What is Catecholaminergic?


Catecholaminergic means “related to catecholamines”.


The catecholamine neurotransmitters include dopamine, epinephrine (adrenaline), and norepinephrine (noradrenaline).

A catecholaminergic agent (or drug) is a chemical which functions to directly modulate the catecholamine systems in the body or brain.

Examples include adrenergics and dopaminergics.

An Overview of the Biology of Obsessive-Compulsive Disorder


The biology of obsessive-compulsive disorder (OCD) refers biologically based theories about the mechanism of OCD.

Cognitive models generally fall into the category of executive dysfunction or modulatory control. Neuroanatomically, functional and structural neuroimaging studies implicate the prefrontal cortex (PFC), basal ganglia (BG), insula, and posterior cingulate cortex (PCC). Genetic and neurochemical studies implicate glutamate and monoamine neurotransmitters, especially serotonin and dopamine.

Refer to Obsessive-Compulsive Spectrum.



The cortico-basal ganglia-thalamo-cortical loop (CBGTC) model is based on the observation that the basal ganglia loops related to the OFC and ACC are implicated in OCD by neuroimaging studies, although the directionality of volumetric and functional changes is not consistent. Causal evidence from OCD secondary to neuropsychiatric disorders supports the CBGTC model. Obsessions may arise from failure of the circuit to gate information that is normally implicitly processed, leading to representation in explicit processing systems such as the dlPFC and hippocampus, and thereby resulting in obsessions.

Abnormal affect in OCD has been hypothesized to result from dysfunction in the OFC, ventral striatum, and amygdala. OCD is characterised by high levels of anxiety, high rates of comorbidity with major depressive disorder, and blunted response to reward. This is reflected by reduced amygdala and ventral striatum response to positive stimuli, and elevated amygdala response to fearful stimuli. Furthermore, deep brain stimulation of the nucleus accumbens is an effective treatment of OCD, and symptom improvement correlates with reduced binding of dopamine receptors. The reduced binding, due to the ability of the radioligand tracers to be displaced by endogenous dopamine, is taken to reflect increased basal dopamine release. Affective dysregulation due to blunted reward, and elevated fear sensitivity may promote compulsivity by assigning excessive motivational salience to avoidance behaviour.

The ventral striatum is important in action selection, and receives inputs from the medial OFC that signal various aspects of value for stimulus association outcomes. By assigning abnormal values to certain behaviours, OFC may lead to compulsive behaviour through modulating action selection in the ventral striatum. A number of abnormalities have been found in the OFC, including reduced volume, increased resting state activity, and reduced activity during cognitive tasks. The difference between resting and cognitive paradigms may be due to increased signal to noise ratio, a possible mechanism of aberrant valuation. OFC-striatum connectivity also predicts symptom severity, although the opposite has been found in some studies.

Besides abnormal valuation of stimuli or tasks, compulsions may be driven by dysfunction in error monitoring that leads to excessive uncertainty.

OCD has also been conceptualised as resulting from dysfunction in response inhibition, and fear extinction. While hyperactivation of the OFC as a whole during resting is observed in OCD, hyperactivation of the lateral OFC and hypoactivation of the mOFC is seen. This is congruent with the localization of fear/avoidance behaviours to the lOFC and emotional regulation to the mOFC. Hyperactivity of the dACC during monitoring task, along with hyperactivity of the lOFC and amygadala may all contribute to generating obsessions, reduced regulation by the mOFC may enable them.

One model suggests that obsessions do not drive compulsions, but are rather byproducts of compulsions, as evidenced by some studies reporting excessive reliance on habit. Dysfunctional habit based learning may be a driver behind neuroimaging studies of memory reporting increased hippocampus activity. The conscious processing of information that is normally implicitly processing may be the underlying cause of obsessions.

Functional Neuroimaging

Functional neuroimaging studies have implicated multiple regions in OCD. Symptom provocation is associated with increased likelihood of activation in the bilateral orbitofrontal cortex (OFC), right anterior PFC, left dorsolateral prefrontal cortex (dlPFC), bilateral anterior cingulate cortex (ACC), left precuneus, right premotor cortex, left superior temporal gyrus (STG), bilateral external globus pallidus, left hippocampus, right insula, left caudate, right posterior cingulate cortex (PCC), and right superior parietal lobule. The medial portion of the orbitofrontal cortex connects with the paralimbic-limbic system, including the insular cortex, cingulate gryus, amygdala, and hypothalamus. This area is involved in encoding the representation of the value of an expected outcome, which is used to anticipate positive and negative consequences that are likely to follow a given action. During affective tasks hyperactivation has been observed in the ACC, insula and head of the caudate and putamen, regions implicated in salience, arousal, and habit. Hypoactivation during affective tasks is observed in the medial prefrontal cortex (mPFC) and posterior caudate, which are implicated in behavioural and cognitive control. During non-affective tasks, hyperactivation has been observed in the precuneus and PCC, while hypoactivation has been observed in the pallidum, ventral anterior thalamus and posterior caudate. An older meta analysis found hyperactivity in the OFC and ACC. An ALE meta analysis of various functional neuroimaging paradigms observed various abnormalities during Go/no go, interference, and task switching paradigms. Decreased likelihood of activation in right putamen and cerebellum was reported during Go/no go. During interference tasks, likelihood of activation was reported in the left superior frontal gyrus, right precentral gyrus, and left cingulate gyrus, to be decreased, and in the right caudate to be increased. Task switching was associated with extensive decreased likelihood of activation in the middle, medial, inferior, superior frontal gyri, caudate, cingulate and precuneus. A separate ALE meta analysis found consistent abnormalities in orbitofrontal, striatal, lateral frontal, anterior cingulate, middle occipital and parietal, and cerebellar regions.

Structural Neuroimaging

Differences in grey matter, white matter and structural connectivity have been observed in OCD. One meta-analysis reported grey matter increases in the bilateral lenticular nuclei, and grey matter decreases in the ACC (anterior cingulate cortex) and mPFC (medial prefrontal cortex).[14] Another meta-analysis reported that global volumes are not decreased, but the left ACC and OFC demonstrate decreased volume, while the thalamus but not basal ganglia have increased volumes. An ALE meta analysis found increased grey matter in the left postcentral gyrus, middle frontal region, putamen, thalamus, left ACC, and culmen, while decreased grey matter was reported in the right temporal gyrus and left insula extending to the inferior frontal gyrus.

Overlapping abnormalities in white matter volume and diffusivity have been reported. Increased white matter volume and decreased Fractional anisotropy has been observed in anterior midline tracts, interpreted as indicating increased crossings. However, given these effects were most pronounced in medicated adults, it is possible that medication plays a role An ALE meta analysis has observed increased FA in the superior longitudinal fasiculus and corpus callosum, and decreased FA in inferior longitudinal and cingulum fibres.


Glutamate, an excitatory neurotransmitter has been implicated in OCD. MRS studies have observed decreased Glx (glutamate, glutamine and GABA) in the striatum. However, increased Glx has been reported in the ACC. Furthermore, increased cerebrospinal fluid (CSF) glutamate and glycine have been found. Various preclinical models have supported glutamate signalling dysfunction in OCD, and treatment with glutamatergic agents such as the glutamate-inhibiting riluzole has been reported to be efficacious.

Reduced dopamine D1 receptors and dopamine D2 receptors in the striatum have been reported in people with OCD, along with both increased and decreased reports of dopamine transporter (DAT) binding. While antipsychotics are sometimes used to treat refractory OCD, they frequently fail in treating or exacerbate OCD symptoms. Treatment with deep brain stimulation is effective in OCD, and response correlates with increased dopamine in the nucleus accumbens. Combined this evidence suggests that OCD may be associated with both increased and decreased dopamine signalling, or that a unidirectional model may not be adequate.

Drug challenge studies have implicated 5-HT2A and 5-HT2A in OCD. Administration of meta-Chlorophenylpiperazine (mCPP), a non selective serotonin (5-HT) release and receptor agonist with a preference for 5-HT2C has been reported to exacerbate OCD symptoms. Psilocybin, a 5-HT2C, 5-HT2A and 5-HT1A receptor agonist has been associated with acute improvement of OCD symptoms. In vivo neuroimaging has found abnormalities with 5-HT2A and serotonin transporter (5-HTT). Inconsistent binding potentials have been observed for 5-HT2A, with both decreased and increased and binding potentials being reported. Inconsistent results have been reported in with respect to 5-HTT as well, with increased, decreased and no changes being reported.

Oestrogen and OCD

Aromatase is an enzyme expressed in several gonadic tissue sites. It is the rate limiting step in the conversion of androgens to oestrogen. This conversion can significantly impact oestrogen levels in brain areas. These OCD-linked effects have been demonstrated by Aromatase knockout mice (ArKO), who lack a functional enzyme to convert androgens to oestrogen. This ArKO knockout strategy has provided a model to examine the physiological impact of lower than normal amounts of oestrogen.

