Psychosis or Gnosis: A Social History of LSD

One MK-ULTRA veteran wept in front of his colleagues at the end of his first trip. ‘I didn’t want to leave it,’ he explained. ‘I felt I would be going back to a place where I wouldn’t be able to hold on to this kind of beauty.’ His colleagues assumed he was having a bad trip and wrote a report stating that the drug had made him psychotic.

— Martin A. Lee and Bruce Shlaine

Glossary

  • Mitochondria - The structure inside the cell in which energy is produced by respiration is called the mitochondria. The vitality of the mitochondria, their capacity for oxidative energy production, is influenced by nutrition and hormones.
  • Thyroid - Thyroid hormone is necessary for respiration on the cellular level, and makes possible all higher biological functions. Without the metabolic efficiency, which is promoted by thyroid hormone, life couldn’t get much beyond the single-cell stage. Without adequate thyroid, we become sluggish, clumsy, cold, anemic, and subject to infections, heart disease, headaches, cancer, and many other diseases, and seem to be prematurely aged, because none of our tissues can function normally.
  • Fermentation - The conversion of glucose to lactic acid, providing some usable energy, but many times less than oxidation provides. Lactic acid, produced by splitting glucose to pyruvic acid followed by its reduction, is associated with calcium uptake and nitric oxide production, depletes energy, contributing to cell death. The presence of oxygen normally restrains fermentation so that glucose is converted to carbon dioxide instead of lactic acid.
  • Oxidative Metabolism (Mitochondrial Respiration) - The ability of cells to consume oxygen and produce useful biological energy.
  • Carbon Dioxide - Carbon dioxide, produced in the cells, releases oxygen into the tissues, relaxes blood vessels, prevents edema, eliminates ammonia, and increases the efficiency of oxidative metabolism.
  • Serotonin - Just friction, or scratching or stretching the intestine is enough to cause it to release serotonin into the bloodstream. Serotonin increases the permeability of the intestine and blood vessels, and so is likely to be a major cause of the absorption of endotoxin (and other harmful material) during intestinal irritation or stress. The biological meaning of serotonin might be very different without endotoxin, but that hasn't been investigated. In the brain, serotonin regulates circulation and mitochondrial function, temperature, respiration and appetite, alertness and learning, secretion of prolactin, growth hormones and stress hormones, and participates in the most complex biochemical webs. The simple availability of oxygen, and the ability to use it, are regulated by carbon dioxide and serotonin, which act in opposite directions. Carbon dioxide inhibits the release of serotonin. Carbon dioxide and serotonin are regulated most importantly by thyroid function.

A couple of weekends ago, I was able to witness a few friends drop acid and wander through the vineyards of Napa Valley. This was entertaining for two reasons, 1) many of my friends are ballet dancers and upon taking the drug began an assault on the senses with aerial acrobatics, and 2) lysergic acid diethylamide (LSD) is a serotonin antagonist (Martin, 1985; Gaddum and Hameed, 1954; Savini, 1956), suggesting that their actions during that time were ostensibly related to their drowned out serotonin levels.

I've written about serotonin a few times, but the subject repeatedly draws me back in with its intricate history that coincides with LSD. While I'm not promoting the illegal use of LSD in this article per se, the drug's history and widespread use is helpful in understanding the genesis of serotonin's bizarre cultural identity as the "happy chemical."

LSD as a Psychotomimetic

In 1938, Dr. Albert Hoffman, a chemist working for Sandoz in Switzerland, synthesized LSD. Five years later, Hoffman accidentally absorbed the substance through his fingers and experienced, "a remarkable but not unpleasant state of intoxication ... characterized by an intense stimulation of the imagination and an altered state of awareness of the world."

The psychological properties of LSD were later discussed in the 1947 issue of Swiss Archives of Neurology, where a colleague of Dr. Hoffman's, Dr. Werner Stoll, reported that LSD produced disturbances in perceptionhallucinations, and accelerated thinking. No unfavorable aftereffects were described.

According to the book, Acid Dreams, by Martin A. Lee and Bruce Shlain, alongside these discoveries was the Central Intelligence Agency's (CIA) quest to develop a speech-inducing drug, or "Truth Drug," for use in intelligence interrogations. General William Donovan, chief of the Office of Strategic Services, insisted that the need for such a weapon was so acute as to warrant any and every attempt to find it.

The CIA experimented with dozens of substances including marijuana, alcohol, cocaine, heroin, PCP, amyl nitrate, mushrooms, DMT, barbiturates, laughing gas, and speed in a multimillion-dollar twenty-five-year quest to conquer the mind. However, out of all these substances, none received as much attention or enthusiasm as LSD.

The CIA embraced LSD as a mind control drug and began testing the substance in doses of 100-150 micrograms in mock interrogation trials. Initial experiments with LSD were incredible, causing participants to unearth secrets while later forgetting the event ever happened. However, further studies revealed that those who were unwittingly subjected to high doses  of LSD experienced "marked anxiety and loss of reality contact" and intense distortion of time, place and body image. 

In 1949 Dr. Paul Hoch, a prominent psychiatrist, proposed that the symptoms produced by LSD, mescaline and related drugs were similar to those of schizophrenia. As Hoch put it, "LSD and Mescaline disorganize the psychic integration of the individual." Hoch dubbed LSD as a "psychotomimetic" or "madness-mimicking" agent causing a sensation in the scientific community leading to dozens of theories regarding the biochemical basis for the drug and experimental psychiatry in general. 

Realizing that LSD was not the "Truth Drug" in the traditional sense, the CIA shifted gears and began looking for new ways to utilize LSD in clandestine warfare. 

