Clusterbusters Thoughts, Musings, Hypotheses and Theories.
Clusterbusters Thoughts,
Musings, Hypotheses and Theories.
[MC;2004]
I noticed Melatonin in the list of Indole psychedelic
derivatives in TIHKAL by Alexander Shulgin. Reminded me that there is an
interesting relationship between DMT, Psilocybin, Serotonin and Melatonin. All
are not only structurally similar, but convertable to one another by enzymatic
and other natural processes.
Other studies showed that Serotonin and other related molecules could rapidly break down into DMT when bodily systems stopped functioning. Which would explain the sense of timelessness and other tripps stuff in near-death experiences. Also in car crashes when your 'life flashes before your eyes and a second lasts minutes' this could be a rapid release of a DMT/serotonin related compound.
DMT could actually be thought of as what "Launches" us into the next world during death, OR a convenient way for nature to provide the mind with a boost of awareness if death is imminent.
DMT and Melatonin are produced naturally in the body. The following text is edited from a site selling the amino acid Tryptophan as a way of naturally increasing the body's own DMT production.
"The dark room environment dramatically alters the chemistry of the brain, manifesting especially in neuro-endocrine systems which govern consciousness and regulate body functions. An important neurotransmitter involved in waking consciousness (serotonin) converts into a regulatory hormone (melatonin) that shuts down the organ systems, quieting the body in preparation for sleep. The pineal gland initiates a cascade of inhibitory reactions, permitting visions and dream states to emerge in our conscious awareness. Eventually, the brain synthesizes the "spirit molecules" 5-methoxy-dimethyltryptamine (5-MeO-DMT) and dimethyltryptamine (DMT),The spirit molecules are synthesized from the amino acid tryptophan in a series of biochemical steps, which simplified are: tryptophan ® serotonin ® melatonin ® pinoline and finally 5-MeO-DMT ® DMT."
It's just so ODD, so ponderous - so WEIRD - that the molecule which stops the Beast, is the same molecule family that governs sleep, dreams, waking attention, near-death experiences and spiritual states of consciousness. WTF? ;) so much left to be learned about all this ....very exciting stuff
Discussion on how and why some medications may interfere with psychedelics breaking a cluster.
[BW/PSM:2004]
Indomethacin is a nonsteroidal anti-inflammatory indole
derivative designated chemically as 1-(4-chlorobenzoyl)-5-methoxy-
2-methyl-1-H-indole-3-acetic acid. Indomethacin is practically insoluble in
water and sparingly soluble in alcohol. It has a pKa of 4.5 and is stable in
neutral or slightly acidic media and decomposes in strong alkali.
Will this medication block Clusterbusting actions?
I don't know to a certainty. On the one hand, maybe it is the indole structure which makes indomethacin effective in dealing with CH and CPH.
But there are hundreds of compounds having the indole structure which are not active, as well.
If I had to guess, I'd say no because of the fact that with indomethacin there is an awful lot of stuff hanging off the nitrogen atom at the bottom of the pentagonal section of the indolestructural core. The various other compounds we have been looking at (DMT, psilocin, serotonin, LSD, sumatriptan and all the other triptans) do not have this; all their "addons" are to one side or the other, leaving the "bottom" of the indole hexagon/pentagon structure clean.
If the theory we are operating under is correct -- that our magic compounds work by occupying the same receptor sites as serotonin -- then it stands to reason that only molecules of a certain shape will fit in the receptor's "keyhole". I (and neurochemists investigating the psychedelic phenomenon) have always presumed that the part that fits into the serotonin keyhole is the indole hexagon/pentagon, leaving the various sidechains which differentiate one compound from another more or less "waving in the breeze".
After looking at the molecular diagram of indomethacin, I don't see how it could possibly bind to the same receptor keyhole as the others -- that bulky group hanging off the nitrogen atom would prevent it.
Here's a link to a site showing a molecular diagram of indomethacin:
Here's a link to a site with diagrams of ergotamine, methysergide, and a whole bunch of various triptans:
Notice how ergotamine and all the triptans have just a single hydrogen atom attached to the nitrogen atom at the bottom of the indole "pentagon" (the pyrrole nitrogen), while indomethacin has another entire benzene ring and more attached to it.
