What is Bretazenil?


Bretazenil (Ro16-6028) is an imidazopyrrolobenzodiazepine anxiolytic drug which is derived from the benzodiazepine family, and was invented in 1988.

It is most closely related in structure to the GABA antagonist flumazenil, although its effects are somewhat different. It is classified as a high-potency benzodiazepine due to its high affinity binding to benzodiazepine binding sites where it acts as a partial agonist. Its profile as a partial agonist and preclinical trial data suggests that it may have a reduced adverse effect profile. In particular bretazenil has been proposed to cause a less strong development of tolerance and withdrawal syndrome. Bretazenil differs from traditional 1,4-benzodiazepines by being a partial agonist and because it binds to α1, α2, α3, α4, α5 and α6 subunit containing GABAA receptor benzodiazepine receptor complexes. 1,4-benzodiazepines bind only to α1, α2, α3 and α5 GABAA benzodiazepine receptor complexes.

Brief History

Bretazenil was originally developed as an anti-anxiety drug and has been studied for its use as an anticonvulsant but has never commercialised. It is a partial agonist for GABAA receptors in the brain. David Nutt from the University of Bristol has suggested bretazenil as a possible base from which to make a better social drug, as it displays several of the positive effects of alcohol intoxication such as relaxation and sociability, but without the bad effects such as aggression, amnesia, nausea, loss of coordination, liver disease and brain damage. The effects of bretazenil can also be quickly reversed by the action of flumazenil, which is used as an antidote to benzodiazepine overdose, in contrast to alcohol for which there is no effective and reliable antidote.

Traditional benzodiazepines are associated with side effects such as drowsiness, physical dependence and abuse potential. It was hoped that bretazenil and other partial agonists would be an improvement on traditional benzodiazepines which are full agonists due to preclinical evidence that their side effect profile was less than that of full agonist benzodiazepines. For a variety of reasons however, bretazenil and other partial agonists such as pazinaclone and abecarnil were not clinically successful. However, research continues into other compounds with partial agonist and compounds which are selective for certain GABAA benzodiazepine receptor subtypes.

Tolerance and Dependence

In a study in rats, cross-tolerance between the benzodiazepine drug chlordiazepoxide and bretazenil has been demonstrated. In a primate study bretazenil was found to be able to replace the full agonist diazepam in diazepam dependent primates without precipitating withdrawal effects, demonstrating cross tolerance between bretazenil and benzodiazepine agonists, whereas other partial agonists precipitated a withdrawal syndrome. The differences are likely due to differences in intrinsic properties between different benzodiazepine partial agonists. Cross-tolerance has also been shown between bretazenil and full agonist benzodiazepines in rats. In rats tolerance is slower to develop to the anticonvulsant effects compared to the benzodiazepine site full agonist diazepam. However, tolerance developed to the anticonvulsant effects of bretazenil partial agonist more quickly than they developed to imidazenil.


Bretazenil has a more broad spectrum of action than traditional benzodiazepines as it has been shown to have low affinity binding to α4 and α6 GABAA receptors in addition to acting on α1, α2, α3 and α5 subunits which traditional benzodiazepine drugs work on. The partial agonist imidazenil does not, however, act at these subunits. 0.5mg of bretazenil is approximately equivalent in its psychomotor-impairing effect to 10 mg of diazepam. Bretazenil produces marked sedative-hypnotic effects when taken alone and when combined with alcohol. This human study also indicates that bretazenil is possibly more sedative than diazepam. The reason is unknown, but the study suggests the possibility that a full-agonist metabolite may be generated in humans but not animals previously tested or else that there are significant differences in benzodiazepine receptor population in animals and humans.

In a study of monkeys bretazenil has been found to antagonize the effects of full agonist benzodiazepines. However, bretazenil has been found to enhance the effects of neurosteroids acting on the neurosteroid binding site of the GABAA receptor. Another study found that bretazenil acted as an antagonist provoking withdrawal symptoms in monkeys who were physically dependent on the full agonist benzodiazepine triazolam.

Partial agonists of benzodiazepine receptors have been proposed as a possible alternative to full agonists of the benzodiazepine site to overcome the problems of tolerance, dependence and withdrawal which limits the role of benzodiazepines in the treatment of anxiety, insomnia and epilepsy. Such adverse effects appear to be less problematic with bretazenil than full agonists. Bretazenil has also been found to have less abuse potential than benzodiazepine full agonists such as diazepam and alprazolam, however long-term use of bretazenil would still be expected to result in dependence and addiction.

Bretazenil alters the sleep EEG profile and causes a reduction in cortisol secretion and increases significantly the release of prolactin. Bretazenil has effective hypnotic properties but impairs cognitive ability in humans. Bretazenil causes a reduction in the number of movements between sleep stages and delays movement into REM sleep. At a dosage of 0.5 mg of bretazenil REM sleep is decreased and stage 2 sleep is lengthened.

What is Barbiturate Overdose?


Barbiturate overdose is poisoning due to excessive doses of barbiturates.

Refer to Barbiturate Dependence.


Symptoms typically include difficulty thinking, poor coordination, decreased level of consciousness, and a decreased effort to breathe (respiratory depression). Complications of overdose can include noncardiogenic pulmonary oedema. If death occurs this is typically due to a lack of breathing.

Barbiturate overdose may occur by accident or purposefully in an attempt to cause death. The toxic effects are additive to those of alcohol and benzodiazepines. The lethal dose varies with a person’s tolerance and how the drug is taken. The effects of barbiturates occur via the GABA neurotransmitter. Exposure may be verified by testing the urine or blood.

Treatment involves supporting a person’s breathing and blood pressure. While there is no antidote, activated charcoal may be useful. Multiple doses of charcoal may be required. Haemodialysis may occasionally be considered. Urine alkalinisation has not been found to be useful. While once a common cause of overdose, barbiturates are now a rare cause.

Mechanism of Action

Barbiturates increase the time that the chloride pore of the GABAA receptor is opened, thereby increasing the efficacy of GABA. In contrast, benzodiazepines increase the frequency with which the chloride pore is opened, thereby increasing GABA’s potency.


Treatment involves supporting a person’s breathing and blood pressure. While there is no antidote, activated charcoal may be useful. Multiple doses of charcoal may be required. Haemodialysis may occasionally be considered. Urine alkalinisation has not been found to be useful.

If a person is drowsy but awake and can swallow and breathe without difficulty, the treatment can be as simple as monitoring the person closely. If the person is not breathing, it may involve mechanical ventilation until the drug has worn off. Psychiatric consult is generally recommended.

Notable Cases

People who are known to have committed suicide by barbiturate overdose include, Gillian Bennett, Charles Boyer, Ruan Lingyu, Dalida, Jeannine “The Singing Nun” Deckers, Felix Hausdorff, Abbie Hoffman, Phyllis Hyman, C. P. Ramanujam, George Sanders, Jean Seberg, Lupe Vélez and the members of Heaven’s Gate cult. Others who have died as a result of barbiturate overdose include Pier Angeli, Brian Epstein, Judy Garland, Jimi Hendrix, Marilyn Monroe, Inger Stevens, Dinah Washington, Ellen Wilkinson, and Alan Wilson; in some cases these have been speculated to be suicides as well. Those who died of a combination of barbiturates and other drugs include Rainer Werner Fassbinder, Dorothy Kilgallen, Malcolm Lowry, Edie Sedgwick and Kenneth Williams. Dorothy Dandridge died of either an overdose or an unrelated embolism. Ingeborg Bachmann may have died of the consequences of barbiturate withdrawal (she was hospitalised with burns, the doctors treating her not being aware of her barbiturate addiction). Maurice Chevalier unsuccessfully attempted suicide in March 1971 by swallowing a large amount of barbiturates and slitting his wrists; however, he suffered severe organ damage as a result and died from multiple organ failure nine months later.

Differential Diagnosis

The differential diagnosis should include intoxication by other substances with sedative effects, such as benzodiazepines, anticonvulsants (carbamazepine), alcohols (ethanol, ethylene glycol, methanol), opioids, carbon monoxide, sleep aids, and gamma-Hydroxybutyric acid (GHB – a known date rape drug). Natural disease that can result in disorientation may be in the differential, including hypoglycaemia and myxoedema coma. In the right setting, hypothermia should be ruled out.

What is Barbiturate Dependence?


Barbiturate dependence develops with regular use of barbiturates. This in turn may lead to a need for increasing doses of the drug to get the original desired pharmacological or therapeutic effect.

Refer to Barbiturate Overdose.


Barbiturate use can lead to both addiction and physical dependence, and as such they have a high potential for excess or non-medical use, however, it does not affect all users. Management of barbiturate dependence involves considering the affected person’s age, comorbidity and the pharmacological pathways of barbiturates.

Psychological addiction to barbiturates can develop quickly. The patients will then have a strong desire to take any barbiturate-like drug. The chronic use of barbiturates leads to moderate degradation of the personality with narrowing of interests, passivity and loss of volition. The somatic signs include hypomimia, problems articulating, weakening of reflexes, and ataxia.

The GABAA receptor, one of barbiturates’ main sites of action, is thought to play a pivotal role in the development of tolerance to and dependence on barbiturates, as well as the euphoric “high” that results from their use. The mechanism by which barbiturate tolerance develops is believed to be different from that of ethanol or benzodiazepines, even though these drugs have been shown to exhibit cross-tolerance with each other and poly drug administration of barbiturates and alcohol used to be common.

The management of a physical dependence on barbiturates is stabilisation on the long-acting barbiturate phenobarbital followed by a gradual titration down of dose. People who use barbiturates tend to prefer rapid-acting barbiturates (amobarbital, pentobarbital, secobarbital) rather than long-acting barbiturates (barbital, phenobarbital). The slowly eliminated phenobarbital lessens the severity of the withdrawal syndrome and reduces the chances of serious barbiturate withdrawal effects such as seizures. A cold turkey withdrawal can in some cases lead to death. Antipsychotics are not recommended for barbiturate withdrawal (or other CNS depressant withdrawal states) especially clozapine, olanzapine or low potency phenothiazines e.g. chlorpromazine as they lower the seizure threshold and can worsen withdrawal effects; if used extreme caution is required. The withdrawal symptoms after ending barbiturate consumption are quite severe and last from 4 to 7 days.

What is Ramelteon?


Ramelteon, sold under the brand name Rozerem among others, is a sleep agent medication that selectively binds to the MT1 and MT2 receptors in the suprachiasmatic nucleus (SCN), instead of binding to GABAA receptors, such as with drugs like zolpidem.

It appears to speed the onset of sleep and alter the total amount of sleep a person gets. It is approved by the US Food and Drug Administration (FDA) for long-term use.

Ramelteon does not show any appreciable binding to GABAA receptors, which are associated with anxiolytic, myorelaxant, and amnesic effects.

Brief History

Ramelteon was approved for use in the United States in July 2005.

Medical Uses

Ramelteon is approved in the United States for the treatment of insomnia characterised by difficulty with sleep onset.

A systematic review, published in 2014, concluded “ramelteon was found to be beneficial in preventing delirium in medically ill individuals when compared to placebo.”

Mechanism of Action

Ramelteon is a melatonin receptor agonist with both high affinity for melatonin MT1 and MT2 receptors and selectivity over the MT3 receptor. Ramelteon demonstrates full agonist activity in vitro in cells expressing human MT1 or MT2 receptors, and high selectivity for human MT1 and MT2 receptors compared to the MT3 receptor.

The activity of ramelteon at the MT1 and MT2 receptors is believed to contribute to its sleep-promoting properties, as these receptors, acted upon by endogenous melatonin, are thought to be involved in the maintenance of the circadian rhythm underlying the normal sleep-wake cycle. Ramelteon has no appreciable affinity for the GABA receptor complex or for receptors that bind neuropeptides, cytokines, serotonin, dopamine, noradrenaline, acetylcholine, and opioids. Ramelteon also does not interfere with the activity of a number of selected enzymes in a standard panel.

The major metabolite of ramelteon, M-II, is active and has approximately one tenth and one fifth the binding affinity of the parent molecule for the human MT1 and MT2 receptors, respectively, and is 17-25-fold less potent than ramelteon in in vitro functional assays. Although the potency of M-II at MT1 and MT2 receptors is lower than the parent drug, M-II circulates at higher concentrations than the parent producing 20-100-fold greater mean systemic exposure when compared to ramelteon. M-II has weak affinity for the serotonin 5-HT2B receptor, but no appreciable affinity for other receptors or enzymes. Similar to ramelteon, M-II does not interfere with the activity of a number of endogenous enzymes.

Adverse Effects

Ramelteon has not been shown to produce dependence and has shown no potential for abuse, and the withdrawal and rebound insomnia that is typical with GABA modulators is not present in ramelteon.