Studies with ArKO mice have been used to show that varying levels of oestrogen affect the onset of OCD behaviours. Lower amounts of oestrogen are associated with an increase of OCD behaviours in males more than females.

Variation in oestrogen can lead to increased levels of OCD symptoms within women as well. The disorder itself has a later onset in women, and tends to show two distinct peaks of onset. The first peak occurs around puberty and the second around the age of childbearing. These peaks correlate with time periods where oestrogen levels are highest in women.

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.

What is Gamma-Aminobutyric Acid?


gamma-Aminobutyric acid (or γ-aminobutyric acid or GABA), is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system.

GABA is sold as a dietary supplement in many countries. It has been traditionally thought that exogenous GABA (i.e. taken as a supplement) does not cross the blood-brain barrier, however data obtained from more current research indicates that it may be possible.

Brief History

In 1883, GABA was first synthesized, and it was first known only as a plant and microbe metabolic product.

In 1950, GABA was discovered as an integral part of the mammalian central nervous system.

In 1959, it was shown that at an inhibitory synapse on crayfish muscle fibres GABA acts like stimulation of the inhibitory nerve. Both inhibition by nerve stimulation and by applied GABA are blocked by picrotoxin.



Refer to GABA Receptor.

Two general classes of GABA receptor are known:

  • GABAA in which the receptor is part of a ligand-gated ion channel complex; and
  • GABAB metabotropic receptors, which are G protein-coupled receptors that open or close ion channels via intermediaries (G proteins).

Neurons that produce GABA as their output are called GABAergic neurons, and have chiefly inhibitory action at receptors in the adult vertebrate. Medium spiny cells are a typical example of inhibitory central nervous system GABAergic cells. In contrast, GABA exhibits both excitatory and inhibitory actions in insects, mediating muscle activation at synapses between nerves and muscle cells, and also the stimulation of certain glands. In mammals, some GABAergic neurons, such as chandelier cells, are also able to excite their glutamatergic counterparts.

Release, Reuptake, and Metabolism Cycle of GABA.

GABAA receptors are ligand-activated chloride channels: when activated by GABA, they allow the flow of chloride ions across the membrane of the cell. Whether this chloride flow is depolarising (makes the voltage across the cell’s membrane less negative), shunting (has no effect on the cell’s membrane potential), or inhibitory/hyperpolarising (makes the cell’s membrane more negative) depends on the direction of the flow of chloride. When net chloride flows out of the cell, GABA is depolarising; when chloride flows into the cell, GABA is inhibitory or hyperpolarising. When the net flow of chloride is close to zero, the action of GABA is shunting. Shunting inhibition has no direct effect on the membrane potential of the cell; however, it reduces the effect of any coincident synaptic input by reducing the electrical resistance of the cell’s membrane. Shunting inhibition can “override” the excitatory effect of depolarising GABA, resulting in overall inhibition even if the membrane potential becomes less negative. It was thought that a developmental switch in the molecular machinery controlling the concentration of chloride inside the cell changes the functional role of GABA between neonatal and adult stages. As the brain develops into adulthood, GABA’s role changes from excitatory to inhibitory.

Brain Development

While GABA is an inhibitory transmitter in the mature brain, its actions were thought to be primarily excitatory in the developing brain. The gradient of chloride was reported to be reversed in immature neurons, with its reversal potential higher than the resting membrane potential of the cell; activation of a GABA-A receptor thus leads to efflux of Cl− ions from the cell (that is, a depolarising current). The differential gradient of chloride in immature neurons was shown to be primarily due to the higher concentration of NKCC1 co-transporters relative to KCC2 co-transporters in immature cells. GABAergic interneurons mature faster in the hippocampus and the GABA signalling machinery appears earlier than glutamatergic transmission. Thus, GABA is considered the major excitatory neurotransmitter in many regions of the brain before the maturation of glutamatergic synapses.

In the developmental stages preceding the formation of synaptic contacts, GABA is synthesized by neurons and acts both as an autocrine (acting on the same cell) and paracrine (acting on nearby cells) signalling mediator. The ganglionic eminences also contribute greatly to building up the GABAergic cortical cell population.

GABA regulates the proliferation of neural progenitor cells, the migration and differentiation the elongation of neurites and the formation of synapses.

GABA also regulates the growth of embryonic and neural stem cells. GABA can influence the development of neural progenitor cells via brain-derived neurotrophic factor (BDNF) expression. GABA activates the GABAA receptor, causing cell cycle arrest in the S-phase, limiting growth.

Beyond the Nervous System

Besides the nervous system, GABA is also produced at relatively high levels in the insulin-producing β-cells of the pancreas. The β-cells secrete GABA along with insulin and the GABA binds to GABA receptors on the neighbouring islet α-cells and inhibits them from secreting glucagon (which would counteract insulin’s effects).

GABA can promote the replication and survival of β-cells and also promote the conversion of α-cells to β-cells, which may lead to new treatments for diabetes.

Alongside GABAergic mechanisms, GABA has also been detected in other peripheral tissues including intestines, stomach, Fallopian tubes, uterus, ovaries, testes, kidneys, urinary bladder, the lungs and liver, albeit at much lower levels than in neurons or β-cells.

Experiments on mice have shown that hypothyroidism induced by fluoride poisoning can be halted by administering GABA. The test also found that the thyroid recovered naturally without further assistance after the Fluoride had been expelled by the GABA.

Immune cells express receptors for GABA and administration of GABA can suppress inflammatory immune responses and promote “regulatory” immune responses, such that GABA administration has been shown to inhibit autoimmune diseases in several animal models.

In 2018, GABA has shown to regulate secretion of a greater number of cytokines. In plasma of T1D patients, levels of 26 cytokines are increased and of those, 16 are inhibited by GABA in the cell assays.

In 2007, an excitatory GABAergic system was described in the airway epithelium. The system is activated by exposure to allergens and may participate in the mechanisms of asthma. GABAergic systems have also been found in the testis and in the eye lens.

GABA occurs in plants.

Structure and Conformation

GABA is found mostly as a zwitterion (i.e. with the carboxyl group deprotonated and the amino group protonated). Its conformation depends on its environment. In the gas phase, a highly folded conformation is strongly favoured due to the electrostatic attraction between the two functional groups. The stabilisation is about 50 kcal/mol, according to quantum chemistry calculations. In the solid state, an extended conformation is found, with a trans conformation at the amino end and a gauche conformation at the carboxyl end. This is due to the packing interactions with the neighbouring molecules. In solution, five different conformations, some folded and some extended, are found as a result of solvation effects. The conformational flexibility of GABA is important for its biological function, as it has been found to bind to different receptors with different conformations. Many GABA analogues with pharmaceutical applications have more rigid structures in order to control the binding better.


GABA is primarily synthesized from glutamate via the enzyme glutamate decarboxylase (GAD) with pyridoxal phosphate (the active form of vitamin B6) as a cofactor. This process converts glutamate (the principal excitatory neurotransmitter) into GABA (the principal inhibitory neurotransmitter).

GABA can also be synthesized from putrescine by diamine oxidase and aldehyde dehydrogenase.

Traditionally it was thought that exogenous GABA did not penetrate the blood–brain barrier, however more current research indicates that it may be possible, or that exogenous GABA (i.e. in the form of nutritional supplements) could exert GABAergic effects on the enteric nervous system which in turn stimulate endogenous GABA production. The direct involvement of GABA in the glutamate-glutamine cycle makes the question of whether GABA can penetrate the blood-brain barrier somewhat misleading, because both glutamate and glutamine can freely cross the barrier and convert to GABA within the brain.


GABA transaminase enzymes catalyse the conversion of 4-aminobutanoic acid (GABA) and 2-oxoglutarate (α-ketoglutarate) into succinic semialdehyde and glutamate. Succinic semialdehyde is then oxidized into succinic acid by succinic semialdehyde dehydrogenase and as such enters the citric acid cycle as a usable source of energy.


Drugs that act as allosteric modulators of GABA receptors (known as GABA analogues or GABAergic drugs), or increase the available amount of GABA, typically have relaxing, anti-anxiety, and anti-convulsive effects. Many of the substances below are known to cause anterograde amnesia and retrograde amnesia.