I might be wrong about this -- I am not a neurochemist after all -- but if I personally was taking indo, I wouldn't bother to detox from it before trying psilocin or LSD. I just can't visualize any way to flip and twist the indo molecule into an orientation that would allow it to fit into the same "socket" or "keyhole" that the others do. Of course, if I took a sizeable dose and didn't get high from it, I'd rethink the detox. But as a prediction, my take on it says there should be no interference.
Verapamil Discussion:
[PSM:2004]
Even though verapamil does work on 5-HT receptors, it is
apparently a different subclass of the 5-HT receptors than that upon which the
psychedelics work. I remain unconvinced that verapamil blocks the action of
psilocybin, or at least that it completely blocks the action. I still agree
with Flash that the greatest chance of success is to be completely free of any
other meds, but I believe it's fair to say the jury is still out on verapamil,
so in an emergency situation it's better to take verap than any of the
triptans.
Discussion on detoxing, half-lives and why you should wait that 5 days
Using Imitrex as an example, why, based upon the half-live factors
below, do people need to detox for 5 days prior to dosing? It has a 1/2 life
elimination rate of 2 hours.
Therefore:
t+2 hrs = 1/2 dose
t+4 hrs =
1/4 dose
t+6 hrs = 1/8 dose
t+8 hrs = 1/16 dose
t+10 hrs = 1/32
dose
t+12 hrs = 1/64 dose
[Ueli;2005]
Could be, but I'm not entirely sure about that. Your
calculation holds for the Imitrex circulating in the blood stream, but we are
interested in the Imitrex bound to the 5HT receptors. Only if the binding time
to the receptors is short (minutes or less) we will have a dynamic equilibrium
and the amount docked to the receptors is proportional to the serum
concentration. I think this needs some further investigations.
[flo;2005]
Quite apart from half-lifes, administering a drug usually
turns various genes off and others on. A very common effect of administering a
neutotransmitter or hormone agonist (including nicotine, morphine, and
corticosteroids) is that natural production of that chemical in the body
decreases, and the number of receptors for it on the cell surface changes. This
sets up a dependency - keep taking the drug, and things are semi-manageable;
stop, and things get bad. Do triptans cause this type of dependency? Not sure
at this point, but I believe they sometimes can, depending on the individual
and the dose regimen.
[PF;2005]
Half-life pertains to both/either elimination or
matabolization. If you know how long all the different matabolites of the
various triptans remain active, you still need to know how long the effects are
for up and down regulation of the receptors.
[BB;2005]
Let's use aspirin as an example...
The plasma half-life
for aspirin is approximately 15 minutes; that for salicylate lengthens as the
dose increases: Doses of 300 to 650 mg aspirin have a half-life of 3.1 to 3.2
hours.
Why is it that people who use aspirin as a blood thinner and to
reduce the risk of stroke and angina don't take an aspirin every 3.2 hours?
Although aspirin has a half-life of 3.2 hours, it's effect on blood
thinning lasts about five days.
Doses of 300 to 650 mg aspirin have a half-life of 3.2 hours.
It's
therapeutic effects begin to occur within an hour.
Its anticoagulation
effects last 8 days.
Ibuprofen inactivates aspirins anticoagulation effect
because it "competes for same receptors".
Question on how psilocybin may work to treat clusters
Psilocybin and LSD stimulate phosphoinositide hydrolysis; the literature indicates that this is specific to 5-ht2c and 5-ht2a agonists (with 5-ht2c being particularly effective). Triptans, which are 5-ht1 agonists, do not stimulate this process, and methysergide (a mixed 5-ht2 agonist) antagonises PI hydrolysis. Serotonin itself stimulates PI hydrolysis. Lithium has a wide variety of effects on the body, but changes in phosphoinositide metabolism are usually alluded to when explaining the action of lithium.
