Serotonin Release Normal Mechanism Of Action Biology Essay

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For a hard core of PTSD cases, no amount of antidepressants or psychotherapy can rid them of the horror of systematic abuse or a bad near-death experience, and the slightest reminder triggers vivid flashbacks.

In 2004 the FDA approved a study on terminal cancer patients to view MDMA use and its potential to lessen patient fears, quell thoughts of suicide and make it easier for them to deal with loved ones. Patients treated with MDMA also experienced major pain relief as well. (4) MDMA however was criminalized in most countries around 1985 due to its becoming recreationally used without and scientific reasons for its usage. (2)

MDMA works by stimulating serotonin release as well as inhibiting serotonin synthesis and blocking serotonin reuptake. This combination of actions both increases synaptic cleft levels of serotonin as well as decreasing its presynaptic stores. (16) (3). Cell bodies of the serotonin pathway are located within the Raphe nucleus in the brainstem. Tryptophan is the amino acid in which serotonin is derived. Tryptophan is brought into the presynaptic neuron via a Na+/tryptophan co transporter. Within the presynaptic neuron tryptophan is converted into serotonin via enzymatic oxidation and decarboxylation. Serotonin enters vesicles via a Serotonin/H+ antiporter known as the vesicular monoamine transporter, or VMAT. Serotonin can also be recycled, re-entering the presynaptic neuron via selective monoamine transporters such as SERT. Serotonin within the neuronal cytoplasm either can be put back into vesicles through VMAT for future release, or can be degraded by MAO into DOPGAL. The signaling cascade for vesicle fusion with the presynaptic neuron is initiated by cell membrane depolarization. As the membrane depolarizes Voltage Gated Ca+2 open, increasing intracellular calcium ion levels. Calcium ions react with the SNARE complex, causing a conformational change, which allows vesicles to bind with the cell membrane and be released into the synaptic cleft.

Serotonin is involved in the regulation of several processes within the brain, including mood, emotions, aggression, sleep, appetite, anxiety, memory, and perceptions. Serotonin release in the front brain regulates cognition, memory, and perceptions. The serotonin neurons in the hippocampus regulate memory. The serotonin neurons in other limbic areas such as the amygdala also regulate mood.(39)

Serotonin Release: Mechanism of Action Under the Influence of MDMA

MDMA enters the Presynaptic neuron through a monoamine transporter (SERT). Once inside, MDMA inhibits VMAT, not allowing Serotonin to enter their respected vesicles. Increased intracellular levels of serotonin facilitate the reversal of serotonin reuptake transporters, thus increasing the amount of serotonin in the synaptic cleft. (5)The excess release of serotonin by MDMA causes the mood elevating effects experienced by MDMA users. MDMA's "loving" effects were hypothesized to be, at least partly, the result of indirect oxytocin secretion via activation of the serotonin system. (8)(9) Oxytocin is a hormone released following events like hugging, orgasm, and childbirth, and thought to facilitate bonding and the establishment of trust. Based on studies in rats, MDMA is believed to cause the release of oxytocin, at least in part, by both directly and indirectly agonizing the serotonin 5-HT1A receptor. A placebo-controlled study in 15 human volunteers found that 100 mg MDMA increased blood levels of oxytocin and the amount of oxytocin increase was correlated with the subjective effects of MDMA. (8)(9)

However, by releasing large amounts of serotonin, MDMA causes the brain to become significantly depleted of this important neurotransmitter. This contributes to the negative behavioral after effects that users often experience for several days after taking MDMA. MDMA also down regulates SERT. With the lack of available serotonin as well as a reduction of the transporter responsible for its uptake, these two factors contribute to the phenomenon known as "Suicide Tuesday". (7) "Suicide Tuesday" is one of the adverse side effects. Since serotonin is necessary for regulating mood, the significant decrease in 5HT leads to deep depression. (10)

