cellular level (e.g., to up/down-regulate transmitter function as
necessary) as well as at higher levels where more global pathologies (schizophrenia
being the stand-out example) are the problem.
Note that it is
possible that we are already addressing this issue without our knowledge.
For example, after being on the market for more than a decade by this point
SSRIs (specifically, I believe it was Prozac) were recently found to promote
the growth of new neurons in the brain (I wish I could be more specific
here, but I couldn't find the article to fact-check myself). It is possible
that other drugs may have similar secondary effects that are responsible
for their positive influence. Indeed, maybe these should be regarded as
primary effects from the theraputic perspective.
While no one can
refute the notion that *nurture* has a strong influence on the ultimate
design of the brain, nature can hardly be discounted where any biological
phenomenon is concerned. While some disorders are inherited outright, other
genetic components only confer a *predisposition* toward an unhealthy outcome.
Either way, the move "beyond pharmacology" will have to address the genetic
components that result in faulty wiring in the first place.
What helped me get
around to doing the mundane chores was having a part of cordless headphones
connected to either my computer or tv. Lately, I've been using the mp3
player to the same end. It helps me keep my mind occupied while I'm
doing things like, for example, (from today) filling my car's tires, the
bike tires, hanging up the bird house, and trimming bushes, all of which
take me away from the computer or tv or anything else I would rather be
Part of this may also be
that the "pleasurable" effect of experiencing books on tape (or whatever)
stimulates dopamine pathways. This transmitter is also the involved
in movement (the lack of it results in Parkinson's and Parkinsonian symptoms
in other conditions). If you recall the movie Awakenings with
Robin Williams, one of the treatments that worked was to expose the patients
to things they enjoyed. This brought them out of their catatonic
states and got them up and moving again. And it wasn't just playing
*any* music that would do it. In one case, they had to play Jimi
Hendrix to motivate a particular patient. Interesting.
[Posted to the neuroscience
group on MySpace.com]
>Could someone please
explain to me how a new generation drug like strattera evidently differs
so substantially in its chemistry compared to classic ADHD drugs (e.g.,
ritalin and adderall) that it can be considered a "non-stimulant"?
to also dump out neurotransmitter vesicles, so there is an abundance of
NTs in the synapse. I'm going to stick to that generalization without going
any deeper because, otherwise I will reveal my ignorance.
However, there are
sometimes secondary effects via the circuitry. For example, Analytic [another
member of the forum] pointed out in the Amphetamines thread in this group
that "Amphetamine... binds directly to beta-NE receptors causing increased
dopamine release." Again, you've got DA release, but because you've activated
something "upstream" (as opposed to directly activating DA receptors and/or
blocking DA reuptake).
>...why aren't other
drugs such as Wellbutrin and Provigil--which act almost exclusively on
dopamine to my knowledge-- classified as stimulants?
(aka bupropion) also acts on norepinephrine reuptake (i.e., it inhibits
both). I've read that it also has an effect as an SSRI as well, but not
great enough to be regarded on the level of, say, Prozac (aka fluoxetine).
As a result, most sources seem to avoid saying they know its actual mechanism
of action. (I read a bunch about it back when a friend started it and asked
me how it worked; I hit dead ends in most sources I tried.)
I don't know much
at all about Provigil, but I read that it does not work directly on dopamine
receptors. For those outside the field, this is relatively easy to test
by making (cloning/expressing) copies of all the known dopamine receptors
and seeing whether a given drug binds (i.e., sticks) to them. There are
more involved approaches than that, of course. These are usually tried
as well, just in case someone can get a publication out of it.
>Is there any truly
definitive medical definition of “stimulant”; or is it more of a colloquial
I don't know the
answer to this one or any of the rest. (Didn't want you to think I just
missed them though.) Anyone?
A final point for
anyone interested in this topic: Don't just focus on the NT involved. You
also have to consider the mode of action (e.g., inhibitory vs. excitatory
effects on the receptor, reuptake inhibitor, or transporter overloader...
or whatever they call this last category) as well as the brain area(s)
At this stage of
the game, we're taking a "shotgun" approach to brain function by throwing
a bunch of chemicals at pretty much every brain region and hoping they'll
produce a strong therapeutic effect by hitting the desired targets. In
the meantime, there's often a lot of collateral damage in the form of side
effects... and these vary across the population taking the drug in question.
It's still a very messy approach.
What's in the future?:
chemicals that will target subpopulations of receptors. (e.g., SSRIs keep
more serotonin active in the system, but what if only one subtype is the
problem? There are more than a dozen known types of serotonin receptors.