Spearheading new wave LSD research was Dr. Sidney Gottlieb, who believed that there were strategic advantages for the use of LSD in covert operations. For instance, by dosing high ranking officials causing them to act foolishly in public. However, not much was known about LSD outside of the laboratory, so an effort was made to begin dosing LSD to CIA trainees in a "normal setting" without any warning or explanation whatsoever. 

These drawings were done by an artist under the influence of LSD as part of a test conducted by the US government in the late 1950's. The artist was given a dose of LSD and free access to an activity box full of crayons and pencils. His subject was the medic.

These drawings were done by an artist under the influence of LSD as part of a test conducted by the US government in the late 1950's. The artist was given a dose of LSD and free access to an activity box full of crayons and pencils. His subject was the medic.

These drawings were done by an artist under the influence of LSD as part of a test conducted by the US government in the late 1950's. The artist was given a dose of LSD and free access to an activity box full of crayons and pencils. His subject was the medic.

Eventually, the CIA's medical Office felt that the test should not be "confined merely to male volunteer trainee personnel, but that it should be broadened to include all components of the Agency." The Project Committee concurred and numerous CIA agents began using LSD, sometimes on repeated occasions. Everyone was fair game, and surprise trips became part of the job. Perhaps by coincidence, after the CIA got heavily involved with LSD they began funding various parapsychology research, including ESP, subliminal perception and other phenomenon associated with altered states.

By the mid-1960s fifteen hundred military personnel had served as guinea pigs in LSD experiments. 

LSD as A Psychedelic

While the CIA viewed LSD as an instrument of psychological torture, the drug was being used therapeutically by a small group of Canadian physicians based in Saskatchewan. One of the researchers, Dr. Osmond, rejected Hoch's view of LSD as a "psychotomimetic" after medicinally using it with alcoholics. His patients described an LSD session as insightful and rewarding, some even calling it an experience of great beauty.

In fact, 'acid therapy' became quite popular in the 1950s for a wide range of problems, including: juvenile delinquencynarcotics addictionsevere character neurosis, and the like. In some cases the therapy was so profound, that the person underwent dramatic personality changes, and a revamping of value systems, religious and philosophical beliefs, and basic lifestyle.

LSD as a therapy seemed in stark contrast to the madness-inducing agent described by the CIA. Such an error may be explained by the limited scope of the scientists evaluating the effects of the drug, perhaps typified by an agent who noted, "tripping and psychosis are one in the same."

Additionally, weeping in front of your colleagues in the 1950s could suggest that you had gone temporarily insane:

One MK-ULTRA veteran wept in front of his colleagues at the end of his first trip. ‘I didn’t want to leave it,’ he explained. ‘I felt I would be going back to a place where I wouldn’t be able to hold on to this kind of beauty.’ His colleagues assumed he was having a bad trip and wrote a report stating that the drug had made him psychotic
— Martin A. Lee and Bruce Shlaine (Acid Dreams)

The language used to describe the effects of LSD disturbed Dr. Osmond. For example, hallucination and psychosis were loaded terms that reflected pathological orientation. He felt that truly objective science would not make value judgments on a substance that produced altered states of consciousness. Aldous Huxley identified with Osmond's dismay and together they termed the word psychedelic.

LSD as A Serotonin Antagonist

While originally thought to act on the brain, research on human subjects showed that a tiny amount (0.1%) of the original dose of LSD entered the brain, and it only remained there for twenty minutes. Some scientists thought LSD might act as a trigger mechanism, releasing or inhibiting a naturally occurring substance.  

In parallel with LSD research was Vittorio Erspamer's identification of an amine in the intestine, that  caused the intestines to contract. Later, an English group extracted an amine that caused blood vessels to contract, and Erspamer demonstrated that the two amines were chemically the same. The amine was named enteramine, and was later referred to as  serotonin (Martin, 1985).

In 1951 pharmacologist John Gaddum was employed to create a sensitive assay for measuring serotonin for further studies. Gaddum tested serotonin with a variety of substances that acted on smooth muscle, and found that LSD blocked the effects of serotonin. Because Sandoz had handed out samples of LSD to scientists in 1947, Gaddum was familiar with LSD's mental effects, and reasoned that the brain might also contain serotonin. A couple of years later he suggested, "that the mental effects of lysergic acid diethylamide [LSD] are due to the interference with the normal action of this HT [5-hydrotrptamine, serotonin]."

...the mental effects of lysergic acid [LSD] diethylamide are due to the interference with the normal action of this HT [5-hydrotrptamine, serotonin].
— Gaddum JH, Amin AH, Crawford BB. The Distribution of Substance P and 5-Hydroxytryptamine in The Central Nervous System of The Dog. J. Physiol. (I954) I26, 596-6I8.

However, the question remained: how could a chemical primarily produced in the stomach temporarily (and sometimes permanently) alter a person's view of the world and suspend their belief system?

In Dr. Peat's article, Serotonin: Effect in disease, aging and inflammation, he mentions that Aldous Huxley was one of the first people to inquire about the biological meaning of drugs like LSD.

