Serotonin (5-hydroxytryptamine, ST, 5HT) is a hydroxylated tryptamine, a class of compounds which rose to widespread fame in the psychedelic drug community with the publication of Alexander Shulgin’s work “Tryptamines I Have Known and Loved“. Most of the body’s serotonin (80%+) is produced and contained in the digestive tract, where it regulates intestinal movements. The remainder is synthesized in Raphe cells deep along the midline core of the brainstem, where it is involved in activities such as mood, appetite, sleep, muscle contraction, memory, and learning. Raphe cells start to fire slowly, and their firing also tails off slowly. This reflects a system designed to modulate slower state-dependent activities, rather than a quick response to external stimuli.

Serotonin is present in all bilaterally symmetric animals, and acts to modulate digestive movements and is involved in the perception of resource availability. For very simple animals resources could only mean food, but in more advanced animals such as primates this also includes social status (or lack of it). Serotonin can modulate an animal’s rate of growth, desire to reproduce, and overall mood in relation to the perceived abundance or scarcity of these resources. In roundworms serotonin is released as a signal in response to positive events such as finding a new grazing ground or meeting a suitable mate. Lobsters injected with serotonin begin to display dominant social behavior, regardless of previous social status.

There are at least three major families of serotonin receptors. Many psychedelic drugs, such as psilocybin, act as partial serotonin agonists primarily active at the 5HT2 receptor. But there is some action at additional receptors, including not surprisingly the 5HT3 receptor involved in feelings of nausea. 5HT3 antagonists such as ondansetron are used during chemotherapy and are considered the gold standard in anti-nausea treatment.

In primates, many serotonin terminals end in the fourth layer of the visual cortex, where they can influence visual perception. Additionally, the temporal lobe is rich in serotonin nerve cell endings, meaning serotonin action has a significant influence on the stream of visual interpretations and association arising from external stimuli. Serotonin tends to act generally as an inhibitor in the cortex, where it reduces the excitatory responses evoked by other sensory stimuli. It also tends to preserve the general noise level of firing in the background, reducing the signal to noise ratio in contrast to the action of norepinephrine.

In humans, low serotonin levels are correlated with certain states of depression. This is reinforced by the fact that consumption of the serotonin precursor 5-hydroxytryptophan (5HTP) causes alleviation of depressive symptoms in some patients. The brain normally has a dense concentration of postsynaptic 5HT2 receptors in the prefrontal cortex, the location in the brain thought to play an “executive” role in coordinating sensory response. Patients who have had a major depressive incident tend to have even higher numbers of these receptors, which is thought to be a result of the brain compensating for lower serotonin levels. In the brain stems of depressed subjects, autopsies have also shown reduced serotonin levels.

Increases in serotonin levels tend to have the opposite effect, increasing outward social behaviours. In monkeys, serotonin agonist drugs increase the approaching, grooming, resting, and eating activities typical of the dominant males. They also reduce inward social solitary, vigilant, and avoidance behaviors. This is reflected in humans under the influence of MDMA, an amphetamine derivative which simultaneously releases large amounts of serotonin while blocking its reuptake. Subjects become much more social and talkative, empathy towards others is increased, and anxiety and paranoia disappear. This has made MDMA and related compounds ideal for psychiatric therapy, particularly for couples and those who have experienced intensely traumatic events.

But the “serotonin as happiness” message sold by drug companies pushing antidepressants is not a complete story. A depressed person may have decreased serotonin levels in response to environmental or other factors, and an antidepressant will certainly raise them. But if these stress factors do not change along with the serotonin levels (through changes in behavior or the environment itself), it is unlikely to create lasting positive change. Serotonin appears to act to regulate the extent or intensity of moods, with less influence on the direct attitude of the mood itself. Similar to the use of MDMA in therapy, these drugs should be regarded as a catalyst to move in the correct direction, and not a magic bullet.

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