In general, GABA does not cross the blood-brain barrier, although certain areas of the brain that have no effective blood–brain barrier, such as the periventricular nucleus, can be reached by drugs such as systemically injected GABA. At least one study suggests that orally administered GABA increases the amount of human growth hormone (HGH). GABA directly injected to the brain has been reported to have both stimulatory and inhibitory effects on the production of growth hormone, depending on the physiology of the individual. Certain pro-drugs of GABA (e.g. picamilon) have been developed to permeate the blood-brain barrier, then separate into GABA and the carrier molecule once inside the brain. Prodrugs allow for a direct increase of GABA levels throughout all areas of the brain, in a manner following the distribution pattern of the pro-drug prior to metabolism.

GABA enhanced the catabolism of serotonin into N-acetylserotonin (the precursor of melatonin) in rats. It is thus suspected that GABA is involved in the synthesis of melatonin and thus might exert regulatory effects on sleep and reproductive functions.


Although in chemical terms, GABA is an amino acid (as it has both a primary amine and a carboxylic acid functional group), it is rarely referred to as such in the professional, scientific, or medical community. By convention the term “amino acid”, when used without a qualifier, refers specifically to an alpha amino acid. GABA is not an alpha amino acid, meaning the amino group is not attached to the alpha carbon. Nor is it incorporated into proteins as are many alpha-amino acids.

GABAergic Drugs

GABAA receptor ligands are shown in the following table.

Activity at GABAALigand
Orthosteric AgonistMuscimol, GABA, gaboxadol (THIP), isoguvacine, progabide, piperidine-4-sulfonic acid (partial agonist).
Positive allosteric modulatorsBarbiturates, benzodiazepines, neuroactive steroids, niacin/niacinamide, nonbenzodiazepines (i.e. z-drugs, e.g. zolpidem, eszopiclone), etomidate, etaqualone, alcohol (ethanol), theanine, methaqualone, propofol, stiripentol, and anaesthetics (including volatile anaesthetics), glutethimide.
Orthosteric (competitive) AntagonistBicuculline, gabazine, thujone, and flumazenil.
Uncompetitive antagonist (e.g. channel blocker)Picrotoxin, and cicutoxin.
Negative allosteric modulatorsNeuroactive steroids (Pregnenolone sulfate), furosemide, oenanthotoxin, and amentoflavone.

Additionally, carisoprodol is an enhancer of GABAA activity. Ro15-4513 is a reducer of GABAA activity

GABAergic pro-drugs include chloral hydrate, which is metabolised to trichloroethanol, which then acts via the GABAA receptor.

Skullcap and valerian are plants containing GABAergic substances[citation needed]. Furthermore, the plant kava contains GABAergic compounds, including kavain, dihydrokavain, methysticin, dihydromethysticin and yangonin.

Other GABAergic modulators include:

  • GABAB receptor ligands.
    • Agonists: baclofen, propofol, GHB, and phenibut.
    • Antagonists: phaclofen and saclofen.
  • GABA reuptake inhibitors: deramciclane, hyperforin, and tiagabine.
  • GABA transaminase inhibitors: gabaculine, phenelzine, valproate, vigabatrin, and lemon balm (Melissa officinalis).
  • GABA analogues: pregabalin, gabapentin, picamilon, and progabide.

In Plants

GABA is also found in plants. It is the most abundant amino acid in the apoplast of tomatoes. Evidence also suggests a role in cell signalling in plants.

What is a Serotonin-Norepinephrine Reuptake Inhibitor?


Serotonin-norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant drugs that treat major depressive disorder (MDD), anxiety disorders, obsessive-compulsive disorder (OCD), social phobia, attention-deficit hyperactivity disorder (ADHD), chronic neuropathic pain, fibromyalgia syndrome (FMS), and menopausal symptoms. SNRIs are monoamine reuptake inhibitors; specifically, they inhibit the reuptake of serotonin and norepinephrine. These neurotransmitters are thought to play an important role in mood regulation. SNRIs can be contrasted with the more widely used selective serotonin reuptake inhibitors (SSRIs), which act upon serotonin only.

The human serotonin transporter (SERT) and norepinephrine transporter (NET) are membrane transport proteins that are responsible for the reuptake of serotonin and norepinephrine from the synaptic cleft back into the presynaptic nerve terminal. Dual inhibition of serotonin and norepinephrine reuptake can offer advantages over other antidepressant drugs by treating a wider range of symptoms. They can be especially useful in concomitant chronic or neuropathic pain.

SNRIs, along with SSRIs and norepinephrine reuptake inhibitors (NRIs), are second-generation antidepressants. Over the past two decades, second-generation antidepressants have simply replaced first-generation antidepressants, such as tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), as the drugs of choice for the treatment of MDD due to their improved tolerability and safety profile.


There are eight FDA approved SNRIs in the United States, with venlafaxine being the first drug to be developed in 1993 and levomilnacipran being the latest drug to be developed in 2013. The drugs vary by their other medical uses, chemical structure, adverse effects, and efficacy.

  • Atomoxetine.
  • Desvenlafaxine.
  • Duloxetine.
  • Levomilnacipran.
  • Milnacipran.
  • Sibutramine.
  • Tramadol.
  • Venlafaxine.

Brief History

Refer to Development and Discovery of SSRI Drugs.

In 1952, iproniazid, an antimycobacterial agent, was discovered to have psychoactive properties while researched as a possible treatment for tuberculosis. Researchers noted that patients given iproniazid became cheerful, more optimistic, and more physically active. Soon after its development, iproniazid and related substances were shown to slow enzymatic breakdown of serotonin, dopamine, and norepinephrine via inhibition of the enzyme monoamine oxidase. For this reason, this class of drugs became known as monoamine oxidase inhibitors, or MAOIs. During this time development of distinctively different antidepressant agents was also researched. Imipramine became the first clinically useful tricyclic antidepressant (TCA). Imipramine was found to affect numerous neurotransmitter systems and to block the reuptake of norepinephrine and serotonin from the synapse, therefore increasing the levels of these neurotransmitters. Use of MAOIs and TCAs gave major advances in treatment of depression but their use was limited by unpleasant side effects and significant safety and toxicity issues.

Throughout the 1960s and 1970s, the catecholamine hypothesis of emotion and its relation to depression was of wide interest and that the decreased levels of certain neurotransmitters, such as norepinephrine, serotonin, and dopamine might play a role in the pathogenesis of depression. This led to the development of fluoxetine, the first SSRI. The improved safety and tolerability profile of the SSRIs in patients with MDD, compared with TCAs and MAOIs, represented yet another important advance in the treatment of depression.

Since the late 1980s, SSRIs have dominated the antidepressant drug market. Today, there is increased interest in antidepressant drugs with broader mechanisms of action that may offer improvements in efficacy and tolerability. In 1993, a new drug was introduced to the US market called venlafaxine, a SNRI. Venlafaxine was the first compound described in a new class of antidepressive substances called phenylethylamines. These substances are unrelated to TCA and other SSRIs. Venlafaxine blocks the neuronal reuptake of serotonin, noradrenaline, and, to a lesser extent, dopamine in the central nervous system. In contrast with several other antidepressant drugs, venlafaxine can induce a rapid onset of action mainly due to a subsequent norepinephrine reuptake inhibition.

Mechanism of Action

Monoamines are connected to the pathophysiology of depression. Symptoms may occur because concentrations of neurotransmitters, such as norepinephrine and serotonin, are insufficient, leading to downstream changes. Medications for depression affect the transmission of serotonin, norepinephrine, and dopamine. Older and more unselective antidepressants like TCAs and MAOIs inhibit the reuptake or metabolism of norepinephrine and serotonin in the brain, which results in higher concentrations of neurotransmitters. Antidepressants that have dual mechanisms of action inhibit the reuptake of both serotonin and norepinephrine and, in some cases, inhibit with weak effect the reuptake of dopamine. Antidepressants affect variable neuronal receptors like muscarinic-cholinergic, α1- and α2-adrenergic, and H1-histaminergic receptors, and sodium channels in the cardiac muscle, leading to decreased cardiac conduction and cardiotoxicity {source needed}. Selectivity of antidepressant agents are based on the neurotransmitters that are thought to influence symptoms of depression. Drugs that selectively block the reuptake of serotonin and norepinephrine effectively treat depression and are better tolerated than TCAs. TCAs have comprehensive effects on various neurotransmitters receptors, which leads to lack of tolerability and increased risk of toxicity.

Tricyclic Antidepressants

TCAs were the first medications that had dual mechanism of action. The mechanism of action of tricyclic secondary amine antidepressants is only partly understood. TCAs have dual inhibition effects on norepinephrine reuptake transporters and serotonin reuptake transporters. Increased norepinephrine and serotonin concentrations are obtained by inhibiting both of these transporter proteins. TCAs have substantially more affinity for norepinephrine reuptake proteins than the SSRIs. This is because of a formation of secondary amine TCA metabolites.