In Huxley's classic book, The Doors of Perception, he theorizes that we each have a 'filter' or 'reducing valve' that limits the amount of information we receive through our senses:

According to such a theory, each one of us is potentially Mind at Large. But in so far as we are animals, our business is at all costs to survive. To make biological survival possible, Mind at Large has to be funneled through the reducing valve of the brain and nervous system. What comes out at the other end is a measly trickle of the kind of consciousness which will help us to stay alive on the surface of this Particular planet.
— Aldous Huxley

Huxley suggested that drugs like LSD temporarily remove the filter:

Most people, most of the time, know only what comes through the reducing valve and is consecrated as genuinely real by the local language. Certain persons, however, seem to be born with a kind of by-pass that circumvents the reducing valve. In others temporary bypasses may be acquired either spontaneously, or as the result of deliberate “spiritual exercises,” or through hypnosis, or by means of drugs. Through these permanent or temporary by-passes there flows, not indeed the perception “of everything that is happening everywhere in the universe” (for the by-pass does not abolish the reducing valve, which still excludes the total content of Mind at Large), but something more than, and above and something different from, the carefully selected utilitarian material which our narrowed, individual minds regard as a complete, or at least sufficient, picture of reality
— Aldous Huxley

I think serotonin provides a compelling physiological mechanism for Huxley's 'reducing valve'. For example, in a paper entitled, The serotonergic system and mysticism: could LSD and the nondrug-induced mystical experience share common neural mechanisms?, the author states

By its normal action it [serotonin] modulates awareness of the environmental surroundings and filters a high proportion of this information before it can be processed, thereby only allowing the amount of information that is necessary for survival. LSD works to open this filter, and so an increased amount of somatosensory data is processed with a corresponding increase in what is deemed important.
— Goodman N. The serotonergic system and mysticism: could LSD and the nondrug-induced mystical experience share common neural mechanisms? J Psychoactive Drugs. 2002 Jul-Sep;34(3):263-72.

LSD's modulation of serotonin could explain the dramatic shifts in personality noted by Dr. Osmond and others during 'acid therapy'. While serotonin is ingrained into the cultural zeitgeist as the 'happy chemical', low serotonin is associated with playfulness (Popova and Bertogaeva, 1975), while high levels are associated with aggression and anxiety (Mcmillen, et al., 1987; Ieni, et al., 1985; Malick, et al., 1976). 

Similarly, chronic bowel disorders are associated with the so-called "type D personality" ('D' stands for distressed).  Elevated levels of serotonin are seen in inflammatory gut diseases such as IBS, celiac, and Crohn's (Spiller R, et al., 2007). Serotonin causes inflammation in the intestine (Bischoff S, et al., 2008) and elevated levels of serotonin are a marker for appendicitis (Kalra U, et al., 1997). Unsurprisingly, endotoxin causes the release of serotonin (Davis R, et al., 1961)

In his article, Serotonin, inflammation, depression, mitochondria, energy, and mad Love, Phil points out that the feeling of love is associated with low serotonin levels (Langeslag, 2009). Love can definitely make you do some 'crazy' things, which is the stereotypical archetype of someone on LSD. 

Serotonin and Energetics

From a bioenergetic point of view, serotonin's association with stress, depression, and non-love align with its inhibition of oxidative metabolism (Assouline-Cohen et al. 1998; Koren-Schwartzer N, et al. 1994).

In one study, serotonin  induced swelling in mitochondria (Watanabe et al. 1969), while ATP reversed the swelling, supporting Gilbert Ling’s association-Induction model, suggesting that serotonin and ATP are acting in opposite directions.

Things that interfere with respiration tend to increase the tryptophan hydroxylase enzyme that produces new serotonin. For instance, estrogen (Hiroi, et al. 2006), and the "essential fatty acids" (McNamara R, et al. 2008).

A Logical Diet

Drugs such as ondansetron and cyproheptadine act as serotonin antagonists and have a variety of therapeutic uses. Similarly, serotonin reuptake enhancers are effective for anxiety and depression (Wilde, et al., 1995; Kamoun, et al., 1994).

Those with low thyroid tend to have high levels of serotonin (Henley, et al., 1997, 1998; Neckers and Sze, 1976; Schwark, et al., 1975).  

Active thyroid hormone is needed to produce carbon dioxide (CO2), which allows cells to bind serotonin. High oxygen tensions accelerate serotonin synthesis in vitro, and animals breathing pure oxygen make more serotonin than controls. On the other hand, animals living at high altitudes (i.e., the Haldane effect) do not seem to experience serious difficulties (Martin, 1985). 

Whereas thyroid increases carbon dioxide levels, serotonin, histamine and estrogen activates carbonic anhydrase, an enzyme that breaks down carbon dioxide (Vullo, et al., 2007; Barnett, et al., 2008). Carbonic anhydrase inhibitors have been researched for their various anti-cancer effects (Supuran, et al., 2000; 2000; 2001). 

Moreover, carbon dioxide and serotonin are involved in the biology of torpor and hibernation. Hibernating animals produce less carbon dioxide while serotonin is "crucially involved" in the transition to the hibernation state (Popova, et al. 1993; Popova and Voitenko, 1981). Administering thyroid hormone to hibernating squirrels wakes them up (Selye, 1947). I don't think it's far-fetched to suggest that low thyroid is a hibernation-like state in humans.

Those that find great relief from SSRIs, tryptophan, or 5-HTP might be interested to know that serotonin activates the pituitary's secretion of ACTH (Martin, 1985; Heisler, et al. 2007), which invariably leads to the production of cortisol (Lefebvre H, et al., 1992; Selye, 1952). Constance Martin and Hans Selye have both noted that cortisol, a short-term protective, long-term degenerative "stress" hormone, can produce feelings of euphoria and wellness followed by psychic depression and suicidal tendencies (Selye, 1952; Martin, 1985). 