Six percent of ramelteon-treated patients in clinical trials discontinued due to an adverse event, compared with two percent in the placebo arms. The most frequent adverse events leading to discontinuation were somnolence, dizziness, nausea, fatigue, headache, and insomnia. The US official Prescribing Information warns of rare cases of anaphylactic reactions, abnormal thinking, worsening of depression or suicidal thinking in patients with pre-existing depression, and decreased testosterone and increased prolactin levels. It also notes that ramelteon is not recommended for use in patients with severe sleep apnoea.

In mice treated with ramelteon for two years, increases in liver and testicular tumours were observed, but only at doses at least 20 times greater than the recommended human dose on a milligram/kilogram basis.

Drug Interactions

Ramelteon has been evaluated for potential drug interactions with the following medications and showed no significant effects: omeprazole, theophylline, dextromethorphan, and midazolam, digoxin and warfarin. There were no clinically meaningful effects when ramelteon was co-administered with any of these drugs.

A drug interaction study showed that there were no clinically meaningful effects or an increase in adverse events when ramelteon and the SSRI Prozac (fluoxetine) were co-administered. When co-administered with ramelteon, fluvoxamine (strong CYP1A2 inhibitor) increased AUC approximately 190-fold, and the Cmax increased approximately 70-fold, compared to ramelteon administered alone. Ramelteon and fluvoxamine should not be co-administered.

Ramelteon has significant drug-drug interaction with the following drugs: amiodarone, ciprofloxacin, fluvoxamine, ticlopidine.

Ramelteon should be administered with caution in patients taking other CYP1A2 inhibitors, strong CYP3A4 inhibitors such as ketoconazole, and strong CYP2C9 inhibitors such as fluconazole.

Efficacy may be reduced when ramelteon is used in combination with potent CYP enzyme inducers such as rifampin, since ramelteon concentrations may be decreased.

What is Midazolam?


Midazolam, sold under the brand name Versed, among others, is a benzodiazepine medication used for anaesthesia, procedural sedation, trouble sleeping, and severe agitation.

It works by inducing sleepiness, decreasing anxiety, and causing a loss of ability to create new memories. It is also useful for the treatment of seizures. Midazolam can be given by mouth, intravenously, or injection into a muscle, by spraying into the nose, or through the cheek. When given intravenously, it typically begins working within five minutes; when injected into a muscle, it can take fifteen minutes to begin working. Effects last for between one and six hours.

Side effects can include a decrease in efforts to breathe, low blood pressure, and sleepiness. Tolerance to its effects and withdrawal syndrome may occur following long-term use. Paradoxical effects, such as increased activity, can occur especially in children and older people. There is evidence of risk when used during pregnancy but no evidence of harm with a single dose during breastfeeding. It belongs to the benzodiazepine class of drugs and works by increasing the activity of the GABA neurotransmitter in the brain.

Midazolam was patented in 1974 and came into medical use in 1982. It is on the World Health Organisation’s List of Essential Medicines. Midazolam is available as a generic medication. In many countries, it is a controlled substance.

Brief History

Midazolam is among about 35 benzodiazepines currently used medically, and was synthesized in 1975 by Walser and Fryer at Hoffmann-LaRoche, Inc in the United States. Owing to its water solubility, it was found to be less likely to cause thrombophlebitis than similar drugs. The anticonvulsant properties of midazolam were studied in the late 1970s, but not until the 1990s did it emerge as an effective treatment for convulsive status epilepticus. As of 2010, it is the most commonly used benzodiazepine in anaesthetic medicine. In acute medicine, midazolam has become more popular than other benzodiazepines, such as lorazepam and diazepam, because it is shorter lasting, is more potent, and causes less pain at the injection site. Midazolam is also becoming increasingly popular in veterinary medicine due to its water solubility. In 2018 it was revealed the CIA considered using Midazolam as a “truth serum” on terrorist suspects in project “Medication”.

Medical Uses


Midazolam is sometimes used for the acute management of seizures. Long-term use for the management of epilepsy is not recommended due to the significant risk of tolerance (which renders midazolam and other benzodiazepines ineffective) and the significant side effect of sedation. A benefit of midazolam is that in children it can be given in the cheek or in the nose for acute seizures, including status epilepticus. Midazolam is effective for status epilepticus that has not improved following other treatments or when intravenous access cannot be obtained, and has advantages of being water-soluble, having a rapid onset of action and not causing metabolic acidosis from the propylene glycol vehicle (which is not required due to its solubility in water), which occurs with other benzodiazepines.

Drawbacks include a high degree of breakthrough seizures – due to the short half-life of midazolam – in over 50% of people treated, as well as treatment failure in 14-18% of people with refractory status epilepticus. Tolerance develops rapidly to the anticonvulsant effect, and the dose may need to be increased by several times to maintain anticonvulsant therapeutic effects. With prolonged use, tolerance and tachyphylaxis can occur and the elimination half-life may increase, up to days. There is evidence buccal and intranasal midazolam is easier to administer and more effective than rectally administered diazepam in the emergency control of seizures.

Procedural Sedation

Intravenous midazolam is indicated for procedural sedation (often in combination with an opioid, such as fentanyl), for preoperative sedation, for the induction of general anaesthesia, and for sedation of people who are ventilated in critical care units. Midazolam is superior to diazepam in impairing memory of endoscopy procedures, but propofol has a quicker recovery time and a better memory-impairing effect. It is the most popular benzodiazepine in the intensive care unit (ICU) because of its short elimination half-life, combined with its water solubility and its suitability for continuous infusion. However, for long-term sedation, lorazepam is preferred due to its long duration of action, and propofol has advantages over midazolam when used in the ICU for sedation, such as shorter weaning time and earlier tracheal extubation.

Midazolam is sometimes used in neonatal intensive care units. When used, additional caution is required in newborns; midazolam should not be used for longer than 72 hours due to risks of tachyphylaxis, and the possibility of development of a benzodiazepine withdrawal syndrome, as well as neurological complications. Bolus injections should be avoided due to the increased risk of cardiovascular depression, as well as neurological complications. Midazolam is also sometimes used in newborns who are receiving mechanical ventilation, although morphine is preferred, owing to its better safety profile for this indication.

Sedation using midazolam can be used to relieve anxiety and manage behaviour in children undergoing dental treatment.


Midazolam, in combination with an antipsychotic drug, is indicated for the acute management of schizophrenia when it is associated with aggressive or out-of-control behaviour.

End of Life Care

In the final stages of end-of-life care, midazolam is routinely used at low doses via subcutaneous injection to help with agitation, myoclonus, restlessness or anxiety in the last hours or days of life. At higher doses during the last weeks of life, midazolam is considered a first line agent in palliative continuous deep sedation therapy when it is necessary to alleviate intolerable suffering not responsive to other treatments, but the need for this is rare.


Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, in alcohol- or other drug-dependent individuals or those with comorbid psychiatric disorders.[31] Additional caution is required in critically ill patients, as accumulation of midazolam and its active metabolites may occur.[32] Kidney or liver impairments may slow down the elimination of midazolam leading to prolonged and enhanced effects.[33][34] Contraindications include hypersensitivity, acute narrow-angle glaucoma, shock, hypotension, or head injury. Most are relative contraindications.

Side Effects

Refer to Long-term Effects of Benzodiazepine Use.

Side effects of midazolam in the elderly are listed above. People experiencing amnesia as a side effect of midazolam are generally unaware their memory is impaired, unless they had previously known it as a side effect.

Long-term use of benzodiazepines has been associated with long-lasting deficits of memory, and show only partial recovery six months after stopping benzodiazepines. It is unclear whether full recovery occurs after longer periods of abstinence. Benzodiazepines can cause or worsen depression. Paradoxical excitement occasionally occurs with benzodiazepines, including a worsening of seizures. Children and elderly individuals or those with a history of excessive alcohol use and individuals with a history of aggressive behaviour or anger are at increased risk of paradoxical effects. Paradoxical reactions are particularly associated with intravenous administration. After night-time administration of midazolam, residual ‘hangover’ effects, such as sleepiness and impaired psychomotor and cognitive functions, may persist into the next day. This may impair the ability of users to drive safely and may increase the risk of falls and hip fractures. Sedation, respiratory depression and hypotension due to a reduction in systematic vascular resistance, and an increase in heart rate can occur. If intravenous midazolam is given too quickly, hypotension may occur. A “midazolam infusion syndrome” may result from high doses, and is characterised by delayed arousal hours to days after discontinuation of midazolam, and may lead to an increase in the length of ventilatory support needed.

In susceptible individuals, midazolam has been known to cause a paradoxical reaction, a well-documented complication with benzodiazepines. When this occurs, the individual may experience anxiety, involuntary movements, aggressive or violent behaviour, uncontrollable crying or verbalisation, and other similar effects. This seems to be related to the altered state of consciousness or disinhibition produced by the drug. Paradoxical behaviour is often not recalled by the patient due to the amnesia-producing properties of the drug. In extreme situations, flumazenil can be administered to inhibit or reverse the effects of midazolam. Antipsychotic medications, such as haloperidol, have also been used for this purpose.

Midazolam is known to cause respiratory depression. In healthy humans, 0.15 mg/kg of midazolam may cause respiratory depression, which is postulated to be a central nervous system (CNS) effect. When midazolam is administered in combination with fentanyl, the incidence of hypoxemia or apnoea becomes more likely.

Although the incidence of respiratory depression/arrest is low (0.1-0.5%) when midazolam is administered alone at normal doses, the concomitant use with CNS acting drugs, mainly analgesic opiates, may increase the possibility of hypotension, respiratory depression, respiratory arrest, and death, even at therapeutic doses. Potential drug interactions involving at least one CNS depressant were observed for 84% of midazolam users who were subsequently required to receive the benzodiazepine antagonist flumazenil. Therefore, efforts directed toward monitoring drug interactions and preventing injuries from midazolam administration are expected to have a substantial impact on the safe use of this drug

Pregnancy and Breastfeeding

Midazolam, when taken during the third trimester of pregnancy, may cause risk to the neonate, including benzodiazepine withdrawal syndrome, with possible symptoms including hypotonia, apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. Symptoms of hypotonia and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth. Other neonatal withdrawal symptoms include hyperexcitability, tremor, and gastrointestinal upset (diarrhoea or vomiting). Breastfeeding by mothers using midazolam is not recommended.


Additional caution is required in the elderly, as they are more sensitive to the pharmacological effects of benzodiazepines, metabolise them more slowly, and are more prone to adverse effects, including drowsiness, amnesia (especially anterograde amnesia), ataxia, hangover effects, confusion, and falls.

Tolerance, Dependence, and Withdrawal

A benzodiazepine dependence occurs in about one-third of individuals who are treated with benzodiazepines for longer than 4 weeks, which typically results in tolerance and benzodiazepine withdrawal syndrome when the dose is reduced too rapidly. Midazolam infusions may induce tolerance and a withdrawal syndrome in a matter of days. The risk factors for dependence include dependent personality, use of a benzodiazepine that is short-acting, high potency and long-term use of benzodiazepines. Withdrawal symptoms from midazolam can range from insomnia and anxiety to seizures and psychosis. Withdrawal symptoms can sometimes resemble a person’s underlying condition. Gradual reduction of midazolam after regular use can minimise withdrawal and rebound effects. Tolerance and the resultant withdrawal syndrome may be due to receptor down-regulation and GABAA receptor alterations in gene expression, which causes long-term changes in the function of the GABAergic neuronal system.

Chronic users of benzodiazepine medication who are given midazolam experience reduced therapeutic effects of midazolam, due to tolerance to benzodiazepines. Prolonged infusions with midazolam results in the development of tolerance; if midazolam is given for a few days or more a withdrawal syndrome can occur. Therefore, preventing a withdrawal syndrome requires that a prolonged infusion be gradually withdrawn, and sometimes, continued tapering of dose with an oral long-acting benzodiazepine such as clorazepate dipotassium. When signs of tolerance to midazolam occur during intensive care unit sedation the addition of an opioid or propofol is recommended. Withdrawal symptoms can include irritability, abnormal reflexes, tremors, clonus, hypertonicity, delirium and seizures, nausea, vomiting, diarrhoea, tachycardia, hypertension, and tachypnoea. In those with significant dependence, sudden discontinuation may result in withdrawal symptoms such as status epilepticus that may be fatal.


Refer to Benzodiazepine Overdose.