In addition, the TCAs interact with adrenergic receptors. This interaction seems to be critical for increased availability of norepinephrine in or near the synaptic clefts. Actions of imipramine-like tricyclic antidepressants have complex, secondary adaptions to their initial and sustained actions as inhibitors of norepinephrine transport and variable blockade of serotonin transport.

Norepinephrine interacts with postsynaptic α and β adrenergic receptor subtypes and presynaptic α2 autoreceptors. The α2 receptors include presynaptic autoreceptors which limit the neurophysiological activity of noradrenergic neurons in the central nervous system. Formation of norepinephrine is reduced by autoreceptors through the rate-limiting enzyme tyrosine hydroxylase, an effect mediated by decreased cyclic AMP-mediated phosphorylation-activation of the enzyme. α2 receptors also cause decreased intracellular cyclic AMP expression which results in smooth muscle relaxation or decreased secretion.

TCAs activate a negative feedback mechanism through their effects on presynaptic receptors. One probable explanation for the effects on decreased neurotransmitter release is that, as the receptors activate, inhibition of neurotransmitter release occurs (including suppression of voltage-gated Ca2+ currents and activation of G protein-coupled receptor-operated K+ currents). Repeated exposure of agents with this type of mechanism leads to inhibition of neurotransmitter release, but repeated administration of TCAs finally leads to decreased responses by α2 receptors. The desensitization of these responses may be due to increased exposure to endogenous norepinephrine or from the prolonged occupation of the norepinephrine transport mechanisms (via an allosteric effect). The adaptation allows the presynaptic synthesis and secretion of norepinephrine to return to, or even exceed, normal levels of norepinephrine in the synaptic clefts. Overall, inhibition of norepinephrine reuptake induced by TCAs leads to decreased rates of neuron firing (mediated through α2 autoreceptors), metabolic activity, and release of neurotransmitters.

TCAs do not block dopamine transport directly but might facilitate dopaminergic effects indirectly by inhibiting dopamine transport into noradrenergic terminals of the cerebral cortex. Because they affect so many different receptors, TCAs have adverse effects, poor tolerability, and an increased risk of toxicity.

Selective Serotonin Reuptake Inhibitors

Selective serotonin reuptake inhibitors (SSRIs) selectively inhibit the reuptake of serotonin and are a widely used group of antidepressants. With increased receptor selectivity compared to TCAs, undesired effects such as poor tolerability are avoided. Serotonin is synthesized from an amino acid called L-tryptophan. Active transport system regulates the uptake of tryptophan across the blood-brain barrier. Serotonergic pathways are classified into two main ways in the brain: the ascending projections from the medial and dorsal raphe and the descending projections from the caudal raphe into the spinal cord.

Selective Norepinephrine Reuptake Inhibitors

Noradrenergic neurons are located in two major regions in the brain. These regions are locus coeruleus and lateral tegmental. With administration of SNRIs, neuronal activity in locus coeruleus region is induced because of increased concentration of norepinephrine in the synaptic cleft. This results in activation of α2 adrenergic receptors, as discussed previously.

Assays have shown that SNRIs have insignificant penchant for mACh, α1 and α2 adrenergic, or H1 receptors.

Dual Serotonin and Norepinephrine Reuptake Inhibitors

Agents with dual serotonin and norepinephrine reuptake inhibition (SNRIs) are sometimes called non-tricyclic serotonin and norepinephrine reuptake inhibitors. Clinical studies suggest that compounds that increase the concentration in the synaptic cleft of both norepinephrine and serotonin are more successful than single acting agents in the treatment of depression, but the data is not conclusive whether SNRIs are a more effective treatment option over SSRIs for depression. Dual reuptake inhibitors have low affinity at neuronal receptors of the other neurotransmitters, which have low adverse effects compared with the TCAs. Nontricyclic antidepressants have improved potency and onset action acceleration in antidepressant response than SSRIs alone, which give the impression that synergism is an efficient property in mediating antidepressant activity.

The non-tricyclic SNRIs have several important differences that are based on pharmacokinetics, metabolism to active metabolites, inhibition of CYP isoforms, effect of drug-drug interactions, and the half-life of the nontricyclic SNRIs.

Combination of mechanisms of action in a single active agent is an important development in psychopharmacology.

Structure Activity Relationship (SAR)

Aryloxypropanamine Scaffold

Several reuptake inhibitors contain an aryloxypropanamine scaffold. This structural motif has potential for high affinity binding to biogenic amine transports. Drugs containing an aryloxypropanamine scaffold have selectivity profile for norepinephrine and serotonin transporters that depends on the substitution pattern of the aryloxy ring. Selective NRIs contain a substituent in 2′ position of the aryloxy ring but SSRIs contain a substituent in 4′ position of the aryloxy ring. Atomoxetine, nisoxetine and reboxetine all have a substitution group in the 2′ position and are selective NRIs while compounds that have a substitution group in the 4′ position (like fluoxetine and paroxetine) are SSRIs. Duloxetine contains a phenyl group fused at the 2′ and 3′ positions, therefore it has dual selective norepinephrine and serotonin reuptake inhibitory effects and has similar potencies for the both transporters. The nature of the aromatic substituent also has a significant influence on the activity and selectivity of the compounds as inhibitors of the serotonin or the norepinephrine transporters.

Cycloalkanol Ethylamine Scaffold

Venlafaxine and desvenlafaxine contain a cycloalkanol ethylamine scaffold. Increasing the electron-withdrawing nature of the aromatic ring provides a more potent inhibitory effect of norepinephrine uptake and improves the selectivity for norepinephrine over the serotonin transporter. Effects of chloro, methoxy and trifluoromethyl substituents in the aromatic ring of cycloalkanol ethylamine scaffold were tested. The results showed that the strongest electron-withdrawing m-trifluoromethyl analogue exhibited the most potent inhibitory effect of norepinephrine and the most selectivity over serotonin uptake. WY-46824, a piperazine-containing derivative, has shown norepinephrine and dopamine reuptake inhibition. Further synthesis and testing identified WAY-256805, a potent norepinephrine reuptake inhibitor that exhibited excellent selectivity and was efficacious in animal models of depression, pain, and thermoregulatory dysfunction.


Milnacipran is structurally different from other SNRIs. The SAR of milnacipran derivatives at transporter level is still largely unclear and is based on in vivo efficacy that was reported in 1987. N-methylation of milnacipran in substituent group R4 and R5 reduces the norepinephrine and serotonin activity. Researches on different secondary amides in substitution groups R6 and R7 showed that π electrons play an important role in the interaction between transporters and ligands. A phenyl group in substituent R6 showed effect on norepinephrine transporters. Substituent groups in R6 and R7 with allylic double bond showed significant improved effect on both norepinephrine and serotonin transporters. Studies show that introducing a 2-methyl group in substituent R3, the potency at norepinephrine and serotonin transporters are almost abolished. Methyl groups in substituent groups R1 and R2 also abolish the potency at norepinephrine and serotonin transporters. Researchers found that replacing one of the ethyl groups of milnacipran with an allyl moiety increases the norepinephrine potency. The pharmacophore of milnacipran derivatives is still largely unclear.

The conformation of milnacipran is an important part of its pharmacophore. Changing the SAR in milnacipran changes the stereochemistry of the compound and affects the norepinephrine and serotonin concentration. Milnacipran is marketed as a racemic mixture. Effects of milnacipran reside in the (1S,2R)-isomer and substitution of the phenyl group in the (1S,2R)-isomer has negative impact on norepinephrine concentration. Milnacipran has low molecular weight and low lipophilicity. Because of these properties, milnacipran exhibits almost ideal pharmacokinetics in humans such as high bioavailability, low inter-subject variability, limited liver enzyme interaction, moderate tissue distribution and a reasonably long elimination half-life. Milnacipran’s lack of drug-drug interactions via cytochrome P450 enzymes is thought to be an attractive feature because many of the central nervous system drugs are highly lipophilic and are mainly eliminated by liver enzymes.

Future Development of SAR

The application of an aryloxypropanamine scaffold has generated a number of potent MAOIs. Before the development of duloxetine, the exploration of aryloxypropanamine SAR resulted in the identification of fluoxetine and atomoxetine. The same motif can be found in reboxetine where it is constrained in a morpholine ring system. Some studies have been made where the oxygen in reboxetine is replaced by sulfur to give arylthiomethyl morpholine. Some of the arylthiomethyl morpholine derivatives maintain potent levels of serotonin and norepinephrine reuptake inhibition. Dual serotonin and norepinephrine reuptake inhibition resides in different enantiomers for arylthiomethyl morpholine scaffold. Possible drug candidates with dual serotonin and norepinephrine reuptake inhibitory activity have also been derived from piperazine, 3-amino-pyrrolidine and benzylamine templates.