References

  • Assouline-Cohen M, Ben-Porat H, Beitner R. Activation of membrane skeleton-bound phosphofructokinase in erythrocytes induced by serotonin. Gen Pharmacol. 1994 Oct;25(6):1257-62. "We show here that serotonin, both in vivo and in vitro, induced a marked activation of phosphofructokinase, the rate-limiting enzyme in glycolysis, in the membrane-skeleton fraction from erythrocytes. Concomitantly, the hormone induced a striking increase in lactate content, reflecting stimulation of glycolysis."
  • Barnett DH, Sheng S, Charn TH, Waheed A, Sly WS, Lin CY, Liu ET, Katzenellenbogen BS. Estrogen receptor regulation of carbonic anhydrase XII through a distal enhancer in breast cancer. Cancer Res. 2008 May 1;68(9):3505-15. doi: 10.1158/0008-5472.CAN-07-6151.
  • Bischoff SC, Mailer R, Pabst O, Weier G, Sedlik W, Li Z, Chen JJ, Murphy DL, Gershon MD. Role of serotonin in intestinal inflammation: knockout of serotonin reuptake transporter exacerbates 2,4,6-trinitrobenzene sulfonic acid colitis in mice. Am J Physiol Gastrointest Liver Physiol. 2009 Mar;296(3):G685-95. doi: 10.1152/ajpgi.90685.2008. Epub 2008 Dec 18. "Serotonin (5-HT) regulates peristaltic and secretory reflexes in the gut. The serotonin reuptake transporter (SERT; SLC6A4), which inactivates 5-HT, is expressed in the intestinal mucosa and the enteric nervous system. Stool water content is increased and colonic motility is irregular in mice with a targeted deletion of SERT. We tested the hypotheses that 5-HT plays a role in regulating intestinal inflammation and that the potentiation of serotonergic signaling that results from SERT deletion is proinflammatory. Rectal installation of 2,4,6-trinitrobenzene sulfonic acid (TNBS) was used to induce an immune-mediated colitis, which was compared in SERT knockout mice and littermate controls. Intestinal myeloperoxidase and histamine levels were significantly increased, whereas the survival rate and state of health were significantly decreased in TNBS-treated mice that lacked SERT. Deletion of SERT thus increases the severity of TNBS colitis. These data suggest that 5-HT and its SERT-mediated termination play roles in intestinal immune/inflammatory responses in mice."
  • Davis Rb, Meeker Wr Jr, Bailey Wl. Serotonin release by bacterial endotoxin. Proc Soc Exp Biol Med. 1961 Dec;108:774-6.
  • Gaddum and Hameed. Drugs Which Antagonize 5-Hyddroxytryptamine. Brit. J. Pharmacol. (1954), 9, 240. "Ergot Alkaloids.-Tryptamine forms part of the molecule of lysergic acid, certain derivatives of which are very active antagonists of HT on the rat's uterus and the rabbit's ear." "The drugs which do antagonize HT have given different results when tested on different tissues. LSD is a very active and specific antagonist for HT in experiments on the rat's uterus or the rabbit's ear, but had little effect in experiments on the guinea-pig's ileum even when high concentrations were used."
  • Gaddum JH, Amin AH, Crawford BB. The Distribution of Substance P and 5-Hydroxytryptamine in The Central Nervous System of The Dog. J. Physiol. (I954) I26, 596-6I8. "Attention has already been drawn (Gaddum, 1953 b) to the possibility that there may be some connexion between the two known powerful actions of lysergic acid diethylamide, which seriously affects the brain in a dose of 1 [kg/kg (Stoll, 1947) and antagonizes some of the actions of HT on isolated organs in a concentration of 1 Ktg/l. The evidence for the presence of HT in certain parts of the brain may be used to support the theory that the mental effects of lysergic acid diethylamide are due to interference with the normal action of this HT."
  • Goodman N. The serotonergic system and mysticism: could LSD and the nondrug-induced mystical experience share common neural mechanisms? J Psychoactive Drugs. 2002 Jul-Sep;34(3):263-72. "This article aims to explore, through established scientific research and documented accounts of personal experience, the similarities between religious mystical experiences and some effects of D-lysergic diethylamide or LSD. LSD predominantly works upon the serotonergic (serotonin-using neurons) diffuse neuromodulatory system, which projects its axons to virtually all areas of the brain including the neocortex. By its normal action it modulates awareness of the environmental surroundings and filters a high proportion of this information before it can be processed, thereby only allowing the amount of information that is necessary for survival. LSD works to open this filter, and so an increased amount of somatosensory data is processed with a corresponding increase in what is deemed important. This article describes the effects and actions of LSD, and due to the similarities with the nondrug-induced mystical experience the author proposes that the two could have common modes of action upon the brain. This could lead to avenues of research into mysticism and a wealth of knowledge on consciousness and how we perceive the universe."
  • Greenway SE, Pack AT, Greenway FL. Treatment of depression with cyproheptadine. Pharmacotherapy. 1995 May-Jun;15(3):357-60.
  • Heisler LK, Pronchuk N, Nonogaki K, Zhou L, Raber J, Tung L, Yeo GS, O'Rahilly S, Colmers WF, Elmquist JK, Tecott LH. Serotonin activates the hypothalamic-pituitary-adrenal axis via serotonin 2C receptor stimulation. J Neurosci. 2007 Jun 27;27(26):6956-64. "A possibility receiving little attention is that 5-HT regulates upstream corticotropin-releasing hormone (CRH) signaling systems via activation of serotonin 2C receptors (5-HT(2C)Rs) in the paraventricular nucleus of the hypothalamus (PVH)." "These findings thus provide a mechanistic explanation for the longstanding observation of HPA axis stimulation in response to 5-HT and thereby give insight into the neural circuitry mediating the complex neuroendocrine responses to stress."
