LSD and Brain Parts Involved.
LSD has been shown to be selectively concentrated in the visual and limbic areas, as well as the pineal gland in rats and monkeys. LSD is eventually metabolized by the body (mainly the liver) and is excreted by the kidneys.
It holds the majority of the serotonergic neurons. It is part of the ascending reticular activating system" (known to be involved in the regulation of attention, arousal and the sleep-wake cycle). Serotonin inhibits the ascending traffic, maybe to protect the brain from sensory overload. The Raphe Nuclei is also involved in the regulation of pain.
LSD acts as a partial agonist by binding to the 5HT receptors. Since serotonin has an inhibiting action at the 5HT receptors, LSD, being a partial agonist will cause disinhibition to take place.
This is the main location of noradrenergic cell bodies. It is located in the pons. It mediates arousal.
LSD affects the rate of firing of the Locus Coerulus. Since the Locus Coerulus is also part of the ascending reticular activating system, LSD affects such things as our attention and arousal. LSD enhances the reactivity of Locus Coerulus to sensory stimulation. However, it is important to note that the action of LSD is not direct since the application of LSD to the Locus Coerulus will not result into a different rate of firing.
LSD and serotonin are structurally similar. LSD binds mainly with 5HT2 receptors. It is now believed that LSD acts as a partial agonist at the post-synaptic 5Ht receptors, as well as autoreceptors of serotonin. Not only does it decrease the utilization and turnover of serotonin, LSD has also been found to decrease the release and synthesis of serotonin.
LSD, as noted above, decreases the firing of serotonergic neurons in the Raphe nuclei. LSD therefore causes a disinhibition of activity in the limbic system and secondary visual areas in the brain.
LSD and Serotonin.
How do we know that LSD affects humans by interfering with serotonin pathways?
Strassman (1992) based his claim on two case reports.
The first case was a 40-year-old white male. He had a history of extensive use of hallucinogens, especially psilocybin (or Mexican) mushrooms. Although this case is not directly related to LSD, we make inferences from it since the receptors through which LSD act is very similar to those through which psilocybin act. When he started taking allopurinol as a treatment for his gout, he noticed that he needed more mushrooms to elicit a full hallucinogenic effect: where he needed 5 to 7 g of dried mushrooms before, he now needed 15 to 20 g. His peers who also took the mushrooms with him did not notice any change in potency. It seemed that it was only the sensitivity of the subject that had changed.
Allopurinol causes levels of tryptophan (precursor to serotonin) to rise in rat brains. It is therefore possible that more serotonin is thus produced and can therefore compete with LSD for the binding sites on the post-synaptic membrane.
The second case was a 38-year-old white male, again with a history of extensive use of hallucinogens. He started taking fluoxetine as a treatment for his obsessionality and dysthymia. He noticed that his sensitivity to LSD decreased. Doses that used to produce a full effect now produced only a half or a third of the full effect.
Fluoxetine is a potent and selective inhibitor of presynaptic serotonin reuptake, therefore increasing the amount of serotonin in the synaptic cleft. Again, serotonin would compete with LSD for the 5HT receptors, therefore causing a decreased sensitivity to LSD.