SSRIs are indiscriminant among these.)
methods. (e.g., Many mood disorders originate in the prefrontal cortex
and/or limbic system, yet the drugs applied affect common receptors found
throughout the brain, not just in the errant brain regions.)
(e.g., The sky's the limit here, guys.)
Anyone looking to
be a millionaire should look into solving any and all of these problems.
[Posted to the neuroscience
group on MySpace.com]
>is there anything
special in the head that sends crap to our bodies to enable us to move
I'm not sure if
this is a serious post or not, but I guess I'll address it either way.
On a gross level,
certain neurotransmitters are usually associated with specific functions.
For example, the one typically associated with movement (thanks to its
role in Parkinson's disease) is dopamine (commonly abbreviated DA), although
acetyl choline (aka ACh) acts at the neuromuscular junction so that neurons
can basically tell specific muscles to "jump" at a given moment.
As for thinking,
well, that's a bit more difficult to address concisely. By that, I mean
that "thinking" has a lot to do with the architecture of the brain as much
as the neurotransmitters, but most of that has never been worked out. That
being said, the main NT usually associated with the brain is glutamate
(yes, the basic amino acid), although GABA is also very important (you
would have nothing but a continuous seizure without it), as well as countless
neuromodulators and several other neurotransmitters like NO and serotonin
Note that most of
these transmitters play multiple roles (e.g., DA in pleasure-seekig behavior
and addiction), so the story is much more complicated that the above might
lead you to believe. Regardless, that's a start.
Search for "neuroscience"
and some of the above terms and you will likely find some good primers
on the web. I also posted some links on here earlier to good resources
including my own links page (shameless plug).
would argue that people try to achieve balance. They look for excitement
when things are dull and try to find calm when things are too intense.
In a sense, you're self-medicating with something other than external chemicals.
Ultimately, in treating
mental disorders, I'm sure the attention will be directed toward the wiring,
not just the currents (i.e, "chemicals") running through them. That's where
the real problem lies. The hope is that the wiring will slowly alter itself
into a healthy configuration while the patient uses the drugs as a crutch.
Unfortunately, they typically need this crutch all their lives.
One approach toward
altering aberrant connections is to combine behaviorism with pharmacotherapy
such that, at least in this example, disorders such as post-traumatic stress
disorder may be "cured" (or at least attenuated sufficiently that it no
longer impairs function). The paradigm is to treat the patient with canabanoids
(read: marijuana and/or its derivatives) while exposing the patient to
the normally caustic stimuli (e.g., gunshots, police sirens, or whatever
else normally triggers a panic attack). Since he is relaxed by the drugs
under the controlled conditions, the exposure fails to trigger as dramatic
a response. This is essentially an exercise in extinction by behaviorist
methodology, just "suped up" (or down, as the case may be) by the presence
of the drug(s).
Pot also has the
much-studied effect of "unwiring" emotional memories in the amygdala, which
is exactly where these PTD memories most persistently reside (they also
trigger cortical episode memories of the events surrounding the initial
stressor, such as being in the battlefield, but the emotional component
is in the amygdala). The future of addiction therapy lies down a similar
path. And, I note the irony of giving drugs to addicts, but a number of
therapies (methadone being the standout) have been accepted.
Tom Cruise quoted
in the Boston Herald: "When you talk about postpartum, you can take people
today, women, and what you do is you use vitamins. There is a hormonal
thing that is going on, scientifically, you can prove that. But when you
talk about emotional, chemical imbalances in people, there is no science
behind that.'' (from http://thetrack.bostonherald.com/moreTrack/view.bg?articleid=88217)
Yep, he's an authority. Apparently, hormones are made from vitamins. Everything
you learned in biochemistry is wrong. Well, according to Jerry Maguire.
As always, things
are rarely so black and white that they can be prescribed without a lengthy
list of possible side effects. But there's a huge gulf between possible
and probable. Which one do you plan your day around?
>Did you do acid
during your Pink Floyd days?
No, but that was
something I really wanted to try. However, I was always afraid to do it
for a couple reasons. A lot of my friends were doing it at the time (late
'80s, early '90s), so I heard the good and the bad. I saw some of them
become burnouts from it. You know the type that has a 5 second delay between
when you ask them a question and when you can get an answer out of them?
Also, some of them were doing it often enough to experience flashbacks,
and that was something I really didn't want to deal with. It's one thing
to set aside an afternoon to trip, but I didn't like the fact that there
was no control when it came to the flashbacks.