  • Henley WN, Koehnle TJ. Thyroid hormones and the treatment of depression: an examination of basic hormonal actions in the mature mammalian brain. Synapse 1997 Sep;27(1):36-44."In spite of a large clinical literature, little is known about the mechanism by which thyroid hormones elevate mood. The lack of mechanistic insight reflects, in large part, a longstanding bias that the mature mammalian central nervous system is not an important target site for thyroid hormones." "This paper offers the hypothesis that the thyroid hormones influence affective state via postreceptor mechanisms that facilitate signal transduction pathways in the adult mammalian brain. This influence is generalizable to widely recognized targets of antidepressant therapies such as noradrenergic and serotonergic neurotransmission." 
  • Henley WN, Vladic F. Hypothyroid-induced changes in autonomic control have a central serotonergic component. Am J Physiol 1997 Feb;272(2 Pt 2):H894-903. "In Exp III, Hypo had larger decrements in mean arterial pressure (-9.0 vs. -5.1%), heart rate ( -13.9 vs. – 7.7%), and body temperature (-4.5 vs. -2.7%) in response to 8-OH-DPAT in comparison to Eu. Parasympathetic involvement in the differential responses to 8-OH-DPAT was less clear than with DOI. Deranged autonomic control in hypothyroidism may be caused, in part, by changes in central serotonergic activity."
  • Hiroi R, McDevitt RA, Neumaier JF. Estrogen selectively increases tryptophan hydroxylase-2 mRNA expression in distinct subregions of rat midbrain raphe nucleus: association between gene expression and anxiety behavior in the open field. Biol Psychiatry. 2006 Aug 1;60(3):288-95. Epub 2006 Feb 3. "estrogen may increase the capacity for serotonin synthesis in discrete subgroups of raphe neurons, and reinforce previous observations that different subregions of DRN contribute to distinct components of anxiety behavior."
  • Ieni JR, Thurmond JB. Maternal aggression in mice: effects of treatments with PCPA, 5-HTP and 5-HT receptor antagonists. Eur J Pharmacol. 1985 May 8;111(2):211-20. "Drug treatments which influence brain serotonergic systems were administered to lactating female mice during the early postpartum period, and their effects on aggressive behavior, locomotor activity and brain monoamines were examined. P-chlorophenylalanine (200 and 400 mg/kg) and 5-hydroxytryptophan (100 mg/kg) inhibited fighting behavior of postpartum mice toward unfamiliar male intruder mice. These drug-treated postpartum females showed increased latencies to attack male intruders and also reduced frequencies of attack. In addition, postpartum mice treated with the serotonin receptor antagonists, mianserin (2 and 4 mg/kg), methysergide (4 mg/kg) and methiothepin (0.25 and 0.5 mg/kg), displayed significantly less aggressive behavior than control mice, as measured by reduced number of attacks. Whole brain monoamine and monoamine metabolite levels were measured after drug treatments. The behavioral results are discussed in terms of drug-induced changes in brain chemistry and indicate a possible role for serotonin in the mediation of maternal aggressive behavior of mice."
  • Kalra U, Chitkara N, Dadoo RC, Singh GP, Gulati P, Narula S. Evaluation of plasma serotonin concentration in acute appendicitis. Indian J Gastroenterol. 1997 Jan;16(1):18-9. "The levels in patients with acute appendicitis were significantly higher (p < 0.001) than in the other groups, giving 93.8% sensitivity and 95.7% specificity to the test. CONCLUSION:Plasma serotonin level is a reliable marker of acute appendicitis, especially in the first 48 hours."
  • Kamoun A, Delalleau B, Ozun M. [Can a serotonin uptake agonist be an authentic antidepressant? Results of a multicenter, multinational therapeutic trial]. Encephale 1994 Sep-Oct;20(5):521-5. "The classical biochemical hypothesis of depression posits a functional deficit in central neurotransmitter systems particularly serotonin (5-HT) and noradrenaline. The major role suggested for 5-HT in this theory led to the development of a large number of compounds which selectively inhibit 5-HT uptake. Numerous clinical trials have demonstrated the antidepressant efficacy of such types of serotoninergic agents, supporting 5-HT deficit as the main origin of depression. Therefore, everything seemed clear: depression was caused by 5-HT deficit. Tianeptine is clearly active in classical animal models predictive of antidepressant activity, and is also active in behavioral screening tests: it antagonizes isolation induced aggression in mice and behavioral despair in rats. Biochemical studies have revealed that in contrast to classical tricyclic antidepressant, tianeptine stimulates 5-HT uptake in vivo in the rat brain. This somewhat surprising property was observed in the cortex and the hippocampus following both acute and chronic administrations. This increase in 5-HT uptake has also been confirmed in rat platelets after acute and chronic administrations. Moreover, in humans, a study in depressed patients demonstrated that tianeptine significantly increased platelet 5-HT uptake after a single administration as well as after 10 and 28 days of treatment."
  • Koren-Schwartzer N, Chen-Zion M, Ben-Porat H, Beitner R. Serotonin-induced decrease in brain ATP, stimulation of brain anaerobic glycolysis and elevation of plasma hemoglobin; the protective action of calmodulin antagonists. Gen Pharmacol. 1994 Oct;25(6):1257-62. "1. Injection of serotonin (5-hydroxytryptamine) to rats, induced a dramatic fall in brain ATP level, accompanied by an increase in P(i). Concomitant to these changes, the activity of cytosolic phosphofructokinase, the rate-limiting enzyme of glycolysis, was significantly enhanced. Stimulation of anaerobic glycolysis was also reflected by a marked increase in lactate content in brain."
  • Langeslag, S. J. E. (in press). Is the serotonergic system altered in romantic love? A literature 