A midazolam overdose is considered a medical emergency and generally requires the immediate attention of medical personnel. Benzodiazepine overdose in healthy individuals is rarely life-threatening with proper medical support; however, the toxicity of benzodiazepines increases when they are combined with other CNS depressants such as alcohol, opioids, or tricyclic antidepressants. The toxicity of benzodiazepine overdose and risk of death is also increased in the elderly and those with obstructive pulmonary disease or when used intravenously. Treatment is supportive; activated charcoal can be used within an hour of the overdose. The antidote for an overdose of midazolam (or any other benzodiazepine) is flumazenil. While effective in reversing the effects of benzodiazepines it is not used in most cases as it may trigger seizures in mixed overdoses and benzodiazepine dependent individuals.

Symptoms of midazolam overdose can include:

  • Ataxia.
  • Dysarthria.
  • Nystagmus.
  • Slurred speech.
  • Somnolence (difficulty staying awake).
  • Mental confusion.
  • Hypotension.
  • Respiratory arrest.
  • Vasomotor collapse.
  • Impaired motor functions.
    • Impaired reflexes.
    • Impaired coordination.
    • Impaired balance.
  • Dizziness.
  • Coma.
  • Death.

Detection in Body Fluids

Concentrations of midazolam or its major metabolite, 1-hydroxymidazolam glucuronide, may be measured in plasma, serum, or whole blood to monitor for safety in those receiving the drug therapeutically, to confirm a diagnosis of poisoning in hospitalised patients, or to assist in a forensic investigation of a case of fatal overdosage. Patients with renal dysfunction may exhibit prolongation of elimination half-life for both the parent drug and its active metabolite, with accumulation of these two substances in the bloodstream and the appearance of adverse depressant effects.


Protease inhibitors, nefazodone, sertraline, grapefruit, fluoxetine, erythromycin, diltiazem, clarithromycin inhibit the metabolism of midazolam, leading to a prolonged action. St John’s wort, rifapentine, rifampin, rifabutin, phenytoin enhance the metabolism of midazolam leading to a reduced action. Sedating antidepressants, antiepileptic drugs such as phenobarbital, phenytoin and carbamazepine, sedative antihistamines, opioids, antipsychotics and alcohol enhance the sedative effects of midazolam. Midazolam is metabolised almost completely by cytochrome P450-3A4. Atorvastatin administration along with midazolam results in a reduced elimination rate of midazolam. St John’s wort decreases the blood levels of midazolam. Grapefruit juice reduces intestinal 3A4 and results in less metabolism and higher plasma concentrations.


Midazolam is a short-acting benzodiazepine in adults with an elimination half-life of 1.5-2.5 hours. In the elderly, as well as young children and adolescents, the elimination half-life is longer. Midazolam is metabolised into an active metabolite alpha1-hydroxymidazolam. Age-related deficits, renal and liver status affect the pharmacokinetic factors of midazolam as well as its active metabolite. However, the active metabolite of midazolam is minor and contributes to only 10% of biological activity of midazolam. Midazolam is poorly absorbed orally, with only 50% of the drug reaching the bloodstream. Midazolam is metabolised by cytochrome P450 (CYP) enzymes and by glucuronide conjugation. The therapeutic as well as adverse effects of midazolam are due to its effects on the GABAA receptors; midazolam does not activate GABAA receptors directly but, as with other benzodiazepines, it enhances the effect of the neurotransmitter GABA on the GABAA receptors (↑ frequency of Cl− channel opening) resulting in neural inhibition. Almost all of the properties can be explained by the actions of benzodiazepines on GABAA receptors. This results in the following pharmacological properties being produced: sedation, induction of sleep, reduction in anxiety, anterograde amnesia, muscle relaxation and anticonvulsant effects.

Society and Culture


Midazolam is available as a generic medication.


Midazolam is available in the United States as a syrup or as an injectable solution.

Dormicum brand midazolam is marketed by Roche as white, oval, 7.5-mg tablets in boxes of two or three blister strips of 10 tablets, and as blue, oval, 15-mg tablets in boxes of two (Dormonid 3x) blister strips of 10 tablets. The tablets are imprinted with “Roche” on one side and the dose of the tablet on the other side. Dormicum is also available as 1-, 3-, and 10-ml ampoules at a concentration of 5 mg/ml. Another manufacturer, Novell Pharmaceutical Laboratories, makes it available as Miloz in 3- and 5-ml ampoules. Midazolam is the only water-soluble benzodiazepine available. Another maker is Roxane Laboratories; the product in an oral solution, Midazolam HCl Syrup, 2 mg/ml clear, in a red to purplish-red syrup, cherry in flavour. It becomes soluble when the injectable solution is buffered to a pH of 2.9-3.7. Midazolam is also available in liquid form. It can be administered intramuscularly, intravenously, intrathecally, intranasally, buccally, or orally.

Legal Status

In the Netherlands, midazolam is a List II drug of the Opium Law. Midazolam is a Schedule IV drug under the Convention on Psychotropic Substances. In the United Kingdom, midazolam is a Schedule 3/Class C controlled drug. In the United States, midazolam (DEA number 2884) is on the Schedule IV list of the Controlled Substances Act as a non-narcotic agent with low potential for abuse.

Marketing Authorisation

In 2011, the European Medicines Agency (EMA) granted a marketing authorisation for a buccal application form of midazolam, sold under the trade name Buccolam. Buccolam was approved for the treatment of prolonged, acute, convulsive seizures in people from three months to less than 18 years of age. This was the first application of a paediatric-use marketing authorisation.

Use in Executions

The drug has been introduced for use in executions by lethal injection in certain jurisdictions in the United States in combination with other drugs. It was introduced to replace pentobarbital after the latter’s manufacturer disallowed that drug’s use for executions. Midazolam acts as a sedative to render the condemned prisoner unconscious, at which time vecuronium bromide and potassium chloride are administered, stopping the prisoner’s breathing and heart, respectively.

Midazolam has been used as part of a three-drug cocktail, with vecuronium bromide and potassium chloride in Florida and Oklahoma prisons. Midazolam has also been used along with hydromorphone in a two-drug protocol in Ohio and Arizona.

The usage of midazolam in executions became controversial after condemned inmate Clayton Lockett apparently regained consciousness and started speaking midway through his 2014 execution when the state of Oklahoma attempted to execute him with an untested three-drug lethal injection combination using 100 mg of midazolam. Prison officials reportedly discussed taking him to a hospital before he was pronounced dead of a heart attack 40 minutes after the execution began. An observing doctor stated that Lockett’s vein had ruptured. It is not clear which drug or drugs caused his death or what quantities of vecuronium bromide and potassium chloride were released before the execution was cancelled.

Notable Incidents

The state of Florida used midazolam to execute William Frederick Happ in October 2013.

The state of Ohio used midazolam in the execution of Dennis McGuire in January 2014; it took McGuire 24 minutes to die after the procedure started, and he gasped and appeared to be choking during that time, leading to questions about the dosing and timing of the drug administration, as well as the choice of drugs.

The execution of Ronald Bert Smith in the state of Alabama on 08 December 2016, “went awry soon after (midazolam) was administered” again putting the effectiveness of the drug in question.

In October 2016, the state of Ohio announced that it would resume executions in January 2017, using a formulation of midazolam, vecuronium bromide, potassium chloride, but this was blocked by a Federal judge. On 26 July 2017, Ronald Phillips was executed with a three-drug cocktail including midazolam after the Supreme Court refused to grant a stay.[86] Prior to this, the last execution in Ohio had been that of Dennis McGuire. Murderer Gary Otte’s lawyers unsuccessfully challenged his Ohio execution, arguing that midazolam might not protect him from serious pain when the other drugs are administered. He died without incident in about 14 minutes on 13 September 2017.

On 24 April 2017, the state of Arkansas carried out a double-execution of Jack Harold Jones, 52, and Marcel Williams, 46. The state of Arkansas attempted to execute eight people before its supply of midazolam expired on 30 April 2017. Two of them were granted a stay of execution, and another, Ledell T. Lee, 51, was executed on 20 April 2017.

Legal Challenges

In Glossip v. Gross, attorneys for three Oklahoma inmates argued that midazolam could not achieve the level of unconsciousness required for surgery, meaning severe pain and suffering was likely. They argued that midazolam was cruel and unusual punishment and thus contrary to the Eighth Amendment to the United States Constitution. In June 2015, the US Supreme Court ruled that they had failed to prove that midazolam was cruel and unusual when compared to known, available alternatives.

The state of Nevada is also known to use midazolam in execution procedures. In July 2018, one of the manufacturers accused state officials of obtaining the medication under false pretences. This incident was the first time a drug company successfully, though temporarily, halted an execution. A previous attempt in 2017, to halt an execution in the state of Arizona by another drug manufacturer was not successful.

What is Clobazam?


Clobazam, sold under the brand name Frisium among others, is a benzodiazepine class medication that was patented in 1968.

Clobazam was first synthesized in 1966 and first published in 1969. Clobazam was originally marketed as an anxioselective anxiolytic since 1970, and an anticonvulsant since 1984. The primary drug-development goal was to provide greater anxiolytic, anti-obsessive efficacy with fewer benzodiazepine-related side effects.

Refer to Triflubazam.

Brief History

Clobazam was discovered at the Maestretti Research Laboratories in Milan and was first published in 1969; Maestretti was acquired by Roussel Uclaf which became part of Sanofi.

Medical Uses

Clobazam is used for its anxiolytic effect, and as an adjunctive therapy in epilepsy.

Clobazam is approved in Canada for add-on use in tonic-clonic, complex partial, and myoclonic seizures. Clobazam is approved for adjunctive therapy in complex partial seizures, certain types of status epilepticus, specifically the mycolonic, myoclonic-absent, simple partial, complex partial, and tonic varieties, and non-status absence seizures. It is also approved for the treatment of anxiety.

In India, clobazam is approved for use as an adjunctive therapy in epilepsy, and in acute and chronic anxiety. In Japan, clobazam is approved for adjunctive therapy in treatment-resistant epilepsy featuring complex partial seizures. In New Zealand, clobazam is marketed as Frisium In the United Kingdom clobazam (Frisium) is approved for short-term (2-4 weeks) relief of acute anxiety in patients who have not responded to other drugs, with or without insomnia and without uncontrolled clinical depression. It was not approved in the United States until 25 October 2011, when it was approved for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients 2 years of age or older.

As an adjunctive therapy in epilepsy, it is used in patients who have not responded to first-line drugs and in children who are refractory to first-line drugs. It is unclear if there are any benefits to clobazam over other seizure medications for children with Rolandic epilepsy or other epileptic syndromes. It is not recommended for use in children between the ages of six months and three years, unless there is a compelling need. In addition to epilepsy and severe anxiety, clobazam is also approved as a short-term (2-4 weeks) adjunctive agent in schizophrenia and other psychotic disorders to manage anxiety or agitation.

Clobazam is sometimes used for refractory epilepsies. However, long-term prophylactic treatment of epilepsy may have considerable drawbacks, most importantly decreased antiepileptic effects due to drug tolerance which may render long-term therapy less effective. Other antiepileptic drugs may therefore be preferred for the long-term management of epilepsy. Furthermore, benzodiazepines may have the drawback, particularly after long-term use, of causing rebound seizures upon abrupt or over-rapid discontinuation of therapy forming part of the benzodiazepine withdrawal syndrome.


Clobazam should be used with great care in patients with the following disorders:

  • Myasthenia gravis.
  • Sleep apnoea.
  • Severe liver diseases such as cirrhosis and hepatitis.
  • Severe respiratory failure.

Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals, and individuals with comorbid psychiatric disorders.

Side Effects

In September 2020, the US Food and Drug Administration (FDA) required the boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.

Refer to Effects of Long-Term Benzodiazepine Use.


Common side effects include fever, drooling, and constipation.

Post-Marketing Experience

  • Hives.
  • Rashes.

Warnings and Precautions

In December 2013, the FDA added warnings to the label for clobazam, that it can cause serious skin reactions, Stevens-Johnson syndrome, and toxic epidermal necrolysis, especially in the first eight weeks of treatment.

Drug Interactions

  • Alcohol increases bioavailability by 50%; compounded depressant effect may precipitate life-threatening toxicity.
  • Cimetidine increases the effects of clobazam.
  • Valproate.


Overdose and intoxication with benzodiazepines, including clobazam, may lead to CNS depression, associated with drowsiness, confusion, and lethargy, possibly progressing to ataxia, respiratory depression, hypotension, and coma or death. The risk of a fatal outcome is increased in cases of combined poisoning with other CNS depressants, including alcohol.

Abuse Potential and Addiction

Refer to Benzodiazepine Use Disorder.

Classic (non-anxioselective) benzodiazepines in animal studies have been shown to increase reward-seeking behaviours which may suggest an increased risk of addictive behavioural patterns. Clobazam abuse has been reported in some countries, according to a 1983 World Health Organisation (WHO) report.

Dependence and Withdrawal

In humans, tolerance to the anticonvulsant effects of clobazam may occur and withdrawal seizures may occur during abrupt or over rapid withdrawal.