Clinical Trials


Several studies have shown that antidepressant drugs which have combined serotonergic and noradrenergic activity are generally more effective than SSRIs, which act upon serotonin reuptake by itself. Serotonergic-noradrenergic antidepressant drugs may have a modest efficacy advantage compared to SSRIs in treating major depressive disorder (MDD), but are slightly less well tolerated. Further research is needed to examine the possible differences of efficacy in specific MDD sub-populations or for specific MDD symptoms, between these classes of antidepressant drugs.


Data from clinical trials have indicated that SNRIs might have pain relieving properties. Although the perception and transmission of pain stimuli in the central nervous system have not been fully elucidated, extensive data support a role for serotonin and norepinephrine in the modulation of pain. Findings from clinical trials in humans have shown these antidepressants can to reduce pain and functional impairment in central and neuropathic pain conditions. This property of SNRIs might be used to reduce doses of other pain relieving medication and lower the frequency of safety, limited efficacy and tolerability issues. Clinical research data have shown in patients with GAD that the SNRI duloxetine is significantly more effective than placebo in reducing pain-related symptoms of GAD, after short-term and long-term treatment. However, findings suggested that such symptoms of physical pain reoccur in relapse situations, which indicates a need for ongoing treatment in patients with GAD and concurrent painful physical symptoms.


SNRIs have been tested for treatment of the following conditions:


Route of Administration

SNRIs are delivered orally, usually in the form of capsules or tablets. It is recommended to take SNRIs in the morning with breakfast, which does not affect drug levels, but may help with certain side effects. Norepinephrine has activating effects in the body and therefore can cause insomnia in some patients if taken at bedtime. SNRIs can also cause nausea, which is usually mild and goes away within a few weeks of treatment, but taking the medication with food can help alleviate this. The drugs themselves are usually a fine crystalline powder that diffuses into the body during digestion.


Dosages vary depending on the SNRI used due to varying potencies of the drug in question as well as multiple strengths for each drug.

Mode of Action

The condition for which SNRIs are mostly indicated, major depressive disorder, is thought to be mainly caused by decreased levels of serotonin and norepinephrine in the synaptic cleft, causing erratic signalling. Based on the monoamine hypothesis of depression, which asserts that decreased concentrations of monoamine neurotransmitters leads to depressive symptoms, the following relations were determined: “Norepinephrine may be related to alertness and energy as well as anxiety, attention, and interest in life; [lack of] serotonin to anxiety, obsessions, and compulsions; and dopamine to attention, motivation, pleasure, and reward, as well as interest in life.” SNRIs work by inhibiting the reuptake of the neurotransmitters serotonin and norepinephrine. This results in increased extracellular concentrations of serotonin and norepinephrine and, consequently, an increase in neurotransmission. Most SNRIs including venlafaxine, desvenlafaxine, and duloxetine, are several fold more selective for serotonin over norepinephrine, while milnacipran is three times more selective for norepinephrine than serotonin. Elevation of norepinephrine levels is thought to be necessary for an antidepressant to be effective against neuropathic pain, a property shared with the older tricyclic antidepressants (TCAs), but not with the SSRIs.

Recent studies have shown that depression may be linked to increased inflammatory response, thus attempts at finding an additional mechanism for SNRIs have been made. Studies have shown that SNRIs as well as SSRIs have significant anti-inflammatory action on microglia in addition to their effect on serotonin and norepinephrine levels. As such, it is possible that an additional mechanism of these drugs that acts in combination with the previously understood mechanism exist. The implication behind these findings suggests use of SNRIs as potential anti-inflammatories following brain injury or any other disease where swelling of the brain is an issue. However, regardless of the mechanism, the efficacy of these drugs in treating the diseases for which they have been indicated has been proven, both clinically and in practice.


Most SNRIs function alongside primary metabolites and secondary metabolites in order to inhibit reuptake of serotonin, norepinepherine, and marginal amounts of dopamine. For example, venlafaxine works alongside its primary metabolite O-desmethylvenlafaxine to strongly inhibit serotonin and norepinephrine reuptake in the brain. The evidence also suggests that dopamine and norepinepherine behave in a co-transportational manner, due to the inactivation of dopamine by norepinephrine reuptake in the frontal cortex, an area of the brain largely lacking in dopamine transporters. This effect of SNRIs results in increased dopamine neurotransmission, in addition to the increases in serotonin and norepinephrine activity. Furthermore, because SNRIs are extremely selective, they have no measurable effects on other, unintended receptors, in contrast to monoamine oxidase inhibition. Pharmaceutical tests have determined that use of both SNRIs or SSRIs can generate significant anti-inflammatory action on microglia, as well.


The half-life of venlafaxine is about 5 hours, and with once-daily dosing, steady-state concentration is achieved after about 3 days, though its active metabolite desvenlafaxine lasts longer. The half-life of desvenlafaxine is about 11 hours, and steady-state concentrations are achieved after 4 to 5 days. The half-life of duloxetine is about 12 hours (range: 8-17 hours), and steady-state is achieved after about 3 days. Milnacipran has a half-life of about 6 to 8 hours, and steady-state levels are reached within 36 to 48 hours.


SNRIs are contraindicated in patients taking MAOIs within the last two weeks due to the increased risk of serotonin syndrome, which can be life-threatening.[65] Other drugs and substances that should be avoided due to increased risk of serotonin syndrome when combined with an SNRI include: other anti-depressants, anti-convulsants, analgesics, antiemetic agents, anti-migraine medications, methylene blue, linezolid, Lithium, St. John’s worts, ecstasy, and LSD. Signs and symptoms of serotonin syndrome include: hyperthermia, rigidity, myoclonus, autonomic instability with fluctuating vital signs, and mental status changes that include extreme agitation progressing to delirium and coma.

Due to the effects of increased norepinephrine levels and, therefore, higher noradrenergic activity, pre-existing hypertension should be controlled before treatment with SNRIs and blood pressure periodically monitored throughout treatment. Duloxetine has also been associated with cases of liver failure and should not be prescribed to patients with chronic alcohol use or liver disease. Studies have found that Duloxetine can increase liver function tests three times above their upper normal limit. Patients suffering from coronary artery disease should caution the use of SNRIs. Furthermore, due to some SNRIs’ actions on obesity, patients with major eating disorders such as anorexia nervosa or bulimia should not be prescribed SNRIs. Duloxetine and milnacipran are also contraindicated in patients with uncontrolled narrow-angle glaucoma, as they have been shown to increase incidence of mydriasis.

Side Effects

Because the SNRIs and SSRIs act in similar ways to elevate serotonin levels, they share many side effects, though to varying degrees. The most common side effects include nausea/vomiting, sweating, loss of appetite, dizziness, headache, increase in suicidal thoughts, and sexual dysfunction. Elevation of norepinephrine levels can sometimes cause anxiety, mildly elevated pulse, and elevated blood pressure. However, norepinephrine-selective antidepressants, such as reboxetine and desipramine, have successfully treated anxiety disorders. People at risk for hypertension and heart disease should monitor their blood pressure. The side effects of upset stomach may be decreased by taking SNRIs with food.

Sexual Dysfunction

SNRIs, similarly to SSRIs, can cause several types of sexual dysfunction, such as erectile dysfunction, decreased libido, sexual anhedonia, and anorgasmia. The two common sexual side effects are diminished interest in sex (libido) and difficulty reaching climax (anorgasmia), which are usually somewhat milder with SNRIs compared to SSRIs. To manage sexual dysfunction, studies have shown that switching to or augmenting with bupropion or adding a PDE5 Inhibitor have decreased symptoms of sexual dysfunction. Studies have shown that PDE5 Inhibitors, such as sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra), and avanafil (Stendra), have sometimes been helpful to decrease the sexual dysfunction, including erectile dysfunction, although they have been shown to be more effective in men than women.

Serotonin Syndrome

A serious, but rare, side effect of SNRIs is serotonin syndrome, which is caused by an excess of serotonin in the body. Serotonin syndrome can be caused by taking multiple serotonergic drugs, such as SSRIs or SNRIs. Other drugs that contribute to serotonin syndrome include MAO inhibitors, linezolid, tedizolid, methylene blue, procarbazine, amphetamines, clomipramine, and more. Early symptoms of serotonin syndrome may include nausea, vomiting, diarrhoea, sweating, agitation, confusion, muscle rigidity, dilated pupils, hyperthermia, rigidity, and goose bumps. More severe symptoms include fever, seizures, irregular heartbeat, delirium, and coma. If signs or symptoms arise, discontinue treatment with serotonergic agents immediately. It is recommended to washout 4 to 5 half-lives of the serotonergic agent before using an MAO inhibitor.