  • Lefebvre H, Contesse V, Delarue C, Feuilloley M, Hery F, Grise P, Raynaud G, Verhofstad AA, Wolf LM, Vaudry H. Serotonin-induced stimulation of cortisol secretion from human adrenocortical tissue is mediated through activation of a serotonin4 receptor subtype. Neuroscience. 1992;47(4):999-1007.
  • Malick JB, Barnett A. The role of serotonergic pathways in isolation-induced aggression in mice. Pharmacol Biochem Behav. 1976 Jul;5(1):55-61. "Male mice that became aggressive following four weeks of social isolation were treated with seven known serotonin receptor antagonists. All of the antiserotonergic drugs selectively antagonized the fighting behavior of the isolated mice; the antiaggressive activity was selective since, at antifighting doses, none of the drugs either significantly altered spontaneous motor activity or impaired inclined-screen performance. Antagonism of 5-HTP-induced head-twitch was used as an in vivo measure of antiserotonergic activity and a statistically significant correlation existed between potency as an antiserotonergic and potency as an antiaggressive. PCPA, a serotonin depletor, also significantly antagonized isolation-induced aggression for at least 24 hr postdrug administration."
  • Martin C. Endocrine Physiology. 1985 "High oxygen tensions accelerate serotonin synthesis in vitro, and animals breathing pure oxygen make larger amounts than controls. On the other hand, animals living at high altitudes do not seem to experience serious difficulties."
  • Martin C. Endocrine Physiology. 1985 "Serotonin is now known to be identical with a regulator initially called enteramine that is released from the cells. It stimulates the contraction of intestinal smooth muscle and increases the tone."
  • Martin C. Endocrine Physiology. 1985. "An alternative suggestion is that the peripheral receptors can be divided into "musculotropic" and "neurotropic" types. LSD, methysergide, and BOL are among the most effective blockers of the smooth muscle effects."
  • Martin C. Endocrine Physiology. 1985. "Cyporpheptadine strongly antagonizes 5-HT stimulation of smooth muscle, but it is a potent histamine blocker as well.
  • Martin C. Endocrine Physiology. 1985. "Glucocorticoids exert early influences on the brain that tend to elevate mood and increase the sense of “well-being”. Larger amounts can bring on temporary euphoria. However, the secondary effects include psychic depression. Patients with chronically elevated levels tend to have mood swings. They have been known to display bizarre behavior and to suffer hallucinations.”
  • Martin C. Endocrine Physiology. 1985. "The amine [serotonin] plays important roles in the regulation of pituitary hormone secretion. It is implicated in promoting prolactin release in response to suckling stimulus, and it affects the secretions of growth hormone, ACTH, TSH, and the gonadotropins." "Serotonin acts centrally to affect renin release, and it promotes ACTH secretion." "Approximately 98% of total serotonin is found outside of the central nervous system. The blood platelets and gastrointestinal tract account for around 95% and serotonin is a component of both central and peripheral mast cells."
  • McMillen BA, Scott SM, Williams HL, Sanghera MK. Effects of gepirone, an aryl-piperazine anxiolytic drug, on aggressive behavior and brain monoaminergic neurotransmission. Naunyn Schmiedebergs Arch Pharmacol. 1987 Apr;335(4):454-64. "In support of this conclusion was the observed potentiation of antiaggressive effects by blocking 5HT receptors wit small doses of methiothepin or methysergide, which would exacerbate the decreased release of 5HT caused by gepirone. These results are in harmony with reports that decreased serotonergic activity has anxiolytic-like effects in animal models of anxiety."
  • McNamara RK, Able J, Liu Y, Jandacek R, Rider T, Tso P, Lipton JW. Omega-3 fatty acid deficiency during perinatal development increases serotonin turnover in the prefrontal cortex and decreases midbrain tryptophan hydroxylase-2 expression in adult female rats: dissociation from estrogenic effects. J Psychiatr Res. 2009 Mar;43(6):656-63. Epub 2008 Nov 4. "Only perinatal DHA-deficient rats exhibited a significant reduction in midbrain TPH-2 mRNA expression (-29%, p=0.03). These preclinical data support a causal link between perinatal omega-3 fatty acid deficiency and reduced central serotonin synthesis in adult female rats that is independent of ovarian hormones including estrogen."
  • Neckers L, Sze. Regulation of 5-hydroxytryptamine metabolism in mouse brain by adrenal glucocorticoids. Brain Res 1975 Jul 25;93(1):123-32. "A single injection of hydrocortisone acetate (HCA; 20 mg/kg, i.p.) accelerated the accumulation of 5-HT in whole brain after inhibition of monoamine oxidase activity by paragyline. The hormone did not appear to change brain tryptophan hydroxylase or 5-hydroxytryptophan decarboxylase activity. However, tryptophan levels in brain were elevated by 50% within 1 h after treatment with HCA." "These results demonstrate that glucocorticoids may directly act on nerve terminals in the regulation of 5-HT synthesis through an action on the uptake of tryptophan."
  • Popova NK, Bertogaeva VD. [Participation of the serotonin-reactive brain structure in certain forms of behavior in golden hamsters]. Farmakol Toksikol. 1975 Mar-Apr;38(2):148-51. "A viviacious play of young hamsters is shown to be accompanied by a drop of the serotonin level in the brain stem and the subsequent slumber - by its rise, while the corticosteroids content of the peripheral blood with the playful behavior experiences no changes. Iprazid and 5-oxytryptophan inhibit the playful activity, while dioxyphenylalanina (DOPA) does not influence it. A similar depression of the serotonin level in the brain stem was also noted in an aggressive behavior and stress conditions arising when adult male-hamsters are grouped together. A conclusion is drawn to the effect that changes in the content of serotonin in the brain stem are not associated with the emotional colouration of the condition, but rather reflect the transition from the somnolence to a highly active behavior."