Clobazam as with other benzodiazepine drugs can lead to physical dependence, addiction, and what is known as the benzodiazepine withdrawal syndrome. Withdrawal from clobazam or other benzodiazepines after regular use often leads to withdrawal symptoms which are similar to those seen during alcohol and barbiturate withdrawal. The higher the dosage and the longer the drug is taken, the greater the risk of experiencing unpleasant withdrawal symptoms. Benzodiazepine treatment should only be discontinued via a slow and gradual dose reduction regimen.


Clobazam is predominantly a positive allosteric modulator at the GABAA receptor with some speculated additional activity at sodium channels and voltage-sensitive calcium channels.

Like other 1,5-benzodiazepines (for example, arfendazam, lofendazam, or CP-1414S), the active metabolite N-desmethylclobazam has less affinity for the α1 subunit of the GABAA receptor compared to the 1,4-benzodiazepines. It has higher affinity for α2 containing receptors, where it has positive modulatory activity.

In a double-blind placebo-controlled trial published in 1990 comparing it to clonazepam, 10 mg of clobazam was shown to be less sedative than either 0.5 mg or 1 mg of clonazepam.

The α1 subtype of the GABAA receptor, was shown to be responsible for the sedative effects of diazepam by McKernan et al. in 2000, who also showed that its anxiolytic and anticonvulsant properties could still be seen in mice whose α1 receptors were insensitive to diazepam.

In 1996, Nakamura et al. reported that clobazam and its active metabolite, N-desmethylclobazam (norclobazam), work by enhancing GABA-activated chloride influx at GABAA receptors, creating a hyperpolarizing, inhibitory postsynaptic potential. It was also reported that these effects were inhibited by the GABA antagonist flumazenil, and that clobazam acts more efficiently in GABA-deficient brain tissue.


Clobazam has two major metabolites: N-desmethylclobazam and 4′-hydroxyclobazam, the former of which is active. The demethylation is facilitated by CYP2C19, CYP3A4, and CYP2B6 and the 4-hydroxyclobazam by CYP2C18 and CYP2C19.


Clobazam is a 1,5-benzodiazepine, meaning that its diazepine ring has nitrogen atoms at the 1 and 5 positions (instead of the usual 1 and 4).

It is not soluble in water and is available in oral form only.

What is a GABA Receptor?


The GABA receptors are a class of receptors that respond to the neurotransmitter gamma-aminobutyric acid (GABA), the chief inhibitory compound in the mature vertebrate central nervous system.

There are two classes of GABA receptors: GABAA and GABAB. GABAA receptors are ligand-gated ion channels (also known as ionotropic receptors); whereas GABAB receptors are G protein-coupled receptors, also called metabotropic receptors.

Ligand-Gated Ion Channels

Ionotropic GABA receptors (iGABARs) are ligand-gated ion channel of the GABA receptors class which are activated by gamma-aminobutyric acid (GABA), and include:

  • GABAA receptors.
  • GABAA-ρ receptors.

The GABAB receptor, a G protein-coupled receptor, is the only metabotropic GABA receptor and its mechanism of action differs significantly from the ionotropic receptors. Functionally, in mature organisms, activation of these receptors typically results in neural inhibition, primarily via the influx of chloride ions, although exceptions to this general principle exist, such as during early development. Structurally, iGABARs are pentameric transmembrane ion channels, meaning they are made up of five subunits. Since there are several classes of subunits and a variety of genes encoding many members of these classes, a wide variety of structurally, and therefore functionally, distinct channels of iGABARs is observed.

GABAA Receptor

It has long been recognised that the fast response of neurons to GABA that is stimulated by bicuculline and picrotoxin is due to direct activation of an anion channel. This channel was subsequently termed the GABAA receptor. Fast-responding GABA receptors are members of a family of Cys-loop ligand-gated ion channels. Members of this superfamily, which includes nicotinic acetylcholine receptors, GABAA receptors, glycine and 5-HT3 receptors, possess a characteristic loop formed by a disulfide bond between two cysteine residues.

In ionotropic GABAA receptors, binding of GABA molecules to their binding sites in the extracellular part of the receptor triggers opening of a chloride ion-selective pore. The increased chloride conductance drives the membrane potential towards the reversal potential of the Cl¯ ion which is about -75 mV in neurons, inhibiting the firing of new action potentials. This mechanism is responsible for the sedative effects of GABAA allosteric agonists. In addition, activation of GABA receptors lead to the so-called shunting inhibition, which reduces the excitability of the cell independent of the changes in membrane potential.

There have been numerous reports of excitatory GABAA receptors. According to the excitatory GABA theory, this phenomenon is due to increased intracellular concentration of Cl¯ ions either during development of the nervous system or in certain cell populations. After this period of development, a chloride pump is upregulated and inserted into the cell membrane, pumping Cl− ions into the extracellular space of the tissue. Further openings via GABA binding to the receptor then produce inhibitory responses. Over-excitation of this receptor induces receptor remodelling and the eventual invagination of the GABA receptor. As a result, further GABA binding becomes inhibited and inhibitory postsynaptic potentials are no longer relevant.

However, the excitatory GABA theory has been questioned as potentially being an artefact of experimental conditions, with most data acquired in in-vitro brain slice experiments susceptible to un-physiological milieu such as deficient energy metabolism and neuronal damage. The controversy arose when a number of studies have shown that GABA in neonatal brain slices becomes inhibitory if glucose in perfusate is supplemented with ketone bodies, pyruvate, or lactate, or that the excitatory GABA was an artefact of neuronal damage. Subsequent studies from originators and proponents of the excitatory GABA theory have questioned these results, but the truth remained elusive until the real effects of GABA could be reliably elucidated in intact living brain. Since then, using technology such as in-vivo electrophysiology/imaging and optogenetics, two in-vivo studies have reported the effect of GABA on neonatal brain, and both have shown that GABA is indeed overall inhibitory, with its activation in the developing rodent brain not resulting in network activation, and instead leading to a decrease of activity.

GABA receptors influence neural function by coordinating with glutamatergic processes.

GABAA-ρ Receptor

A subclass of ionotropic GABA receptors, insensitive to typical allosteric modulators of GABAA receptor channels such as benzodiazepines and barbiturates, was designated GABAС receptor. Native responses of the GABAC receptor type occur in retinal bipolar or horizontal cells across vertebrate species.

GABAС receptors are exclusively composed of ρ (rho) subunits that are related to GABAA receptor subunits. Although the term “GABAС receptor” is frequently used, GABAС may be viewed as a variant within the GABAA receptor family. Others have argued that the differences between GABAС and GABAA receptors are large enough to justify maintaining the distinction between these two subclasses of GABA receptors. However, since GABAС receptors are closely related in sequence, structure, and function to GABAA receptors and since other GABAA receptors besides those containing ρ subunits appear to exhibit GABAС pharmacology, the Nomenclature Committee of the IUPHAR has recommended that the GABAС term no longer be used and these ρ receptors should be designated as the ρ subfamily of the GABAA receptors (GABAA-ρ).

G Protein-Coupled Receptors

GABAB Receptor

A subclass of ionotropic GABA receptors, insensitive to typical allosteric modulators of GABAA receptor channels such as benzodiazepines and barbiturates, was designated GABAС receptor. Native responses of the GABAC receptor type occur in retinal bipolar or horizontal cells across vertebrate species.

GABAС receptors are exclusively composed of ρ (rho) subunits that are related to GABAA receptor subunits. Although the term “GABAС receptor” is frequently used, GABAС may be viewed as a variant within the GABAA receptor family. Others have argued that the differences between GABAС and GABAA receptors are large enough to justify maintaining the distinction between these two subclasses of GABA receptors. However, since GABAС receptors are closely related in sequence, structure, and function to GABAA receptors and since other GABAA receptors besides those containing ρ subunits appear to exhibit GABAС pharmacology, the Nomenclature Committee of the IUPHAR has recommended that the GABAС term no longer be used and these ρ receptors should be designated as the ρ subfamily of the GABAA receptors (GABAA-ρ).

GABA Receptor Gene Polymorphisms

Two separate genes on two chromosomes control GABA synthesis – glutamate decarboxylase and alpha-ketoglutarate decarboxylase genes – though not much research has been done to explain this polygenic phenomenon. GABA receptor genes have been studied more in depth, and many have hypothesized about the deleterious effects of polymorphisms in these receptor genes. The most common single nucleotide polymorphisms (SNPs) occurring in GABA receptor genes rho 1, 2, and 3 (GABBR1, GABBR2, and GABBR3) have been more recently explored in literature, in addition to the potential effects of these polymorphisms. However, some research has demonstrated that there is evidence that these polymorphisms caused by single base pair variations may be harmful.

It was discovered that the minor allele of a single nucleotide polymorphism at GABBR1 known as rs1186902 is significantly associated with a later age of onset for migraines, but for the other SNPs, no differences were discovered between genetic and allelic variations in the control vs. migraine participants. Similarly, in a study examining SNPs in rho 1, 2, and 3, and their implication in essential tremor, a nervous system disorder, it was discovered that there were no differences in the frequencies of the allelic variants of polymorphisms for control vs. essential tremor participants. On the other hand, research examining the effect of SNPs in participants with restless leg syndrome found an “association between GABRR3rs832032 polymorphism and the risk for RLS, and a modifier effect of GABRA4 rs2229940 on the age of onset of RLS” – the latter of which is a modifier gene polymorphism. The most common GABA receptor SNPs do not correlate with deleterious health effects in many cases, but do in a few.

One significant example of a deleterious mutation is the major association between several GABA receptor gene polymorphisms and schizophrenia. Because GABA is integral to the release of inhibitory neurotransmitters which produce a calming effect and play a role in reducing anxiety, stress, and fear, it is not surprising that polymorphisms in these genes result in more consequences relating to mental health than to physical health. Of an analysis on 19 SNPs on various GABA receptor genes, five SNPs in the GABBR2 group were found to be significantly associated with schizophrenia, which produce the unexpected haplotype frequencies not found in the studies mentioned previously.

Several studies have verified association between alcohol use disorder and the rs279858 polymorphism on the GABRA2 gene e, and higher negative alcohol effects scores for individuals who were homozygous at six SNPs. Furthermore, a study examining polymorphisms in the GABA receptor beta 2 subunit gene found an association with schizophrenia and bipolar disorder, and examined three SNPs and their effects on disease frequency and treatment dosage. A major finding of this study was that functional psychosis should be conceptualised as a scale of phenotypes rather than distinct categories.

What is Flumazenil?


Flumazenil (also known as flumazepil, code name Ro 15-1788) is a selective GABAA receptor antagonist administered via injection, otic insertion, or intranasally. Therapeutically, it acts as both an antagonist and antidote to benzodiazepines (particularly in cases of overdose), through competitive inhibition.

It was first characterised in 1981, and was first marketed in 1987 by Hoffmann-La Roche under the trade name Anexate. However, it did not receive US Food and Drug Administration (FDA) approval until 20 December 1991. The developer lost its exclusive patent rights in 2008; so at present, generic formulations of this drug are available. Intravenous flumazenil is primarily used to treat benzodiazepine overdoses and to help reverse anaesthesia. Administration of flumazenil by sublingual lozenge and topical cream has also been tested.

Medical Uses

Flumazenil benefits patients who become excessively drowsy after use of benzodiazepines for either diagnostic or therapeutic procedures.

The drug has been used as an antidote in the treatment of benzodiazepine overdoses. It reverses the effects of benzodiazepines by competitive inhibition at the benzodiazepine (BZ) recognition site on the GABA/benzodiazepine receptor complex. There are many complications that must be taken into consideration when used in the acute care setting. These include lowered seizure threshold, agitation, and anxiousness. Flumazenil’s short half-life requires multiple doses. Because of the potential risks of withdrawal symptoms and the drug’s short half-life, patients must be carefully monitored to prevent recurrence of overdose symptoms or adverse side effects.

Flumazenil is also sometimes used after surgery to reverse the sedative effects of benzodiazepines. This is similar to naloxone’s application to reverse the effect of opiates and opioids following surgery. Administration of the drug requires careful monitoring by an anaesthesiologist due to potential side effects and serious risks associated with over-administration. Likewise, post-surgical monitoring is also necessary because flumazenil can mask the apparent metabolisation (“wearing off”) of the drug after removal of patient life-support and monitoring equipment.

Flumazenil has been effectively used to treat overdoses of non-benzodiazepine hypnotics, such as zolpidem, zaleplon and zopiclone (also known as “Z-drugs”).

It may also be effective in reducing excessive daytime sleepiness while improving vigilance in primary hypersomnias, such as idiopathic hypersomnia.