Some studies suggest there are risks of upper gastrointestinal bleeding, especially venlafaxine, due to impairment of platelet aggregation and depletion of platelet serotonin levels. Similarly to SSRIs, SNRIs may interact with anticoagulants, like warfarin. Currently, there is more evidence of SSRIs having higher risk of bleeding than SNRIs. Studies have suggested caution when using SNRIs or SSRIs with high doses of nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen or naproxen due to an increased risk of upper GI bleeding.


Starting an SNRI Regimen

Due to the extreme changes in noradrenergic activity produced from norepinephrine and serotonin reuptake inhibition, patients that are just starting an SNRI regimen are usually given lower doses than their expected final dosing to allow the body to acclimate to the drug’s effects. As the patient continues along at low doses without any side-effects, the dose is incrementally increased until the patient sees improvement in symptoms without detrimental side-effects.

Discontinuation Syndrome

As with SSRIs, the abrupt discontinuation of an SNRI usually leads to withdrawal, or “discontinuation syndrome“, which could include states of anxiety and other symptoms. Therefore, it is recommended that users seeking to discontinue an SNRI slowly taper the dose under the supervision of a professional. Discontinuation syndrome has been reported to be markedly worse for venlafaxine when compared to other SNRIs. As such, as tramadol is related to venlafaxine, the same conditions apply. This is likely due to venlafaxine’s relatively short half-life and therefore rapid clearance upon discontinuation. In some cases, switching from venlafaxine to fluoxetine, a long-acting SSRI, and then tapering off fluoxetine, may be recommended to reduce discontinuation symptoms. Signs and symptoms of withdrawal from abrupt cessation of an SNRI include dizziness, anxiety, insomnia, nausea, sweating, and flu-like symptoms, such as lethargy and malaise.



Overdosing on SNRIs can be caused by either drug combinations or excessive amounts of the drug itself. Venlafaxine is marginally more toxic in overdose than duloxetine or the SSRIs. Risk of overdose is increased in patients taking multiple serotonergic agents or interacting agents.


Symptoms of SNRI overdose, whether it be a mixed drug interaction or the drug alone, vary in intensity and incidence based on the amount of medicine taken and the individuals sensitivity to SNRI treatment. Possible symptoms may include:

  • Somnolence.
  • Coma.
  • Serotonin syndrome.
  • Seizures.
  • Syncope.
  • Tachycardia.
  • Hypotension.
  • Hypertension.
  • Hyperthermia.
  • Vomiting.


Overdose is usually treated symptomatically, especially in the case of serotonin syndrome, which requires treatment with cyproheptadine and temperature control based on the progression of the serotonin toxicity. Patients are often monitored for vitals and airways cleared to ensure that they are receiving adequate levels of oxygen. Another option is to use activated carbon in the GI tract in order to absorb excess neurotransmitter. It is important to consider drug interactions when dealing with overdose patients, as separate symptoms can arise.

Comparison to SSRIs

Because SNRIs were developed more recently than SSRIs, there are relatively few of them. However, the SNRIs are among the most widely used antidepressants today. In 2009, Cymbalta and Effexor were the 11th- and 12th-most-prescribed branded drugs in the United States, respectively. This translates to the 2nd- and 3rd-most-common antidepressants, behind Lexapro (escitalopram), an SSRI. In some studies, SNRIs demonstrated slightly higher antidepressant efficacy than the SSRIs (response rates 63.6% versus 59.3%). However, in one study escitalopram had a superior efficacy profile to venlafaxine.

Special Populations


Currently, no antidepressants are FDA approved during pregnancy. All SSRIs and SNRIs are Category C, except paroxetine, which is Category D since it has shown association with congenital heart disorders. Use of antidepressants during pregnancy may result in foetus abnormalities affecting functional development of the brain and behaviour. Untreated depression may also affect birth outcomes, so it is recommended to discuss options with a provider to weigh the risks and benefits.


SSRIs and SNRIs have been shown to be effective in treating major depressive disorder and anxiety in paediatric populations. However, there is a risk of increased suicidality in paediatric populations for treatment of major depressive disorder, especially with venlafaxine. Fluoxetine is the only antidepressant that is approved for child/adolescent major depressive disorder.


Most antidepressants, including SNRIs, are safe and effective in the geriatric population. Decisions are often based on co-morbid conditions, drug interactions, and patient tolerance. Due to differences in body composition and metabolism, starting doses are often half that of the recommended dose for younger adults.

What is Diazepam?


Diazepam, first marketed as Valium, is a medicine of the benzodiazepine family that acts as an anxiolytic.

It is commonly used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, benzodiazepine withdrawal syndrome, muscle spasms, insomnia, and restless legs syndrome. It may also be used to cause memory loss during certain medical procedures. It can be taken by mouth, inserted into the rectum, injected into muscle, injected into a vein or used as a nasal spray. When given into a vein, effects begin in one to five minutes and last up to an hour. By mouth, effects begin after 15 to 60 minutes.

Common side effects include sleepiness and trouble with coordination. Serious side effects are rare. They include suicide, decreased breathing, and an increased risk of seizures if used too frequently in those with epilepsy. Occasionally, excitement or agitation may occur. Long term use can result in tolerance, dependence, and withdrawal symptoms on dose reduction. Abrupt stopping after long-term use can be potentially dangerous. After stopping, cognitive problems may persist for six months or longer. It is not recommended during pregnancy or breastfeeding. Its mechanism of action is by increasing the effect of the neurotransmitter gamma-aminobutyric acid (GABA).

Diazepam was patented in 1959 by Hoffmann-La Roche. It has been one of the most frequently prescribed medications in the world since its launch in 1963. In the United States it was the highest selling medication between 1968 and 1982, selling more than 2 billion tablets in 1978 alone. In 2018, it was the 115th most commonly prescribed medication in the United States, with more than 6 million prescriptions. In 1985 the patent ended, and there are more than 500 brands available on the market. It is on the World Health Organisation’s List of Essential Medicines.

Brief History

Diazepam was the second benzodiazepine invented by Leo Sternbach of Hoffmann-La Roche at the company’s Nutley, New Jersey, facility following chlordiazepoxide (Librium), which was approved for use in 1960. Released in 1963 as an improved version of Librium, diazepam became incredibly popular, helping Roche to become a pharmaceutical industry giant. It is 2.5 times more potent than its predecessor, which it quickly surpassed in terms of sales. After this initial success, other pharmaceutical companies began to introduce other benzodiazepine derivatives.

The benzodiazepines gained popularity among medical professionals as an improvement over barbiturates, which have a comparatively narrow therapeutic index, and are far more sedative at therapeutic doses. The benzodiazepines are also far less dangerous; death rarely results from diazepam overdose, except in cases where it is consumed with large amounts of other depressants (such as alcohol or opioids). Benzodiazepine drugs such as diazepam initially had widespread public support, but with time the view changed to one of growing criticism and calls for restrictions on their prescription.

Marketed by Roche using an advertising campaign conceived by the William Douglas McAdams Agency under the leadership of Arthur Sackler, diazepam was the top-selling pharmaceutical in the United States from 1969 to 1982, with peak annual sales in 1978 of 2.3 billion tablets. Diazepam, along with oxazepam, nitrazepam and temazepam, represents 82% of the benzodiazepine market in Australia. While psychiatrists continue to prescribe diazepam for the short-term relief of anxiety, neurology has taken the lead in prescribing diazepam for the palliative treatment of certain types of epilepsy and spastic activity, for example, forms of paresis. It is also the first line of defence for a rare disorder called stiff-person syndrome.

Medical Uses

Diazepam is mainly used to treat anxiety, insomnia, panic attacks and symptoms of acute alcohol withdrawal. It is also used as a premedication for inducing sedation, anxiolysis, or amnesia before certain medical procedures (e.g. endoscopy). In 2020, it was approved for use in the United States as a nasal spray to interrupt seizure activity in people with epilepsy. Diazepam is the most commonly used benzodiazepine for “tapering” benzodiazepine dependence due to the drug’s comparatively long half-life, allowing for more efficient dose reduction. Benzodiazepines have a relatively low toxicity in overdose.

Diazepam has a number of uses including:

  • Treatment of anxiety, panic attacks, and states of agitation.
  • Treatment of neurovegetative symptoms associated with vertigo.
  • Treatment of the symptoms of alcohol, opiate, and benzodiazepine withdrawal.
  • Short-term treatment of insomnia.
  • Treatment of muscle spasms.
  • Treatment of tetanus, together with other measures of intensive treatment.
  • Adjunctive treatment of spastic muscular paresis (paraplegia/tetraplegia) caused by cerebral or spinal cord conditions such as stroke, multiple sclerosis, or spinal cord injury (long-term treatment is coupled with other rehabilitative measures).
  • Palliative treatment of stiff person syndrome.
  • Pre- or postoperative sedation, anxiolysis or amnesia (e.g. before endoscopic or surgical procedures).
  • Treatment of complications with a hallucinogen crisis and stimulant overdoses and psychosis, such as LSD, cocaine, or methamphetamine.