  • Popova NK, Voitenko NN. Brain serotonin metabolism in hibernation. Pharmacol Biochem Behav. 1981 Jun;14(6):773-7. "...marked changes were revealed in 5-HT and 5-HIAA brain level in entering hibernation (body temperature 11-9 degrees C) and arousing (body temperature 22 degrees C) animals. In entry into hibernation an increase in brain 5-HT, decrease in 5-HIAA level and lowered MAO activity was found. In arousal from hibernation 5-HT was decreased, 5-HIAA was increased and MAO activity was found to be increased to the level of the active ground squirrels."
  • Popova NK, Voronova IP, Kulikov AV. Involvement of brain tryptophan hydroxylase in the mechanism of hibernation. Pharmacol Biochem Behav. 1993 Sep;46(1):9-13. "The results support the idea that brain serotonin is crucially involved in the transition to and the maintenance of the hibernation state."
  • receptor gene has been associated with the love trait ‘mania’, which is a possessive and dependent form of love. Given that serotonin 2 receptors in the prefrontal cortex have also been implicated in impulsive aggression, this suggests that stalking behavior may be 
  • review and research suggestions. In E. Cuyler & M. Ackhart (Eds.). Psychology of Relationships. Hauppauge: Nova Science Publishers. "Infatuated individuals think about their beloved a lot. The notions that these frequent thoughts resemble the obsessions of obsessive-compulsive disorder (OCD) patients and that those patients benefit from serotonin reuptake inhibitors (SSRIs), have led to the hypothesis that romantic love is associated with reduced central serotonin levels. In this chapter, the literature on this topic is reviewed and suggestions for future research are made. Previous studies have shown that romantic love is associated with lower blood serotonin levels and with lower serotonin transporter densities, the latter of which has also been observed in OCD patients. Further, SSRIs have been found to decrease feelings of romantic love and the serotonin 2 
  • romantic love indeed. Future research is needed to identify what parts of the serotonergic system, such as which serotonergic projections, brain areas, transmission stages and receptor types, are affected in romantic love and in what way they are altered. Furthermore, challenging the serotonergic system would be useful in determining the causal relationship between central serotonin levels and feelings of romantic love. In addition, future research should specifically investigate the different aspects of romantic love, such as state, trait, requited and unrequited love and its development in time."
  • Savini EC. The Antagonism Between 5-Hydroxytryptamine and Certain Derivatives of Lysergic Acid. Brit. J. Pharmacol. (1956), 11, 313. "The observation that LSD is a powerful antagonist of 5-HT (Gaddum and Hameed, 1954) has been confirmed. Perfusion of a concentration of 1 Mug./1. had a marked effect, increasing for about 2 hr. When low concentrations of LSD are perfused for a short time the response to 5-HT may return after washing (Gaddum and Hameed, 1954). When higher concentrations (20-100 Mg./1.) were perfused for longer times, LSD caused an irreversible effect which was not abolished even by washing for 3 hr."
  • Schwark WS, Keesey RR. Thyroid hormone control of serotonin in developing rat brain. Res Commun Chem Pathol Pharmacol. 1975 Jan;10(1):37-50. "The influence of thyroid hormone on serotonin was studied in different regions of the rat brain. Surgical thyroidectomy of adult male rats led to significant increases in the level of serotonin in the hypothalamus..." "Experimental cretinism, induced by daily propylthiouracil treatment starting at birth, caused increased serotonin levels in all brain regions studied." "The data suggest that thyroid hormone may exert an important regulatory influence on serotonin metabolism in the developing brain."
  • Selye H. Textbook of Endocrinology. 1947. "Hibernation ["winter-sleep"] is a coma-like condition which develops in certain animals, during the winter season, under the influence of cold and the lack of food. Many invertebrates, amphibia, reptiles and some (exceptional) fish, spend the winter in a condition of immobility, during which their metabolism falls to very low levels. It is only in this manner that they can resist the hardships of the cold season." "Thyroidectomy delays while thyroid hormone treatment accelerates the awakening of hibernating animals. This effect of the hormone is probably due tot he stimulation of the metabolism." "All other vital processes [during hibernation] decrease considerably, thus the body temperature may fall in the urchin to +15C and in certain bats even below 0C. In the urchin and respiration rate, which is normal about 50/min., falls to as bout 1/min., while the pulse rate decreases from the normal of 300/min. to 2-3/min." 
  • Selye H. The Story of Adaptation Syndrome. 1952 "Everyone knows today that stressors act upon the adrenal cortex through the discharge of the adrenocorticotrophic hormone (ACTH). This is certainly one of the most conclusively established and most generally accepted links in the chains of events which occur during stress. Indeed, this fact now appears to be so evident that any discussion of it may impress you as superfluous."
  • Selye H. The Story of Adaptation Syndrome. 1952. “Adaptive hormones can cause mental changes in man. Many patients who take ACTH or COL first develop a sense of extraordinary wellbeing and buoyancy, with excitement and insomnia; this is sometimes followed by a depression which may go so far as to create suicidal tendencies.”