The drug has also been used in hepatic encephalopathy. It may have beneficial short‐term effects in people with cirrhosis, but there is no evidence for long-term benefits.

The onset of action is rapid, and effects are usually seen within one to two minutes. The peak effect is seen at six to ten minutes. The recommended dose for adults is 200 μg every 1-2 minutes until the effect is seen, up to a maximum of 3 mg per hour. It is available as a clear, colourless solution for intravenous injection, containing 500 μg in 5 mL.

Many benzodiazepines (including midazolam) have longer half-lives than flumazenil. Therefore, in cases of overdose, repeat doses of flumazenil may be required to prevent recurrent symptoms once the initial dose of flumazenil wears off.

It is hepatically metabolised to inactive compounds which are excreted in the urine. Individuals who are physically dependent on benzodiazepines may suffer benzodiazepine withdrawal symptoms, including seizure, upon rapid administration of flumazenil.

It is not recommended for routine use in those with a decreased level of consciousness.

In terms of drug enforcement initiatives, diversion control programs and required post-marketing surveillance of adverse events, orders for flumazenil may trigger a prescription audit to the search for benzodiazepine misuse and for clinically significant adverse reactions related to their use.

PET Radioligand

Radiolabeled with the radioactive isotope carbon-11, flumazenil may be used as a radioligand in neuroimaging with positron emission tomography to visualize the distribution of GABAA receptors in the human brain.

Treatment for Benzodiazepine Dependence & Tolerance

Epileptic patients who have become tolerant to the anti-seizure effects of the benzodiazepine clonazepam became seizure-free for several days after treatment with 1.5 mg of flumazenil. Similarly, patients who were dependent on high doses of benzodiazepines (median dosage 333 mg diazepam-equivalent) were able to be stabilised on a low dose of clonazepam after 7-8 days of treatment with flumazenil.

Flumazenil has been tested against placebo in benzo-dependent subjects. Results showed that typical benzodiazepine withdrawal effects were reversed with few to no symptoms. Flumazenil was also shown to produce significantly fewer withdrawal symptoms than saline in a randomised, placebo-controlled study with benzodiazepine-dependent subjects. Additionally, relapse rates were much lower during subsequent follow-up.

In vitro studies of tissue cultured cell lines have shown that chronic treatment with flumazenil enhanced the benzodiazepine binding site where such receptors have become more numerous and uncoupling/down-regulation of GABAA has been reversed. After long-term exposure to benzodiazepines, GABAA receptors become down-regulated and uncoupled. Growth of new receptors and recoupling after prolonged flumazenil exposure has also been observed. It is thought this may be due to increased synthesis of receptor proteins.[20]

Flumazenil was found to be more effective than placebo in reducing feelings of hostility and aggression in patients who had been free of benzodiazepines for 4–266 weeks. This may suggest a role for flumazenil in treating protracted benzodiazepine withdrawal symptoms.

Low-dose, slow subcutaneous flumazenil administration is a safe procedure for patients withdrawing from long-term, high-dose benzodiazepine dependency. It has a low risk of seizures even amongst those who have experienced convulsions when previously attempting benzodiazepine withdrawal.

In Italy, the gold standard for treatment of high-dose benzodiazepine dependency is 8-10 days of low-dose, slowly infused flumazenil. One addiction treatment centre in Italy has used flumazenil to treat over 300 patients who were dependent on high doses of benzodiazepines (up to 70 times higher than conventionally prescribed) with physicians being among the clinic’s most common patients.

Clinical Pharmacology

Flumazenil, an imidazobenzodiazepine derivative, antagonizes the actions of benzodiazepines on the central nervous system. Flumazenil competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex. It also exhibits weak partial agonism of GABAA receptor complexes that contain α6-type monomers; the clinical relevance of this is unknown.

Flumazenil does not antagonize all of the central nervous system effects of drugs affecting GABA-ergic neurons by means other than the benzodiazepine receptor (including ethanol, barbiturates, and most anaesthetics) and does not reverse the effects of opioids. It will however antagonize the action of non-benzodiazepine z-drugs, such as zolpidem and zopiclone, because they act via the benzodiazepine site of the GABA receptor – it has been used to successfully treat z-drug overdose.


Intravenous flumazenil has been shown to antagonize sedation, impairment of recall, psychomotor impairment and ventilatory depression produced by benzodiazepines in healthy human volunteers.

The duration and degree of reversal of sedative benzodiazepine effects are related to the dose and plasma concentrations of flumazenil.


Flumazenil is sold under a wide variety of brand names worldwide like Anexate, Lanexat, Mazicon, Romazicon. In India it is manufactured by Roche Bangladesh Pharmaceuticals and USAN Pharmaceuticals.

What is Temazepam?


Temazepam, sold under the brand names Restoril among others, is a medication used to treat insomnia.

Such use should generally be for less than ten days. It is taken by mouth. Effects generally begin within an hour and last for up to eight hours.

Common side effects include sleepiness, anxiety, confusion, and dizziness. Serious side effects may include hallucinations, abuse, anaphylaxis, and suicide. Use is generally not recommended together with opioids. If the dose is rapidly decreased withdrawal may occur. Use during pregnancy or breastfeeding is not recommended. Temazepam is an intermediate acting benzodiazepine and hypnotic. It works by affecting GABA within the brain.

Temazepam was patented in 1962 and came into medical use in 1969. It is available as a generic medication. In 2017, it was the 142nd most commonly prescribed medication in the United States, with more than four million prescriptions.

Brief History

Temazepam was synthesized in 1964, but it came into use in 1981 when its ability to counter insomnia was realised. By the late 1980s, temazepam was one of the most popular and widely prescribed hypnotics on the market and it became one of the most widely prescribed drugs.

Medical Uses

In sleep laboratory studies, temazepam significantly decreased the number of nightly awakenings, but has the drawback of distorting the normal sleep pattern. It is officially indicated for severe insomnia and other severe or disabling sleep disorders. The prescribing guidelines in the UK limit the prescribing of hypnotics to two to four weeks due to concerns of tolerance and dependence.

The United States Air Force uses temazepam as one of the hypnotics approved as a “no-go pill” to help aviators and special-duty personnel sleep in support of mission readiness. “Ground tests” are necessary prior to required authorisation being issued to use the medication in an operational situation, and a 12-hour restriction is imposed on subsequent flight operation. The other hypnotics used as “no-go pills” are zaleplon and zolpidem, which have shorter mandatory recovery periods.


Use of temazepam should be avoided, when possible, in individuals with these conditions:

  • Ataxia (gross lack of coordination of muscle movements).
  • Severe hypoventilation.
  • Acute narrow-angle glaucoma.
  • Severe hepatic deficiencies (hepatitis and liver cirrhosis decrease elimination by a factor of two).
  • Severe renal deficiencies (e.g. patients on dialysis).
  • Sleep apnoea.
  • Severe depression, particularly when accompanied by suicidal tendencies.
  • Acute intoxication with alcohol, narcotics, or other psychoactive substances.
  • Myasthenia gravis (autoimmune disorder causing muscle weakness).
  • Hypersensitivity or allergy to any drug in the benzodiazepine class.

Special Caution Needed

Temazepam should not be used in pregnancy, as it may cause harm to the foetus. The safety and effectiveness of temazepam has not been established in children; therefore, temazepam should generally not be given to individuals under 18 years of age, and should not be used at all in children under six months old. Benzodiazepines also require special caution if used in the elderly, alcohol- or drug-dependent individuals, and individuals with comorbid psychiatric disorders.

Temazepam, similar to other benzodiazepines and nonbenzodiazepine hypnotic drugs, causes impairments in body balance and standing steadiness in individuals who wake up at night or the next morning. Falls and hip fractures are frequently reported. The combination with alcohol increases these impairments. Partial but incomplete tolerance develops to these impairments. The smallest possible effective dose should be used in elderly or very ill patients, as a risk of apnoea and/or cardiac arrest exists. This risk is increased when temazepam is given concomitantly with other drugs that depress the central nervous system (CNS).

Misuse and Dependence

Because benzodiazepines can be abused and lead to dependence, their use should be avoided in people in certain particularly high-risk groups. These groups include people with a history of alcohol or drug dependence, people significantly struggling with their mood or people with longstanding mental health difficulties. If temazepam must be prescribed to people in these groups, they should generally be monitored very closely for signs of misuse and development of dependence.

Adverse Effects

Refer to Benzodiazepine Withdrawal Syndrome.

In September 2020, the US Food and Drug Administration (FDA) required the boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.


Side effects typical of hypnotic benzodiazepines are related to CNS depression, and include somnolence, sedation, dizziness, fatigue, ataxia, headache, lethargy, impairment of memory and learning, longer reaction time and impairment of motor functions (including coordination problems), slurred speech, decreased physical performance, numbed emotions, reduced alertness, muscle weakness, blurred vision (in higher doses), and inattention. Euphoria was rarely reported with its use. According to the FDA, temazepam had an incidence of euphoria of 1.5%, much more rarely reported than headaches and diarrhoea. Anterograde amnesia may also develop, as may respiratory depression in higher doses.

A 2009 meta-analysis found a 44% higher rate of mild infections, such as pharyngitis or sinusitis, in people taking Temazepam or other hypnotic drugs compared to those taking a placebo.

Less Common

Hyperhydrosis, hypotension, burning eyes, increased appetite, changes in libido, hallucinations, faintness, nystagmus, vomiting, pruritus, gastrointestinal disturbances, nightmares, palpitation and paradoxical reactions including restlessness, aggression, violence, overstimulation and agitation have been reported, but are rare (less than 0.5%).

Before taking temazepam, one should ensure that at least 8 hours are available to dedicate to sleep. Failing to do so can increase the side effects of the drug.

Like all benzodiazepines, the use of this drug in combination with alcohol potentiates the side effects, and can lead to toxicity and death.

Though rare, residual “hangover” effects after night-time administration of temazepam occasionally occur. These include sleepiness, impaired psychomotor and cognitive functions which may persist into the next day, impaired driving ability, and possible increased risks of falls and hip fractures, especially in the elderly.


Chronic or excessive use of temazepam may cause drug tolerance, which can develop rapidly, so this drug is not recommended for long-term use. In 1979, the US Institute of Medicine and the National Institute on Drug Abuse stated that most hypnotics lose their sleep-inducing properties after about three to 14 days. In use longer than one to two weeks, tolerance will rapidly develop towards the ability of temazepam to maintain sleep, resulting in a loss of effectiveness. Some studies have observed tolerance to temazepam after as little as one week’s use. Another study examined the short-term effects of the accumulation of temazepam over seven days in elderly inpatients, and found little tolerance developed during the accumulation of the drug. Other studies examined the use of temazepam over six days and saw no evidence of tolerance. A study in 11 young male subjects showed significant tolerance occurs to temazepam’s thermoregulatory effects and sleep inducing properties after one week of use of 30-mg temazepam. Body temperature is well correlated with the sleep-inducing or insomnia-promoting properties of drugs.

In one study, the drug sensitivity of people who had used temazepam for one to 20 years was no different from that of controls. An additional study, in which at least one of the authors is employed by multiple drug companies, examined the efficacy of temazepam treatment on chronic insomnia over three months, and saw no drug tolerance, with the authors even suggesting the drug might become more effective over time.

Establishing continued efficacy beyond a few weeks can be complicated by the difficulty in distinguishing between the return of the original insomnia complaint and withdrawal or rebound related insomnia. Sleep EEG studies on hypnotic benzodiazepines show tolerance tends to occur completely after one to four weeks with sleep EEG returning to pre-treatment levels. The paper concluded that due to concerns about long-term use involving toxicity, tolerance and dependence, as well as to controversy over long-term efficacy, wise prescribers should restrict benzodiazepines to a few weeks and avoid continuing prescriptions for months or years. A review of the literature found the nonpharmacological treatment options were a more effective treatment option for insomnia due to their sustained improvements in sleep quality.

Physical Dependence

Temazepam, like other benzodiazepine drugs, can cause physical dependence and addiction. Withdrawal from temazepam or other benzodiazepines after regular use often leads to benzodiazepine withdrawal syndrome, which resembles symptoms during alcohol and barbiturate withdrawal. The higher the dose and the longer the drug is taken, the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can also occur from standard dosages and after short-term use. Abrupt withdrawal from therapeutic doses of temazepam after long-term use may result in a severe benzodiazepine withdrawal syndrome. Gradual and careful reduction of the dosage, preferably with a long-acting benzodiazepine with long half-life active metabolites, such as chlordiazepoxide or diazepam, are recommended to prevent severe withdrawal syndromes from developing. Other hypnotic benzodiazepines are not recommended. A study in rats found temazepam is cross tolerant with barbiturates and is able to effectively substitute for barbiturates and suppress barbiturate withdrawal signs. Rare cases are reported in the medical literature of psychotic states developing after abrupt withdrawal from benzodiazepines, even from therapeutic doses. Antipsychotics increase the severity of benzodiazepine withdrawal effects with an increase in the intensity and severity of convulsions. Patients who were treated in the hospital with temazepam or nitrazepam have continued taking these after leaving the hospital. Hypnotic uses in the hospital were recommended to be limited to five nights’ use only, to avoid the development of withdrawal symptoms such as insomnia.