[Posted to the experimental
psych group on MySpace.com]
Before I address
the specifics of the possibility of a NMDA/psilocybin connection, let me
look at some general issues:
If you're looking
for pharmacological effects at the level of feelings and/or behavior, receptors
are only one link in a very lengthy chain, and there are a lot of caveats
along the way.
Depending on how
particular you want to be about this analogy, receptors act as "switches"
or "knobs" that trigger and/or modulate firing of neurons. And if you're
talking about a particular compound acting as a neurotransmitter, you also
have to realize that the same NT may act on multiple receptor subtypes
(e.g., the, what, 20+ types of serotonin receptors! I haven't checked for
the latest count), each of which may act in an excitatory or inhibitory
(or even modulatory?) fashion.
At the cellular
level, which neurons are affected is important because, just at the most
basic level, you may be stimulating (or not) an excitatory neuron or an
inhibitory one. As a result, somewhere downstream you may have the completely
opposite effect of activating or depressing something via the same upstream
And then at the
level of brain regions, you may be dealing with a network (or collection
of networks) that contribute a positive or negative effect to a process
(e.g., the prefrontal cortex inhibits impulsive behavior initiated/mediated
by more primitive brain regions while the cortex continues to process and
determine the best course of action in the face of a set of stimuli).
It's a complex story,
and you'll notice that the greatest certainty anyone can offer is at either
extreme. We can speak authoritatively at the level of pharmacology of what
binds to what, and we can speak about behavior and subjective effects on
perception, etc., but everything in between is only incompletely understood...
but it *is* at least incompletely understood.
I have never run
across anything that indicated that psilocybin binds directly to NMDA receptors.
But it's a big world with research constantly going on, so I could be wrong,
but I didn't turn up anything in the literature with a few casual attempts.
As you mentioned earlier, there are simple enough (well, relatively) ways
of testing to see if a given compound as any affinity for given receptor.
Further, if such an affinity was found, follow-ups could be performed in
expression systems (e.g., Xenopus oocytes, etc.) and patch clamped to determine
if there was any biological effect (i.e., acts as agonist? antagonist?
All that being said,
I wouldn't have expected psilocybin to have an effect directly on the NMDA
receptors simply because it is already mimicking a common NT: serotonin.
Of course, once again, it wouldn't be unprecedented for an NT from one
family to make an appearance in another receptor. For example, glycine
(an NT in its own right) is required in not one but two binding sites in
the NMDA receptor in order for it to function.
A little more
about the NMDA receptor
This receptor is
widely-regarded as central in learning and memory (mainly because of empirical
evidence to that effect and partly) because it has a complex mechanism
of gating that facilitates the Hebbian model of "fire together, wire together."
Like other receptors (e.g., GABAa), the NMDA receptor has multiple binding
sites for both endogenous compounds (and ions!) as well as quite a variety
It is also one of
the most plentiful receptors in the cortex (I've heard it said that the
cortex is more that 90% glutamatergic neurons), so even small effects on
this system could conceivably cause large effects collectively. And these
need not be direct effects on the receptors themselves. For example, in
Aghajanian & Marek (1999, cited/linked above), it was pointed out that
there was an increase in glutamatergic release, so this was an upstream
mechanism. Depending on the architecture of the system, this might even
mean that the effects at the serotinergic level were amplified.
All this probably
goes the opiate (aka, more commonly, "opioid") receptors as well, but I
know less about them, so I'm keeping quiet where they're concerned.
So... you were
still not getting to the basis of the euphoric effect you're looking for.
This isn't something I keep up with as much as I'd like to, so rather than
drawing from my own limited knowledge at this point, I'm just going to
give you a possible approach.
Personally, I would
search for what is known about which brain region(s) is(are) involved in
euphoric states. For example, something like this study: "Cortical
gray matter volumes are associated with subjective responses to cocaine
infusion" or ""
Amphetamine-induced dopamine release in human ventral striatum correlates
with euphoria will tell you what is thought to be typically activated/depressed
in order to achieve euphoria. These might also tell you whether your hypothetical
"cascade" of multiple brain regions is on the right track (though I'm guessing
not; as you describe it, such an even is more akin to epilepsy than an
From findings like
those, you might examine the literature for studies of receptor densities
for pharmacological effects of interest. On a related note, you might pursue
the anatomical literature for tract tracing studies to determine which
areas project to/from the region(s) in question. It all depends on what
you're trying to ask (and it may be more than you ever thought was implicit
in the original question).
everything else in neuroscience, you may find that you haven't really found
answers so much as really, really refined questions.
I'll be curious
to see what you come up with, so keep us posted.