  • Spiller R. Serotonin, inflammation, and IBS: fitting the jigsaw together? J Pediatr Gastroenterol Nutr. 2007 Dec;45 Suppl 2:S115-9. doi: 10.1097/MPG.0b013e31812e66da. "...Clinical conditions with an inflammatory basis, such as coeliac and Crohn disease, also are characterised by excess postprandial serotonin release. Several studies report evidence of low-grade inflammation in IBS with diarrhoea. However, reliable markers of low-grade inflammation that may predict response to serotonin antagonists or other anti-inflammatory agents remain a goal for future research."
  • Supuran CT, Briganti F, Tilli S, Chegwidden WR, Scozzafava A. Carbonic anhydrase inhibitors: sulfonamides as antitumor agents? Bioorg Med Chem. 2001 Mar;9(3):703-14. "Three of the derivatives belonging to this new class of CA inhibitors were also tested as inhibitors of tumor cell growth in vitro. These sulfonamides showed potent inhibition of growth against several leukemia, non-small cell lung, ovarian, melanoma, colon, CNS, renal, prostate and breast cancer cell lines."
  • Supuran CT, Scozzafava A. Carbonic anhydrase inhibitors: aromatic sulfonamides and disulfonamides act as efficient tumor growth inhibitors. J Enzyme Inhib. 2000;15(6):597-610. "Aromatic/heterocyclic sulfonamides generally act as strong inhibitors of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1). Here we report the unexpected finding that potent aromatic sulfonamide inhibitors of CA, possessing inhibition constants in the range of 10(-8)-10(-9) M (against all the isozymes), also act as efficient in vitro tumor cell growth inhibitors, with GI50 (molarity of inhibitor producing a 50% inhibition of tumor cell growth) values of 10 nM-35 microM against several leukemia, non-small cell lung cancer, ovarian, melanoma, colon, CNS, renal, prostate and breast cancer cell lines."
  • Supuran CT, Scozzafava A. Carbonic anhydrase inhibitors–Part 94. 1,3,4-thiadiazole-2-sulfonamidederivatives as antitumor agents? Eur J Med Chem. 2000 Sep;35(9):867-74. "Potent sulfonamide inhibitors of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), derivatives of I ,3,4-thiadiazole-2-sulfonamide, possessing inhibition constants in the range of 10(-8)-10(-9) M against isozymes II and IV, were shown to act as efficient in vitro tumour cell growth inhibitors with GI(50) (molarity of inhibitor producing a 50% inhibition of tumour cell growth) values typically in the range of 0.1-30 microM against several leukaemia, non-small cell lung cancer, ovarian, melanoma, colon, CNS, renal, prostate and breast cancer cell lines." "Such derivatives might lead to the development of effective novel types of anticancer agents/therapies."
  • Vullo D, Innocenti A, Nishimori I, Scozzafava A, Kaila K, Supuran CT. Carbonic anhydrase activators: activation of the human isoforms VII (cytosolic) and XIV (transmembrane) with amino acids and amines. Bioorg Med Chem Lett. 2007 Aug 1;17(15):4107-12. Epub 2007 May 21. "An activation study of the human carbonic anhydrase (hCA, EC 4.2.1.1) isozymes VII and XIV using a small library of natural/non-natural amino acids and aromatic/heterocyclic amines is reported. hCA VII was efficiently activated by L-/D-His, dopamine and serotonin (K(A)s of 0.71-0.93 microM). The best hCA XIV activators were histamine (K(A) of 10 nM), L-Phe, L-/D-His and 4-amino-L-Phe (K(A)s of 0.24-2.90 microM). In view of the significant expression levels of CA VII and CA XIV in the brain, selective activation of these isoforms may be useful when developing pharmacologic agents for the management of major disorders such as epilepsy and Alzheimer's disease."
  • Watanabe Y, Shibata S, Kobayashi B. Serotonin-induced swelling of rat liver mitochondria. Endocrinol Jpn. 1969 Feb;16(1):133-47.
  • Wilde MI, Benfield P. Tianeptine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depression and coexisting anxiety and depression. Drugs. 1995 Mar;49(3):411-39. "Tianeptine is a novel antidepressant agent, both structurally (modified tricyclic) and in terms of its pharmacodynamic profile. Unlike other antidepressant agents, tianeptine stimulates the uptake of serotonin (5-hydroxytryptamine; 5-HT) in rat brain synaptosomes and rat and human platelets, increases 5-hydroxyindoleacetic acid (5-HIAA) levels in cerebral tissue and plasma, and reduces serotonergic-induced behaviour. Tianeptine reduces the hypothalamic-pituitary-adrenal response to stress, antagonises stress-induced behavioural deficits and prevents changes in cerebral morphology. The antidepressant efficacy of tianeptine, as shown in 2 trials of patients with major depression or depressed bipolar disorder with or without melancholia, is greater than that of placebo. In patients with major depression without melancholia or psychotic features, depressed bipolar disorder or dysthymic disorder, the antidepressant efficacy of short term (4 weeks to 3 months) tianeptine therapy appears to be similar to that of amitriptyline, imipramine and fluoxetine and may be superior to that of maprotiline in patients with coexisting depression and anxiety." "Progressive therapeutic improvements have been observed with up to 1 year of tianeptine treatment, and long term therapy may reduce the rate of relapse or recurrence. Tianeptine is effective in the treatment of depression in elderly and post-alcohol-withdrawal patient subgroups. Tianeptine was more effective in reducing psychic anxiety than placebo in patients with major depression or depressed bipolar disorder with or without melancholia." " Tianeptine is well tolerated in the short (3 months) and long (up to 1 year) term. The incidence of dry mouth (38 vs 20%), constipation (19 vs 15%), dizziness/syncope (23 vs 13%), drowsiness (17 vs 10%) and postural hypotension (8 vs 3%) are greater with amitriptyline than with tianeptine. Insomnia and nightmares occur in more tianeptine than amitriptyline recipients (20 vs 7%). The relative lack of sedative, anticholinergic and cardiovascular adverse effects with tianeptine makes it particularly suitable for use in the elderly and in patients following alcohol withdrawal; these patients are known to have increased sensitivity to the adverse effects associated with psychotropic drugs."