As with other benzodiazepines, temazepam produces additive CNS-depressant effects when co-administered with other medications which themselves produce CNS depression, such as barbiturates, alcohol, opiates, tricyclic antidepressants, nonselective MAO inhibitors, phenothiazines and other antipsychotics, skeletal muscle relaxants, antihistamines, and anaesthetics. Administration of theophylline or aminophylline has been shown to reduce the sedative effects of temazepam and other benzodiazepines.

Unlike many benzodiazepines, pharmacokinetic interactions involving the P450 system have not been observed with temazepam. Temazepam shows no significant interaction with CYP3A4 inhibitors (e.g. itraconazole, erythromycin). Oral contraceptives may decrease the effectiveness of temazepam and speed up its elimination half-life.


Refer to Benzodiazepine Overdose.

Overdose (or an excess dose(s)) of temazepam results in increasing CNS effects, including:

  • Somnolence (difficulty staying awake).
  • Mental confusion.
  • Respiratory depression.
  • Hypotension.
  • Impaired motor functions.
  • Impaired or absent reflexes.
  • Impaired coordination.
  • Impaired balance.
  • Dizziness, sedation.
  • Coma.
  • Death.

Temazepam had the highest rate of drug intoxication, including overdose, among common benzodiazepines in cases with and without combination with alcohol in a 1985 study. Temazepam and nitrazepam were the two benzodiazepines most commonly detected in overdose-related deaths in an Australian study of drug deaths. A 1993 British study found temazepam to have the highest number of deaths per million prescriptions among medications commonly prescribed in the 1980s (11.9, versus 5.9 for benzodiazepines overall, taken with or without alcohol).

A 1995 Australian study of patients admitted to hospital after benzodiazepine overdose corroborated these results, and found temazepam overdose much more likely to lead to coma than other benzodiazepines (odds ratio 1.86). The authors noted several factors, such as differences in potency, receptor affinity, and rate of absorption between benzodiazepines, could explain this higher toxicity. Although benzodiazepines have a high therapeutic index, temazepam is one of the more dangerous of this class of drugs. The combination of alcohol and temazepam makes death by alcohol poisoning more likely.


Temazepam is a white, crystalline substance, very slightly soluble in water, and sparingly soluble in alcohol. Its main pharmacological action is to increase the effect of the neurotransmitter gamma-aminobutyric acid (GABA) at the GABAA receptor. This causes sedation, motor impairment, ataxia, anxiolysis, an anticonvulsant effect, muscle relaxation, and a reinforcing effect. As a medication before surgery, temazepam decreased cortisol in elderly patients. In rats, it triggered the release of vasopressin into paraventricular nucleus of the hypothalamus and decreased the release of ACTH under stress.


Oral administration of 15 to 45 mg of temazepam in humans resulted in rapid absorption with significant blood levels achieved in fewer than 30 minutes and peak levels at two to three hours. In a single- and multiple-dose absorption, distribution, metabolism, and excretion (ADME) study, using tritium-labelled drug, temazepam was well absorbed and found to have minimal (8%) first-pass drug metabolism. No active metabolites were formed and the only significant metabolite present in blood was the O-conjugate. The unchanged drug was 96% bound to plasma proteins. The blood-level decline of the parent drug was biphasic, with the short half-life ranging from 0.4-0.6 hours and the terminal half-life from 3.5-18.4 hours (mean 8.8 hours), depending on the study population and method of determination.

Temazepam has very good bioavailability, with almost 100% being absorbed following being taken by mouth. The drug is metabolized through conjugation and demethylation prior to excretion. Most of the drug is excreted in the urine, with about 20% appearing in the faeces. The major metabolite was the O-conjugate of temazepam (90%); the O-conjugate of N-desmethyl temazepam was a minor metabolite (7%).

Society and Culture

Recreational Use

Refer to Benzodiazepine Use Disorder.

Temazepam is a drug with a moderate potential for misuse.

Benzodiazepines have been abused orally and intravenously. Different benzodiazepines have different abuse potential; the more rapid the increase in the plasma level following ingestion, the greater the intoxicating effect and the more open to abuse the drug becomes. The speed of onset of action of a particular benzodiazepine correlates well with the ‘popularity’ of that drug for abuse. The two most common reasons for preference were that a benzodiazepine was ‘strong’ and that it gave a good ‘high’.

A 1995 study found that temazepam is more rapidly absorbed and oxazepam is more slowly absorbed than most other benzodiazepines.

A 1985 study found that temazepam and triazolam maintained significantly higher rates of self-injection than a variety of other benzodiazepines. The study tested and compared the abuse liability of temazepam, triazolam, diazepam, lorazepam, oxazepam, flurazepam, alprazolam, chlordiazepoxide, clonazepam, nitrazepam, flunitrazepam, bromazepam, and clorazepate. The study tested self-injection rates on human, baboon, and rat subjects. All test subjects consistently showed a strong preference for temazepam and triazolam over all the rest of the benzodiazepines included in the study.

North America

In North America, temazepam misuse is not widespread. Other benzodiazepines are more commonly prescribed for insomnia. In the United States, temazepam is the fifth-most prescribed benzodiazepine, however there is a major drop off from the top four most prescribed (alprazolam, lorazepam, diazepam, and clonazepam in that order). Individuals abusing benzodiazepines obtain the drug by getting prescriptions from several doctors, forging prescriptions, or buying diverted pharmaceutical products on the illicit market. North America has never had a serious problem with temazepam misuse, but is becoming increasingly vulnerable to the illicit trade of temazepam.


Temazepam is a Schedule 4 drug and requires a prescription. The drug accounts for most benzodiazepine sought by forgery of prescriptions and through pharmacy burglary in Victoria. Due to rife intravenous abuse, the Australian government decided to put it under a more restrictive schedule than it had been, and since March 2004 temazepam capsules have been withdrawn from the Australian market, leaving only 10 mg tablets available. Benzodiazepines are commonly detected by Customs at different ports and airports, arriving by mail, also found occasionally in the baggage of air passengers, mostly small or medium quantities (up to 200-300 tablets) for personal use. From 2003 to 2006, customs detected about 500 illegal importations of benzodiazepines per year, most frequently diazepam. Quantities varied from single tablets to 2,000 tablets.

United Kingdom

In 1987, temazepam was the most widely abused legal prescription drug in the United Kingdom. The use of benzodiazepines by street-drug abusers was part of a polydrug abuse pattern, but many of those entering treatment facilities were declaring temazepam as their main drug of abuse. Temazepam was the most commonly used benzodiazepine in a study, published 1994, of injecting drug users in seven cities, and had been injected from preparations of capsules, tablets, and syrup. The increase in use of heroin, often mixed with other drugs, which most often included temazepam, diazepam, and alcohol, was a major factor in the increase in drug-related deaths in Glasgow and Edinburgh in 1990-1992. Temazepam use was particularly associated with violent or disorderly behaviours and contact with the police in a 1997 study of young single homeless people in Scotland. The BBC series Panorama featured an episode titled “Temazepam Wars”, dealing with the epidemic of temazepam abuse and directly related crime in Paisley, Scotland. The trend was mocked in the 1995 Black Grape song “Temazi Party” (also called “Tramazi Party”).

Medical Research Issues

The Journal of Clinical Sleep Medicine published a paper expressing concerns about benzodiazepine receptor agonist drugs, the benzodiazepines and the Z-drugs used as hypnotics in humans. The paper cites a systematic review of the medical literature concerning insomnia medications and states almost all trials of sleep disorders and drugs are sponsored by the pharmaceutical industry, while this is not the case in general medicine or psychiatry. It cites another study that “found that the odds ratio for finding results favourable to industry in industry-sponsored trials was 3.6 times as high as in non–industry-sponsored studies”. Issues discussed regarding industry-sponsored studies include: comparison of a drug to a placebo, but not to an alternative treatment; unpublished studies with unfavourable outcomes; and trials organized around a placebo baseline followed by drug treatment, but not counterbalanced with parallel-placebo-controlled studies. Quoting a 1979 report that too little research into hypnotics was independent of the drug manufacturers, the authors conclude, “the public desperately needs an equipoised assessment of hypnotic benefits and risks” and the NIH and VA should provide leadership to that end.

Street Terms

Street terms for temazepam include king kong pills (formerly referred to barbiturates, now more commonly refers to temazepam), jellies, jelly, Edinburgh eccies, tams, terms, mazzies, temazies, tammies, temmies, beans, eggs, green eggs, wobbly eggs, knockouts, hardball, norries, oranges (common term in Australia and New Zealand), rugby balls, ruggers, terminators, red and blue, no-gos, num nums, blackout, green devils, drunk pills, brainwash, mind erasers, neurotrashers, tem-tem’s (combined with buprenorphine), mommy’s big helper, vitamin T, big T, TZ, The Mazepam, Resties (North America) and others.


Temazepam is available in English-speaking countries under the following brand names:

  • Euhypnos.
  • Normison.
  • Norkotral.
  • Nortem.
  • Remestan.
  • Restoril.
  • Temaze.
  • Temtabs.
  • Tenox.

In Spain, the drug is sold as ‘temzpem’. In Hungary the drug is sold as Signopam.

Legal Status

  • In Austria, temazepam is listed in UN71 Schedule III under the Psychotropic Substances Decree of 1997.
    • The drug is considered to have a high potential for abuse and addiction, but has accepted medical use for the treatment of severe insomnia.
  • In Australia, temazepam is a Schedule 4 – Prescription Only medicine.
    • It is primarily used for the treatment of insomnia, and is also seen as pre-anaesthetic medication.
  • In Canada, temazepam is a Schedule IV controlled substance requiring a registered doctor’s prescription.
  • In Denmark, temazepam is listed as a Class D substance under the Executive Order 698 of 1993 on Euphoric Substances which means it has a high potential for abuse, but is used for medical and scientific purposes.
  • In Finland, temazepam is more tightly controlled than other benzodiazepines.
    • The temazepam product Normison was pulled out of shelves and banned because the liquid inside gelatin capsules had caused a large increase in intravenous temazepam use.
    • The other temazepam product, Tenox, was not affected and remains as prescription medicine.
    • Temazepam intravenous use has not decreased to the level before Normison came to the market.
  • In France, temazepam is listed as a psychotropic substance as are other similar drugs.
    • It is prescribed with a non-renewable prescription (a new doctor visit every time), available only in 7 or 14-pill packaging for one or two weeks.
    • One brand was withdrawn from the market in 2013.
  • In Hong Kong, temazepam is regulated under Schedule 1 of Hong Kong’s Chapter 134 Dangerous Drugs Ordinance.
    • Temazepam can only be used legally by health professionals and for university research purposes.
    • The substance can be given by pharmacists under a prescription.
    • Anyone who supplies the substance without prescription can be fined HKD$10,000.
    • The penalty for trafficking or manufacturing the substance is a $5,000,000-fine and life imprisonment.
    • Possession of the substance for consumption without license from the Department of Health is illegal with a $1,000,000-fine and/or seven years of jail time.
  • In Ireland, temazepam is a Schedule 3 controlled substance with strict restrictions.
  • In the Netherlands, temazepam is available for prescription as 10- or 20-mg tablets and capsules.
    • Formulations of temazepam containing less than 20 mg are included in List 2 of the Opium Law, while formulations containing 20 mg or more of the drug (along with the gel-capsules) are a List 1 substance of the Opium Law, thus subject to more stringent regulation.
    • Besides being used for insomnia, it is also occasionally used as a preanesthetic medication.
  • In Norway, temazepam is not available as a prescription drug.
    • It is regulated as a Class A substance under Norway’s Narcotics Act.
  • In Portugal, temazepam is a Schedule IV controlled drug under Decree-Law 15/93.
  • In Singapore, temazepam is a Class A controlled drug (Schedule I), making it illegal to possess and requiring a private prescription from a licensed physician to be dispensed.
  • In Slovenia, it is regulated as a Group II (Schedule 2) controlled substance under the Production and Trade in Illicit Drugs Act.
  • In South Africa, temazepam is a Schedule 5 drug, requiring a special prescription, and is restricted to 10- to 30-mg doses.
  • In Sweden, temazepam is classed as a “narcotic” drug listed as both a List II (Schedule II) which denotes it is a drug with limited medicinal use and a high risk of addiction, and is also listed as a List V (Schedule V) substance which denotes the drug is prohibited in Sweden under the Narcotics Drugs Act (1968).
    • Temazepam is banned in Sweden and possession and distribution of even small amounts is punishable by a prison sentence and a fine.
  • In Switzerland, temazepam is a Class B controlled substance, like all other benzodiazepines.
    • This means it is a prescription-only drug.
  • In Thailand, temazepam is a Schedule II controlled drug under the Psychotropic Substances Act.
    • Possession and distribution of the drug is illegal.
  • In the United Kingdom, temazepam is a Class C controlled drug under the Misuse of Drugs Act 1971 (Schedule 3 under the Misuse of Drugs Regulations 2001).
    • If prescribed privately (not on the NHS), temazepam is available only by a special controlled drug prescription form (FP10PCD) and pharmacies are obligated to follow special procedures for storage and dispensing.
    • Additionally, all manufacturers in the UK have replaced the gel-capsules with solid tablets.
    • Temazepam requires safe custody and up until June 2015 was exempt from CD prescription requirements.
  • In the United States, Temazepam is currently a Schedule IV drug under the international Convention on Psychotropic Substances of 1971 and is only available by prescription.
    • Specially coded prescriptions may be required in certain states.