Absorption, Metabolism, and Excretion

Ecstasy molecules that have entered the bloodstream from the stomach and small intestines then travel to the liver. In the liver, some of the ecstasy is metabolized to inactive compounds which then enters venous circulation to the heart, enters pulmonary circulation, where its able to reach the brain once the blood is oxygenated and enters systemic circulation. MDMA is able to bypass the blood brain barrier and reach the brain. (12) MDMA is rapidly absorbed and the half-life of MDMA is roughly 7 hours (15). Non-linear pharmacokinetics have been observed due to stereoselective pharmacokinetics of the enantiomers. (16) MDMA is metabolized to MDA which is the only metabolite reported in blood and plasma. S-(+)- MDA accumulates in blood due to stereoselective metabolism of S-(+)-MDMA. MDA is further metabolized to its 3-hydroxy-4-methoxy and 3,4-dihydroxy derivatives (HMA and HHA). Additional MDMA metabolites include 3-hydroxy-4 methoxymethamphetamine (HMMA) and 3,4-dihydroxymethamphetamine (HHMA). These polar hydroxylated metabolites are conjugated prior to their excretion in urine. Thus, there are still high MDMA levels in the body when the experiential effects have mostly ended, indicating that acute tolerance has developed to the actions of MDMA. (15)

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Figure Metabolism of MDMA (17)

The metabolism may be primarily by cytochrome P450 enzymes and COMT. Two overlapping pathways could be postulated. First pathway involves demethylenation followed by catechol-O-methyl-transferase (COMT) catalyzed methylation and/or glucuronidation/sulfatation. (16) The Second Pathway is that of N-dealkylation, deamination and only for MDA, MDMA, MDE oxidation to the corresponding benzoic acid derivatives conjugated with glycine. Cytochrome P450 enzymes CYP2D1/6 or CYP3A2/4 mainly catalyzed Demethylenation. In humans, MDMA could also be demethylenated by CYP1A2. N-demethylation was mainly catalyzed by CYP1A2, N-deethylation by CYP3A2/4.(16) 65% of MDMA is excreted unchanged in the urine. MDMA and metabolites are primarily excreted as conjugates, such as sulfates and glucuronides.(14)

Perception of the World under the influence of MDMA (18)(19)(20)(21)(22)(23)

mental and physical euphoria

sense of general well-being and contentedness

Decreased negative emotions and behaviors such as:





Increased sociability and feelings of communication being easy or simple

Increased urge to communicate with others.

Increased empathy and feelings of closeness or connection with others

Reduced insecurity, defensiveness, and fear of emotional injury

Decreased irritability, aggression, anger, and jealousy

A sense of increased insightfulness and introspection

Colors and sounds are enhanced, mild closed-eye visuals, improved pattern recognition

Enhanced tactile sensations (touching, hugging, and sex for example all feel better)

Short-term experiential effects, which tend to last less than 4 hours, include:

Physical and Mental affects during and After MDMA ingestion

Short Term Effects

During and sometimes weeks after taking MDMA (21)(22)(23)(24)

Psychological difficulties

confusion, depression

sleep problems

drug craving

severe anxiety


psychotic episodes have been reported

Anxiety, even panic attacks


Irritability or aggression

Fatigue or malaise

Agitation or restlessness

Impaired attention, focus, and concentration, as well as drive and motivation

Paradoxal dysphoria through hypersensitivity, see set and setting

Residual feelings of empathy, emotional sensitivity, and a sense of closeness to others

Physical effects (21)(22)(23)(24)(25)(27)

muscle tension

involuntary teeth clenching


blurred vision

rapid eye movement


decreases appetite

chills or sweating

Increases in heart rate and blood pressure,

Recent research findings also link MDMA to long-term damage to those parts of the brain critical to thought and memory. It is thought that the drug causes damage to the neurons that use the chemical serotonin to communicate with other neurons

rash that looks like acne

liver damage

Dizziness, lightheadedness, or vertigo

Gastrointestinal disturbances, such as diarrhea or constipation

Headache or migraine


Aches and pains, from excessive physical activity (e.g., dancing)

Jaw soreness, from trismus or bruxism

Long-term adverse effects and Major Complications

Serotonergic changes

Serotonergic changes have been demonstrated experimentally in the brains of all mammalian species studied, with most studies involving rats. In these studies, the brains of animals that were given high or repeated doses of MDMA show long-term decreases in all measures of serotonergic functioning, including concentrations of serotonin, tryptophan hydroxylase, and binding of the serotonin transporter protein. (28). MDMA administration did induce a delayed adaptive supersensitivity of 5-HT1A autoreceptors in the Dorsal Raphe Nuclei, a deficit in hippocampal cell proliferation and a depressive-like behavior. These 5-HTT-dependent effects, opposite to those of antidepressants, might contribute to MDMA-induced mood disorders.(28)