Some of the many forms of inositol act as secondary messengers for the serotonin system. It may be that the phospholipase enzymes that are essential for transforming the various forms of phosphoinositol are supressed in cluster headache. The 5-ht2c chemicals specifically break a log-jam and get the serotonin/serotonin-feedback working.
Phospholipase is also responsible for cleaving choline from phosphatidyl choline. A defect in phospholipase would explain the low free choline levels and high phosphatidylcholine levels in the cell membranes of CH patients. Low free choline leads to lower acetycholine, and the cholinergic anti-inflammatory pathway is inhibited, leading to a rise in IL-1B, TNF, and other immune dysfunctions seen in CH.
The phospholipase theory offers a framework for explaining the large number of cluster headache patients that smoke; nicotine is a partial acetylcholine agonist. Nicotine abuse may induce disorder that impairs phospholipase and the cholinergic antiinflammatory pathway. Alternatively, a pre-existing defect in the phospholipase/acetylcholine system could render CH patients more susceptible to nicotine habituation.
[jb]
There is no hard science on this, mainly due to the fact that clinical research of the psychedelics using human subjects has been next to nil for the last three decades.
But my personal theory on this phenomenon runs something like this....
When the molecules of psilocin bind to the 5-HT receptor sites which normally would be occupied by 5-HT (serotonin) molecules instead, the signal that gets sent up the axon of the affected neuron is SLIGHTLY different than the signal which gets sent when it is occupied by a serotonin molecule. One of the results of this slightly altered signal is the various psychedelic perceptions we all know and love -- auditory and visual distortions of perceived objects. But another result is that a signal gets sent to the hypothalamus (or whatever else it is in our brain that periodically gets out of whack and initiates a cluster cycle) telling it to "reset" itself to its normal "non-cluster" mode of operation.
But there's something else going on as well. One of the most widely-reported but least understood subsidiary effects of dosing with a powerful hallucinogen is the "tolerance" and "cross-tolerance" effect. For several days after a significant dose of a hallucinogen such as LSD (and to a perhaps lesser extent with psilocin and mescaline) the receptivity of the binding sites is altered. That is to say that if you take a dose of LSD on Friday you'll get zonked. Take the same sized dose on Saturday and you'll barely get a buzz. Take a third dose on Sunday and you may feel nothing at all. And this works with ANY of the psychedelics -- if you dose with LSD on Friday you not only won't get high from a saturday LSD dose, you won't get high on a Saturday mescaline dose or psilocin dose either. This is known as "cross-tolerance".
It takes several days for the receptivity of the binding sites to return to their "pre-dose" state. And this effect manifests itself even though all detectable traces of LSD (or whatever) have left the bloodstream. This suggests that it's not just a case of the psychedelic molecule hanging around the receptor site for days and days, but that the receptor site has been in some way temporarily ALTERED by the psychedelic experience.
What is the precise nature of this alteration? What are the SUBSIDIARY effects of this alteration apart from preventing you from getting high for several days? Damned if I know, but logic tells me there HAS BEEN an alteration. I hypothesize that for the period of time it takes for the tolerance effect to wear off, the synapses are also operating in a slightly different manner than normal in regards to how they react to (or even perhaps generate?) cluster headaches. My evidence for this is the widely-reported phenomenon of clusterheads who could normally set their watch by the timing and severity of their attacks experiencing more frequent and/or more severe attacks than usual in the few days after dosing. It's as if the synapses are in a state of confusion.
To me, it is no accident that the "tolerance" period and the "whacked out cluster timing" period coincide. I think the odds of these two phenomena being linked causally are pretty high.
The upside of this is that when the synapses do settle down in a few days, they settle down into a "pre-cluster headache cycle" mode. Or at least they do if all has gone well. For many people (myself included) it takes just one "shake up" dose for this to occur. For others it can take several doses.
If you are experiencing increased activity on the third day after dosing, my guess would be that the "tolerance" period of your receptors is ending -- that your personal "no way to get high" window is around three or four days. Your receptors are going through their transition from their "stoned" state to their "ready to get stoned once again" state.
[PSM]
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