Used in treatment of organophosphate poisoning and reduces the risk of seizure induced brain and cardiac damage.

  • Preventive treatment of oxygen toxicity during hyperbaric oxygen therapy.

Dosages should be determined on an individual basis, depending on the condition being treated, severity of symptoms, patient body weight, and any other conditions the person may have.


Intravenous diazepam or lorazepam are first-line treatments for status epilepticus. However, intravenous lorazepam has advantages over intravenous diazepam, including a higher rate of terminating seizures and a more prolonged anticonvulsant effect. Diazepam gel was better than placebo gel in reducing the risk of non-cessation of seizures. Diazepam is rarely used for the long-term treatment of epilepsy because tolerance to its anticonvulsant effects usually develops within six to 12 months of treatment, effectively rendering it useless for that purpose.

The anticonvulsant effects of diazepam can help in the treatment of seizures due to a drug overdose or chemical toxicity as a result of exposure to sarin, VX, or soman (or other organophosphate poisons), lindane, chloroquine, physostigmine, or pyrethroids.

Diazepam is sometimes used intermittently for the prevention of febrile seizures that may occur in children under five years of age. Recurrence rates are reduced, but side effects are common. Long-term use of diazepam for the management of epilepsy is not recommended; however, a subgroup of individuals with treatment-resistant epilepsy benefit from long-term benzodiazepines, and for such individuals, clorazepate has been recommended due to its slower onset of tolerance to the anticonvulsant effects.

Alcohol Withdrawal

Because of its relatively long duration of action, and evidence of safety and efficacy, diazepam is preferred over other benzodiazepines for treatment of persons experiencing moderate to severe alcohol withdrawal. An exception to this is when a medication is required intramuscular in which case either lorazepam or midazolam is recommended.


Diazepam is used for the emergency treatment of eclampsia, when IV magnesium sulfate and blood-pressure control measures have failed. Benzodiazepines do not have any pain-relieving properties themselves, and are generally recommended to avoid in individuals with pain. However, benzodiazepines such as diazepam can be used for their muscle-relaxant properties to alleviate pain caused by muscle spasms and various dystonias, including blepharospasm. Tolerance often develops to the muscle relaxant effects of benzodiazepines such as diazepam. Baclofen or tizanidine is sometimes used as an alternative to diazepam.


Diazepam is marketed in over 500 brands throughout the world. It is supplied in oral, injectable, inhalation, and rectal forms.

The United States military employs a specialised diazepam preparation known as Convulsive Antidote, Nerve Agent (CANA), which contains diazepam. One CANA kit is typically issued to service members, along with three Mark I NAAK kits, when operating in circumstances where chemical weapons in the form of nerve agents are considered a potential hazard. Both of these kits deliver drugs using autoinjectors. They are intended for use in “buddy aid” or “self aid” administration of the drugs in the field prior to decontamination and delivery of the patient to definitive medical care.


Use of diazepam should be avoided, when possible, in individuals with:

  • Ataxia.
  • Severe hypoventilation.
  • Acute narrow-angle glaucoma.
  • Severe hepatic deficiencies (hepatitis and liver cirrhosis decrease elimination by a factor of two).
  • Severe renal deficiencies (for example, patients on dialysis).
  • Liver disorders.
  • Severe sleep apnoea.
  • Severe depression, particularly when accompanied by suicidal tendencies.
  • Psychosis.
  • Pregnancy or breast feeding.
  • Caution required in elderly or debilitated patients.
  • Coma or shock.
  • Abrupt discontinuation of therapy.
  • Acute intoxication with alcohol, narcotics, or other psychoactive substances (with the exception of hallucinogens or some stimulants, where it is occasionally used as a treatment for overdose).
  • History of alcohol or drug dependence.
  • Myasthenia gravis, an autoimmune disorder causing marked fatiguability.
  • Hypersensitivity or allergy to any drug in the benzodiazepine class.


  • Benzodiazepine abuse and misuse should be guarded against when prescribed to those with alcohol or drug dependencies or who have psychiatric disorders.
  • Paediatric patients.
    • Less than 18 years of age, this treatment is usually not indicated, except for treatment of epilepsy, and pre- or postoperative treatment. The smallest possible effective dose should be used for this group of patients.
    • Under 6 months of age, safety and effectiveness have not been established; diazepam should not be given to those in this age group.
  • Elderly and very ill patients can possibly suffer apnoea or cardiac arrest. Concomitant use of other central nervous system depressants increases this risk. The smallest possible effective dose should be used for this group of people. The elderly metabolise benzodiazepines much more slowly than younger adults, and are also more sensitive to the effects of benzodiazepines, even at similar blood plasma levels. Doses of diazepam are recommended to be about half of those given to younger people, and treatment limited to a maximum of two weeks. Long-acting benzodiazepines such as diazepam are not recommended for the elderly. Diazepam can also be dangerous in geriatric patients owing to a significant increased risk of falls.
  • Intravenous or intramuscular injections in hypotensive people or those in shock should be administered carefully and vital signs should be monitored.
  • Benzodiazepines such as diazepam are lipophilic and rapidly penetrate membranes, so rapidly cross over into the placenta with significant uptake of the drug. Use of benzodiazepines including diazepam in late pregnancy, especially high doses, can result in floppy infant syndrome. Diazepam when taken late in pregnancy, during the third trimester, causes a definite risk of a severe benzodiazepine withdrawal syndrome in the neonate with symptoms including hypotonia, and reluctance to suck, to apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. Floppy infant syndrome and sedation in the newborn may also occur. Symptoms of floppy infant syndrome and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth.

Adverse Effects

Adverse effects of benzodiazepines such as diazepam include anterograde amnesia, confusion (especially pronounced in higher doses) and sedation. The elderly are more prone to adverse effects of diazepam, such as confusion, amnesia, ataxia, and hangover effects, as well as falls. Long-term use of benzodiazepines such as diazepam is associated with drug tolerance, benzodiazepine dependence, and benzodiazepine withdrawal syndrome. Like other benzodiazepines, diazepam can impair short-term memory and learning of new information. While benzodiazepine drugs such as diazepam can cause anterograde amnesia, they do not cause retrograde amnesia; information learned before using benzodiazepines is not impaired. Tolerance to the cognitively impairing effects of benzodiazepines does not tend to develop with long-term use, and the elderly are more sensitive to them. Additionally, after cessation of benzodiazepines, cognitive deficits may persist for at least six months; it is unclear whether these impairments take longer than six months to abate or if they are permanent. Benzodiazepines may also cause or worsen depression. Infusions or repeated intravenous injections of diazepam when managing seizures, for example, may lead to drug toxicity, including respiratory depression, sedation and hypotension. Drug tolerance may also develop to infusions of diazepam if it is given for longer than 24 hours. Sedatives and sleeping pills, including diazepam, have been associated with an increased risk of death.

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.

Diazepam has a range of side effects common to most benzodiazepines, including:

  • Suppression of REM sleep and Slow wave sleep.
  • Impaired motor function.
    • Impaired coordination.
    • Impaired balance.
    • Dizziness.
  • Reflex tachycardia.

Less commonly, paradoxical side effects can occur, including nervousness, irritability, excitement, worsening of seizures, insomnia, muscle cramps, changes in libido, and in some cases, rage and violence. These adverse reactions are more likely to occur in children, the elderly, and individuals with a history of a substance use disorder, such as an alcohol use disorder, or a history of aggressive behaviour. In some people, diazepam may increase the propensity toward self-harming behaviours and, in extreme cases, may provoke suicidal tendencies or acts. Very rarely dystonia can occur.

Diazepam may impair the ability to drive vehicles or operate machinery. The impairment is worsened by consumption of alcohol, because both act as central nervous system depressants.

During the course of therapy, tolerance to the sedative effects usually develops, but not to the anxiolytic and myorelaxant effects.

Patients with severe attacks of apnoea during sleep may suffer respiratory depression (hypoventilation), leading to respiratory arrest and death.

Diazepam in doses of 5 mg or more causes significant deterioration in alertness performance combined with increased feelings of sleepiness.

Tolerance and Dependence

Diazepam, as with other benzodiazepine drugs, can cause tolerance, physical dependence, substance use disorder, and benzodiazepine withdrawal syndrome. Withdrawal from diazepam or other benzodiazepines often leads to withdrawal symptoms similar to those seen during barbiturate or alcohol withdrawal. The higher the dose and the longer the drug is taken, the greater the risk of experiencing unpleasant withdrawal symptoms.