Major complications

Some studies indicate that repeated recreational users of MDMA have increased rates of depression and anxiety, even after quitting the drug. The long-term effects most frequently reported included the development of tolerance to MDMA (59%), impaired ability to concentrate (38%), depression (37%) (28) In addition to this, some studies have indicated that repeated recreational users of MDMA may have impaired long-term memory and cognitive function.(29) One common stereotype of an avid MDMA user is that of worn down, sensitive teeth as a result of excessive grinding. MDMA users tend to wear mouth guards, pacifiers, or chew on glow sticks to avoid this. (31)(30)

Hyponatremia is a condition in which your blood level of sodium is abnormally low. This is a result of individuals drinking large amounts of water and/or excessive sweating resulting in sodium and water loss. MDMA users at raves tend to dance without rest, facilitating in the likelihood of being hypoatremic. Hyponatremia also affects marathon runners and bodybuilders, who have been known to die from similar causes, as a result of drinking too much water and sweating out too much salt. Syndrome of inappropriate secretion of antidiuretic hormone contributes to MDMA's hypoatrmic nature as well. (32) Hyponatremia is preventable by drinking fluid electrolyte replenishing beverages such as Gatorade. The dilution of the blood can cause swelling of the brain

Hyperthermia is when the core body temperature raises dangerously over normal until major organ shut down at ~ 42°C. MDMA-related hyperthermia may occur as a symptom of serotonin syndrome, which is caused by increased levels of serotonin. Serotonin Syndrome's effects which include rapid heart rate, loss of muscle coordination or twitching muscles, heavy sweating, shivering, high fever, seizures, irregular heartbeat, and unconsciousness all can contribute to MDMA's hyperthermic effect. MDMA appears to decrease heat loss in the body by causing constriction of blood vessels near the skin. (33) In addition, it can increase heat production by muscles and the brain. These effects may be amplified in people who become dehydrated and are therefore unable to cool by sweating. This temporary reduction the body's ability to regulate its core temperature along with exacerbating this by being in a high temperature high physical exertion can lead to renal failure and death. Mild hyperthermia and/or dehydration can occur from dancing too long, and users may recover with administration of fluids and rest in a cooler environment.

Drug interactions and possible treatments for MDMA's effects

Most of MDMA's effects such as dental damage, hypoatermia, and hyperthermia can be controlled and treated with ease with devices such as a mouth guard, Gatorade, and stepping outside for a bit to collect themselves in a cooler environment. Pharmacological means have been studied to address many of MDMA's other effects. Many MDMA users attempt to replenish the hypothesized deficit of serotonin that is thought to follow the use of MDMA by administering 5-HTP, which is available as a dietary supplement, in an attempt to reduce the depressed mood and unpleasant symptoms in the days following MDMA usage (i.e. Suicide Tuesday). (34) 5-HTP is serotonin's precursor, theoretically supplying the user with more of the raw materials to synthesize the neurotransmitter and reducing the amount of serotonin loss. This attempt is made in vain however because MDMA inhibits reduced the levels of tryptophan hydroxylase which is the rate limiting step for serotonin synthesis. (35)

Paroxetine can have marked decreases in both physiological and subjective effects on MDMA with pretreatment. It seems that paroxetine could interact with MDMA at pharmacodynamic (serotonin transporter) and pharmacokinetic (CYP2D6 metabolism) levels. Marked decrease in the effects of MDMA could lead users to take higher doses of MDMA and to produce potential life-threatening toxic effects. (36) Antiretrovirals are also potent inhibitors of hepatic and intestinal cytochrome P450 systems. By inhibiting the pathway in which MDMA is metabolized, you there inhibit its excretion from the system. There are a number of reported potentially dangerous possible interactions between MDMA and other drugs. Several cases have been reported of death in individuals who ingested MDMA while taking Ritonavir (Norvir), which inhibits multiple CYP450 enzymes. Patients infected with HIV-1 who were treated with ritonavir and saquinavir and then experienced a prolonged effect from a small dose of MDMA. (37)

Dantrolene was found to be effective in treating users suffering MDMA induced hyperthermia. Outcomes showed a better survival rate and more rapid temperature control when Dantrolene was concomitantly used, but did not alter the clinical course when peak body temperature exceeded 42°C. (38)


Alex Manuel Gonzalez