What is a Neurotransmitter?


Neurotransmitters are chemical messengers that transmit a signal from a neuron across the synapse to a target cell, which can be a different neuron, muscle cell, or gland cell. Neurotransmitters are chemical substances made by the neuron specifically to transmit a message.

Neurotransmitters are released from synaptic vesicles in synapses into the synaptic cleft, where they are received by neurotransmitter receptors on the target cell. Many neurotransmitters are synthesized from simple and plentiful precursors such as amino acids, which are readily available and only require a small number of biosynthetic steps for conversion. Neurotransmitters are essential to the function of complex neural systems. The exact number of unique neurotransmitters in humans is unknown, but more than 500 have been identified.

Structure of a typical chemical synapse.


Neurotransmitters are stored in synaptic vesicles, clustered close to the cell membrane at the axon terminal of the presynaptic neuron. Neurotransmitters are released into and diffuse across the synaptic cleft, where they bind to specific receptors on the membrane of the postsynaptic neuron. Binding of neurotransmitters may influence the postsynaptic neuron in either an excitation or inhibitory way, depolarising or repolarising it respectively.

Most of the neurotransmitters are about the size of a single amino acid; however, some neurotransmitters may be the size of larger proteins or peptides. A released neurotransmitter is typically available in the synaptic cleft for a short time before it is metabolised by enzymes, pulled back into the presynaptic neuron through reuptake, or bound to a postsynaptic receptor. Nevertheless, short-term exposure of the receptor to a neurotransmitter is typically sufficient for causing a postsynaptic response by way of synaptic transmission.

Generally, a neurotransmitter is released at the presynaptic terminal in response to a threshold action potential or graded electrical potential in the presynaptic neuron. However, low level ‘baseline’ release also occurs without electrical stimulation.


Until the early 20th century, scientists assumed that the majority of synaptic communication in the brain was electrical. However, through histological examinations by Ramón y Cajal, a 20 to 40 nm gap between neurons, known today as the synaptic cleft, was discovered. The presence of such a gap suggested communication via chemical messengers traversing the synaptic cleft, and in 1921 German pharmacologist Otto Loewi confirmed that neurons can communicate by releasing chemicals. Through a series of experiments involving the vagus nerves of frogs, Loewi was able to manually slow the heart rate of frogs by controlling the amount of saline solution present around the vagus nerve. Upon completion of this experiment, Loewi asserted that sympathetic regulation of cardiac function can be mediated through changes in chemical concentrations. Furthermore, Otto Loewi is credited with discovering acetylcholine (ACh) – the first known neurotransmitter.


There are four main criteria for identifying neurotransmitters:

  1. The chemical must be synthesized in the neuron or otherwise be present in it.
  2. When the neuron is active, the chemical must be released and produce a response in some targets.
  3. The same response must be obtained when the chemical is experimentally placed on the target.
  4. A mechanism must exist for removing the chemical from its site of activation after its work is done.

However, given advances in pharmacology, genetics, and chemical neuroanatomy, the term “neurotransmitter” can be applied to chemicals that:

  • Carry messages between neurons via influence on the postsynaptic membrane.
  • Have little or no effect on membrane voltage, but have a common carrying function such as changing the structure of the synapse.
  • Communicate by sending reverse-direction messages that affect the release or reuptake of transmitters.

The anatomical localisation of neurotransmitters is typically determined using immunocytochemical techniques, which identify the location of either the transmitter substances themselves or of the enzymes that are involved in their synthesis. Immunocytochemical techniques have also revealed that many transmitters, particularly the neuropeptides, are co-localised, that is, a neuron may release more than one transmitter from its synaptic terminal. Various techniques and experiments such as staining, stimulating, and collecting can be used to identify neurotransmitters throughout the central nervous system.


There are many different ways to classify neurotransmitters. Dividing them into amino acids, peptides, and monoamines is sufficient for some classification purposes.

Major neurotransmitters:

  • Amino acids: glutamate, aspartate, D-serine, gamma-Aminobutyric acid (GABA), and glycine.
  • Gasotransmitters: nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S).
  • Monoamines: dopamine (DA), norepinephrine (noradrenaline; NE, NA), epinephrine (adrenaline), histamine, and serotonin (SER, 5-HT).
    • Catecholamines: dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline).
  • Trace amines: phenethylamine, N-methylphenethylamine, tyramine, 3-iodothyronamine, octopamine, tryptamine, etc.
  • Peptides: oxytocin, somatostatin, substance P, cocaine and amphetamine regulated transcript, and opioid peptides.
  • Purines: adenosine triphosphate (ATP) and adenosine.
  • Others: acetylcholine (ACh), anandamide, etc.

In addition, over 50 neuroactive peptides have been found, and new ones are discovered regularly. Many of these are co-released along with a small-molecule transmitter. Nevertheless, in some cases, a peptide is the primary transmitter at a synapse. Beta-Endorphin is a relatively well-known example of a peptide neurotransmitter because it engages in highly specific interactions with opioid receptors in the central nervous system.

Single ions (such as synaptically released zinc) are also considered neurotransmitters by some, as well as some gaseous molecules such as nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S). The gases are produced in the neural cytoplasm and are immediately diffused through the cell membrane into the extracellular fluid and into nearby cells to stimulate production of second messengers. Soluble gas neurotransmitters are difficult to study, as they act rapidly and are immediately broken down, existing for only a few seconds.

The most prevalent transmitter is glutamate, which is excitatory at well over 90% of the synapses in the human brain. The next most prevalent is gamma-Aminobutyric Acid (GABA) which is inhibitory at more than 90% of the synapses that do not use glutamate. Although other transmitters are used in fewer synapses, they may be very important functionally: the great majority of psychoactive drugs exert their effects by altering the actions of some neurotransmitter systems, often acting through transmitters other than glutamate or GABA. Addictive drugs such as cocaine and amphetamines exert their effects primarily on the dopamine system. The addictive opiate drugs exert their effects primarily as functional analogues of opioid peptides, which, in turn, regulate dopamine levels.


Neurons form elaborate networks through which nerve impulses – action potentials – travel. Each neuron has as many as 15,000 connections with neighbouring neurons.

Neurons do not touch each other (except in the case of an electrical synapse through a gap junction); instead, neurons interact at contact points called synapses: a junction within two nerve cells, consisting of a miniature gap within which impulses are carried by a neurotransmitter. A neuron transports its information by way of a nerve impulse called an action potential. When an action potential arrives at the synapse’s presynaptic terminal button, it may stimulate the release of neurotransmitters. These neurotransmitters are released into the synaptic cleft to bind onto the receptors of the postsynaptic membrane and influence another cell, either in an inhibitory or excitatory way. The next neuron may be connected to many more neurons, and if the total of excitatory influences minus inhibitory influences is great enough, it will also “fire”. That is to say, it will create a new action potential at its axon hillock, releasing neurotransmitters and passing on the information to yet another neighbouring neuron.

Excitatory and Inhibitory

A neurotransmitter can influence the function of a neuron through a remarkable number of mechanisms. In its direct actions in influencing a neuron’s electrical excitability, however, a neurotransmitter acts in only one of two ways: excitatory or inhibitory. A neurotransmitter influences trans-membrane ion flow either to increase (excitatory) or to decrease (inhibitory) the probability that the cell with which it comes in contact will produce an action potential. Thus, despite the wide variety of synapses, they all convey messages of only these two types, and they are labelled as such. Type I synapses are excitatory in their actions, whereas type II synapses are inhibitory. Each type has a different appearance and is located on different parts of the neurons under its influence.

Type I (excitatory) synapses are typically located on the shafts or the spines of dendrites, whereas type II (inhibitory) synapses are typically located on a cell body. In addition, Type I synapses have round synaptic vesicles, whereas the vesicles of type II synapses are flattened. The material on the presynaptic and post-synaptic membranes is denser in a Type I synapse than it is in a type II, and the type I synaptic cleft is wider. Finally, the active zone on a Type I synapse is larger than that on a Type II synapse.

The different locations of type I and type II synapses divide a neuron into two zones: an excitatory dendritic tree and an inhibitory cell body. From an inhibitory perspective, excitation comes in over the dendrites and spreads to the axon hillock to trigger an action potential. If the message is to be stopped, it is best stopped by applying inhibition on the cell body, close to the axon hillock where the action potential originates. Another way to conceptualize excitatory-inhibitory interaction is to picture excitation overcoming inhibition. If the cell body is normally in an inhibited state, the only way to generate an action potential at the axon hillock is to reduce the cell body’s inhibition. In this “open the gates” strategy, the excitatory message is like a racehorse ready to run down the track, but first, the inhibitory starting gate must be removed.

Examples of Important Neurotransmitter Actions

As explained above, the only direct action of a neurotransmitter is to activate a receptor. Therefore, the effects of a neurotransmitter system depend on the connections of the neurons that use the transmitter, and the chemical properties of the receptors that the transmitter binds to.

Here are a few examples of important neurotransmitter actions:

  • Glutamate is used at the great majority of fast excitatory synapses in the brain and spinal cord. It is also used at most synapses that are “modifiable”, i.e. capable of increasing or decreasing in strength.
    • Modifiable synapses are thought to be the main memory-storage elements in the brain.
    • Excessive glutamate release can overstimulate the brain and lead to excitotoxicity causing cell death resulting in seizures or strokes.
    • Excitotoxicity has been implicated in certain chronic diseases including ischemic stroke, epilepsy, amyotrophic lateral sclerosis, Alzheimer’s disease, Huntington disease, and Parkinson’s disease.
  • GABA is used at the great majority of fast inhibitory synapses in virtually every part of the brain.
    • Many sedative/tranquilizing drugs act by enhancing the effects of GABA.
    • Correspondingly, glycine is the inhibitory transmitter in the spinal cord.
  • Acetylcholine was the first neurotransmitter discovered in the peripheral and central nervous systems.
    • It activates skeletal muscles in the somatic nervous system and may either excite or inhibit internal organs in the autonomic system.
    • It is distinguished as the transmitter at the neuromuscular junction connecting motor nerves to muscles.
    • The paralytic arrow-poison curare acts by blocking transmission at these synapses.
    • Acetylcholine also operates in many regions of the brain, but using different types of receptors, including nicotinic and muscarinic receptors.
  • Dopamine has a number of important functions in the brain; this includes regulation of motor behaviour, pleasures related to motivation and also emotional arousal.
    • It plays a critical role in the reward system; Parkinson’s disease has been linked to low levels of dopamine and schizophrenia has been linked to high levels of dopamine.
  • Serotonin is a monoamine neurotransmitter.
    • Most is produced by and found in the intestine (approximately 90%), and the remainder in central nervous system neurons.
    • It functions to regulate appetite, sleep, memory and learning, temperature, mood, behaviour, muscle contraction, and function of the cardiovascular system and endocrine system.
    • It is speculated to have a role in depression, as some depressed patients are seen to have lower concentrations of metabolites of serotonin in their cerebrospinal fluid and brain tissue.
  • Norepinephrine which is synthesized in the central nervous system and sympathetic nerves, modulates the responses of the autonomic nervous system, the sleep patterns, focus and alertness.
    • It is synthesized from tyrosine.
  • Epinephrine which is also synthesized from tyrosine is released in the adrenal glands and the brainstem.
    • It plays a role in sleep, with one’s ability to become and stay alert, and the fight-or-flight response.
  • Histamine works with the central nervous system (CNS), specifically the hypothalamus (tuberomammillary nucleus) and CNS mast cells.

Brain Neurotransmitter Systems

Neurons expressing certain types of neurotransmitters sometimes form distinct systems, where activation of the system affects large volumes of the brain, called volume transmission. Major neurotransmitter systems include the noradrenaline (norepinephrine) system, the dopamine system, the serotonin system, and the cholinergic system, among others. Trace amines have a modulatory effect on neurotransmission in monoamine pathways (i.e. dopamine, norepinephrine, and serotonin pathways) throughout the brain via signalling through trace amine-associated receptor 1.

Drug Effects

Understanding the effects of drugs on neurotransmitters comprises a significant portion of research initiatives in the field of neuroscience. Most neuroscientists involved in this field of research believe that such efforts may further advance our understanding of the circuits responsible for various neurological diseases and disorders, as well as ways to effectively treat and someday possibly prevent or cure such illnesses.

Drugs can influence behaviour by altering neurotransmitter activity. For instance, drugs can decrease the rate of synthesis of neurotransmitters by affecting the synthetic enzyme(s) for that neurotransmitter. When neurotransmitter syntheses are blocked, the amount of neurotransmitters available for release becomes substantially lower, resulting in a decrease in neurotransmitter activity. Some drugs block or stimulate the release of specific neurotransmitters. Alternatively, drugs can prevent neurotransmitter storage in synaptic vesicles by causing the synaptic vesicle membranes to leak. Drugs that prevent a neurotransmitter from binding to its receptor are called receptor antagonists. For example, drugs used to treat patients with schizophrenia such as haloperidol, chlorpromazine, and clozapine are antagonists at receptors in the brain for dopamine. Other drugs act by binding to a receptor and mimicking the normal neurotransmitter. Such drugs are called receptor agonists. An example of a receptor agonist is morphine, an opiate that mimics effects of the endogenous neurotransmitter β-endorphin to relieve pain. Other drugs interfere with the deactivation of a neurotransmitter after it has been released, thereby prolonging the action of a neurotransmitter. This can be accomplished by blocking re-uptake or inhibiting degradative enzymes. Lastly, drugs can also prevent an action potential from occurring, blocking neuronal activity throughout the central and peripheral nervous system. Drugs such as tetrodotoxin that block neural activity are typically lethal.

Drugs targeting the neurotransmitter of major systems affect the whole system, which can explain the complexity of action of some drugs. Cocaine, for example, blocks the re-uptake of dopamine back into the presynaptic neuron, leaving the neurotransmitter molecules in the synaptic gap for an extended period of time. Since the dopamine remains in the synapse longer, the neurotransmitter continues to bind to the receptors on the postsynaptic neuron, eliciting a pleasurable emotional response. Physical addiction to cocaine may result from prolonged exposure to excess dopamine in the synapses, which leads to the downregulation of some post-synaptic receptors. After the effects of the drug wear off, an individual can become depressed due to decreased probability of the neurotransmitter binding to a receptor. Fluoxetine is a selective serotonin re-uptake inhibitor (SSRI), which blocks re-uptake of serotonin by the presynaptic cell which increases the amount of serotonin present at the synapse and furthermore allows it to remain there longer, providing potential for the effect of naturally released serotonin. AMPT prevents the conversion of tyrosine to L-DOPA, the precursor to dopamine; reserpine prevents dopamine storage within vesicles; and deprenyl inhibits monoamine oxidase (MAO)-B and thus increases dopamine levels.


An agonist is a chemical capable of binding to a receptor, such as a neurotransmitter receptor, and initiating the same reaction typically produced by the binding of the endogenous substance. An agonist of a neurotransmitter will thus initiate the same receptor response as the transmitter. In neurons, an agonist drug may activate neurotransmitter receptors either directly or indirectly. Direct-binding agonists can be further characterized as full agonists, partial agonists, inverse agonists.

Direct agonists act similar to a neurotransmitter by binding directly to its associated receptor site(s), which may be located on the presynaptic neuron or postsynaptic neuron, or both. Typically, neurotransmitter receptors are located on the postsynaptic neuron, while neurotransmitter autoreceptors are located on the presynaptic neuron, as is the case for monoamine neurotransmitters; in some cases, a neurotransmitter utilises retrograde neurotransmission, a type of feedback signalling in neurons where the neurotransmitter is released postsynaptically and binds to target receptors located on the presynaptic neuron. Nicotine, a compound found in tobacco, is a direct agonist of most nicotinic acetylcholine receptors, mainly located in cholinergic neurons. Opiates, such as morphine, heroin, hydrocodone, oxycodone, codeine, and methadone, are μ-opioid receptor agonists; this action mediates their euphoriant and pain relieving properties.

Indirect agonists increase the binding of neurotransmitters at their target receptors by stimulating the release or preventing the reuptake of neurotransmitters. Some indirect agonists trigger neurotransmitter release and prevent neurotransmitter reuptake. Amphetamine, for example, is an indirect agonist of postsynaptic dopamine, norepinephrine, and serotonin receptors in each their respective neurons; it produces both neurotransmitter release into the presynaptic neuron and subsequently the synaptic cleft and prevents their reuptake from the synaptic cleft by activating TAAR1, a presynaptic G protein-coupled receptor, and binding to a site on VMAT2, a type of monoamine transporter located on synaptic vesicles within monoamine neurons.


An antagonist is a chemical that acts within the body to reduce the physiological activity of another chemical substance (as an opiate); especially one that opposes the action on the nervous system of a drug or a substance occurring naturally in the body by combining with and blocking its nervous receptor.

There are two main types of antagonist: direct-acting Antagonist and indirect-acting Antagonists:

  • Direct-acting antagonist- which takes up space present on receptors which are otherwise taken up by neurotransmitters themselves.
    • This results in neurotransmitters being blocked from binding to the receptors. The most common is called Atropine.
  • Indirect-acting antagonist- drugs that inhibit the release/production of neurotransmitters (e.g., Reserpine).

Drug Antagonists

An antagonist drug is one that attaches (or binds) to a site called a receptor without activating that receptor to produce a biological response. It is therefore said to have no intrinsic activity. An antagonist may also be called a receptor “blocker” because they block the effect of an agonist at the site. The pharmacological effects of an antagonist, therefore, result in preventing the corresponding receptor site’s agonists (e.g. drugs, hormones, neurotransmitters) from binding to and activating it. Antagonists may be “competitive” or “irreversible”.

A competitive antagonist competes with an agonist for binding to the receptor. As the concentration of antagonist increases, the binding of the agonist is progressively inhibited, resulting in a decrease in the physiological response. High concentration of an antagonist can completely inhibit the response. This inhibition can be reversed, however, by an increase of the concentration of the agonist, since the agonist and antagonist compete for binding to the receptor. Competitive antagonists, therefore, can be characterised as shifting the dose–response relationship for the agonist to the right. In the presence of a competitive antagonist, it takes an increased concentration of the agonist to produce the same response observed in the absence of the antagonist.

An irreversible antagonist binds so strongly to the receptor as to render the receptor unavailable for binding to the agonist. Irreversible antagonists may even form covalent chemical bonds with the receptor. In either case, if the concentration of the irreversible antagonist is high enough, the number of unbound receptors remaining for agonist binding may be so low that even high concentrations of the agonist do not produce the maximum biological response.


While intake of neurotransmitter precursors does increase neurotransmitter synthesis, evidence is mixed as to whether neurotransmitter release and postsynaptic receptor firing is increased. Even with increased neurotransmitter release, it is unclear whether this will result in a long-term increase in neurotransmitter signal strength, since the nervous system can adapt to changes such as increased neurotransmitter synthesis and may therefore maintain constant firing. Some neurotransmitters may have a role in depression and there is some evidence to suggest that intake of precursors of these neurotransmitters may be useful in the treatment of mild and moderate depression.

Catecholamine and Trace Amine Precursors

L-DOPA, a precursor of dopamine that crosses the blood–brain barrier, is used in the treatment of Parkinson’s disease. For depressed patients where low activity of the neurotransmitter norepinephrine is implicated, there is only little evidence for benefit of neurotransmitter precursor administration. L-phenylalanine and L-tyrosine are both precursors for dopamine, norepinephrine, and epinephrine. These conversions require vitamin B6, vitamin C, and S-adenosylmethionine. A few studies suggest potential antidepressant effects of L-phenylalanine and L-tyrosine, but there is much room for further research in this area.

Serotonin Precursors

Administration of L-tryptophan, a precursor for serotonin, is seen to double the production of serotonin in the brain. It is significantly more effective than a placebo in the treatment of mild and moderate depression. This conversion requires vitamin C.[24] 5-hydroxytryptophan (5-HTP), also a precursor for serotonin, is more effective than a placebo.

Diseases and Disorders

Diseases and disorders may also affect specific neurotransmitter systems. The following are disorders involved in either an increase, decrease, or imbalance of certain neurotransmitters.


For example, problems in producing dopamine (mainly in the substantia nigra) can result in Parkinson’s disease, a disorder that affects a person’s ability to move as they want to, resulting in stiffness, tremors or shaking, and other symptoms. Some studies suggest that having too little or too much dopamine or problems using dopamine in the thinking and feeling regions of the brain may play a role in disorders like schizophrenia or attention deficit hyperactivity disorder (ADHD). Dopamine is also involved in addiction and drug use, as most recreational drugs cause an influx of dopamine in the brain (especially opioid and methamphetamines) that produces a pleasurable feeling, which is why users constantly crave drugs.


Similarly, after some research suggested that drugs that block the recycling, or reuptake, of serotonin seemed to help some people diagnosed with depression, it was theorized that people with depression might have lower-than-normal serotonin levels. Though widely popularized, this theory was not borne out in subsequent research. Therefore, selective serotonin reuptake inhibitors (SSRIs) are used to increase the amounts of serotonin in synapses.


Furthermore, problems with producing or using glutamate have been suggestively and tentatively linked to many mental disorders, including autism, obsessive compulsive disorder (OCD), schizophrenia, and depression. Having too much glutamate has been linked to neurological diseases such as Parkinson’s disease, multiple sclerosis, Alzheimer’s disease, stroke, and ALS (amyotrophic lateral sclerosis).

Neurotransmitter Imbalance

Generally, there are no scientifically established “norms” for appropriate levels or “balances” of different neurotransmitters. It is in most cases pragmatically impossible to even measure levels of neurotransmitters in a brain or body at any distinct moments in time. Neurotransmitters regulate each other’s release, and weak consistent imbalances in this mutual regulation were linked to temperament in healthy people. Strong imbalances or disruptions to neurotransmitter systems have been associated with many diseases and mental disorders. These include Parkinson’s, depression, insomnia, Attention Deficit Hyperactivity Disorder (ADHD), anxiety, memory loss, dramatic changes in weight and addictions. Chronic physical or emotional stress can be a contributor to neurotransmitter system changes. Genetics also plays a role in neurotransmitter activities. Apart from recreational use, medications that directly and indirectly interact with one or more transmitter or its receptor are commonly prescribed for psychiatric and psychological issues. Notably, drugs interacting with serotonin and norepinephrine are prescribed to patients with problems such as depression and anxiety – though the notion that there is much solid medical evidence to support such interventions has been widely criticised. Studies shown that dopamine imbalance has an influence on multiple sclerosis and other neurological disorders

CAPON Binds Nitric Oxide Synthase, Regulating NMDA Receptor–Mediated Glutamate Neurotransmission.

Elimination of Neurotransmitters

A neurotransmitter must be broken down once it reaches the post-synaptic cell to prevent further excitatory or inhibitory signal transduction. This allows new signals to be produced from the adjacent nerve cells. When the neurotransmitter has been secreted into the synaptic cleft, it binds to specific receptors on the postsynaptic cell, thereby generating a postsynaptic electrical signal. The transmitter must then be removed rapidly to enable the postsynaptic cell to engage in another cycle of neurotransmitter release, binding, and signal generation. Neurotransmitters are terminated in three different ways:

  • Diffusion:
    • The neurotransmitter detaches from receptor, drifting out of the synaptic cleft, here it becomes absorbed by glial cells.
  • Enzyme degradation:
    • Special chemicals called enzymes break it down.
    • Usually, astrocytes absorb the excess neurotransmitters and pass them on to enzymes or pump them directly into the presynaptic neuron.
  • Reuptake:
    • Re-absorption of a neurotransmitter into the neuron.
    • Transporters, or membrane transport proteins, pump neurotransmitters from the synaptic cleft back into axon terminals (the presynaptic neuron) where they are stored.

For example, choline is taken up and recycled by the pre-synaptic neuron to synthesize more ACh. Other neurotransmitters such as dopamine are able to diffuse away from their targeted synaptic junctions and are eliminated from the body via the kidneys, or destroyed in the liver. Each neurotransmitter has very specific degradation pathways at regulatory points, which may be targeted by the body’s regulatory system or drugs.