Withdrawal symptoms can occur from standard dosages and also after short-term use, and can range from insomnia and anxiety to more serious symptoms, including seizures and psychosis. Withdrawal symptoms can sometimes resemble pre-existing conditions and be misdiagnosed. Diazepam may produce less intense withdrawal symptoms due to its long elimination half-life.

Benzodiazepine treatment should be discontinued as soon as possible by a slow and gradual dose reduction regimen. Tolerance develops to the therapeutic effects of benzodiazepines; for example tolerance occurs to the anticonvulsant effects and as a result benzodiazepines are not generally recommended for the long-term management of epilepsy. Dose increases may overcome the effects of tolerance, but tolerance may then develop to the higher dose and adverse effects may increase. The mechanism of tolerance to benzodiazepines includes uncoupling of receptor sites, alterations in gene expression, down-regulation of receptor sites, and desensitisation of receptor sites to the effect of GABA. About one-third of individuals who take benzodiazepines for longer than four weeks become dependent and experience withdrawal syndrome on cessation.

Differences in rates of withdrawal (50-100%) vary depending on the patient sample. For example, a random sample of long-term benzodiazepine users typically finds around 50% experience few or no withdrawal symptoms, with the other 50% experiencing notable withdrawal symptoms. Certain select patient groups show a higher rate of notable withdrawal symptoms, up to 100%.

Rebound anxiety, more severe than baseline anxiety, is also a common withdrawal symptom when discontinuing diazepam or other benzodiazepines. Diazepam is therefore only recommended for short-term therapy at the lowest possible dose owing to risks of severe withdrawal problems from low doses even after gradual reduction. The risk of pharmacological dependence on diazepam is significant, and patients experience symptoms of benzodiazepine withdrawal syndrome if it is taken for six weeks or longer. In humans, tolerance to the anticonvulsant effects of diazepam occurs frequently.


Improper or excessive use of diazepam can lead to dependence. At a particularly high risk for diazepam misuse, substance use disorder or dependence are:

  • People with a history of a substance use disorder or substance dependence. Diazepam increases craving for alcohol in problem alcohol consumers. Diazepam also increases the volume of alcohol consumed by problem drinkers.
  • People with severe personality disorders, such as borderline personality disorder.

Patients from the aforementioned groups should be monitored very closely during therapy for signs of abuse and development of dependence. Therapy should be discontinued if any of these signs are noted, although if dependence has developed, therapy must still be discontinued gradually to avoid severe withdrawal symptoms. Long-term therapy in such instances is not recommended.

People suspected of being dependent on benzodiazepine drugs should be very gradually tapered off the drug. Withdrawals can be life-threatening, particularly when excessive doses have been taken for extended periods of time. Equal prudence should be used whether dependence has occurred in therapeutic or recreational contexts.

Diazepam is a good choice for tapering for those using high doses of other benzodiazepines since it has a long half-life thus withdrawal symptoms are tolerable. The process is very slow (usually from 14 to 28 weeks) but is considered safe when done appropriately.


An individual who has consumed too much diazepam typically displays one or more of these symptoms in a period of approximately four hours immediately following a suspected overdose:

  • Drowsiness.
  • Mental confusion.
  • Hypotension.
  • Impaired motor functions.
    • Impaired reflexes.
    • Impaired coordination.
    • Impaired balance.
    • Dizziness.
  • Coma.

Although not usually fatal when taken alone, a diazepam overdose is considered a medical emergency and generally requires the immediate attention of medical personnel. The antidote for an overdose of diazepam (or any other benzodiazepine) is flumazenil (Anexate). This drug is only used in cases with severe respiratory depression or cardiovascular complications. Because flumazenil is a short-acting drug, and the effects of diazepam can last for days, several doses of flumazenil may be necessary. Artificial respiration and stabilization of cardiovascular functions may also be necessary. Though not routinely indicated, activated charcoal can be used for decontamination of the stomach following a diazepam overdose. Emesis is contraindicated. Dialysis is minimally effective. Hypotension may be treated with levarterenol or metaraminol.

The oral LD50 (lethal dose in 50% of the population) of diazepam is 720 mg/kg in mice and 1240 mg/kg in rats. D.J. Greenblatt and colleagues reported in 1978 on two patients who had taken 500 and 2000 mg of diazepam, respectively, went into moderately deep comas, and were discharged within 48 hours without having experienced any important complications, in spite of having high concentrations of diazepam and its metabolites desmethyldiazepam, oxazepam, and temazepam, according to samples taken in the hospital and as follow-up.

Overdoses of diazepam with alcohol, opiates or other depressants may be fatal.


If diazepam is administered concomitantly with other drugs, attention should be paid to the possible pharmacological interactions. Particular care should be taken with drugs that potentiate the effects of diazepam, such as barbiturates, phenothiazines, opioids, and antidepressants.

Diazepam does not increase or decrease hepatic enzyme activity, and does not alter the metabolism of other compounds. No evidence would suggest diazepam alters its own metabolism with chronic administration.

Agents with an effect on hepatic cytochrome P450 pathways or conjugation can alter the rate of diazepam metabolism. These interactions would be expected to be most significant with long-term diazepam therapy, and their clinical significance is variable.

  • Diazepam increases the central depressive effects of alcohol, other hypnotics/sedatives (e.g. barbiturates), other muscle relaxants, certain antidepressants, sedative antihistamines, opioids, and antipsychotics, as well as anticonvulsants such as phenobarbital, phenytoin, and carbamazepine. The euphoriant effects of opioids may be increased, leading to increased risk of psychological dependence.
  • Cimetidine, omeprazole, oxcarbazepine, ticlopidine, topiramate, ketoconazole, itraconazole, disulfiram, fluvoxamine, isoniazid, erythromycin, probenecid, propranolol, imipramine, ciprofloxacin, fluoxetine, and valproic acid prolong the action of diazepam by inhibiting its elimination.
  • Alcohol in combination with diazepam may cause a synergistic enhancement of the hypotensive properties of benzodiazepines and alcohol.
  • Oral contraceptives significantly decrease the elimination of desmethyldiazepam, a major metabolite of diazepam.
  • Rifampin, phenytoin, carbamazepine, and phenobarbital increase the metabolism of diazepam, thus decreasing drug levels and effects. Dexamethasone and St John’s wort also increase the metabolism of diazepam.
  • Diazepam increases the serum levels of phenobarbital.
  • Nefazodone can cause increased blood levels of benzodiazepines.
  • Cisapride may enhance the absorption, and therefore the sedative activity, of diazepam.
  • Small doses of theophylline may inhibit the action of diazepam.
  • Diazepam may block the action of levodopa (used in the treatment of Parkinson’s disease).
  • Diazepam may alter digoxin serum concentrations.
  • Other drugs that may have interactions with diazepam include antipsychotics (e.g. chlorpromazine), MAO inhibitors, and ranitidine.
  • Because it acts on the GABA receptor, the herb valerian may produce an adverse effect.
  • Foods that acidify the urine can lead to faster absorption and elimination of diazepam, reducing drug levels and activity.
  • Foods that alkalinise the urine can lead to slower absorption and elimination of diazepam, increasing drug levels and activity.
  • Reports conflict as to whether food in general has any effects on the absorption and activity of orally administered diazepam.


Diazepam is a long-acting “classical” benzodiazepine. Other classical benzodiazepines include chlordiazepoxide, clonazepam, lorazepam, oxazepam, nitrazepam, temazepam, flurazepam, bromazepam, and clorazepate. Diazepam has anticonvulsant properties. Benzodiazepines act via micromolar benzodiazepine binding sites as calcium channel blockers and significantly inhibit depolarisation-sensitive calcium uptake in rat nerve cell preparations.

Diazepam inhibits acetylcholine release in mouse hippocampal synaptosomes. This has been found by measuring sodium-dependent high-affinity choline uptake in mouse brain cells in vitro, after pretreatment of the mice with diazepam in vivo. This may play a role in explaining diazepam’s anticonvulsant properties.

Diazepam binds with high affinity to glial cells in animal cell cultures. Diazepam at high doses has been found to decrease histamine turnover in mouse brain via diazepam’s action at the benzodiazepine-GABA receptor complex. Diazepam also decreases prolactin release in rats.

Mechanism of Action

Benzodiazepines are positive allosteric modulators of the GABA type A receptors (GABAA). The GABAA receptors are ligand-gated chloride-selective ion channels that are activated by GABA, the major inhibitory neurotransmitter in the brain. Binding of benzodiazepines to this receptor complex promotes the binding of GABA, which in turn increases the total conduction of chloride ions across the neuronal cell membrane. This increased chloride ion influx hyperpolarises the neuron’s membrane potential. As a result, the difference between resting potential and threshold potential is increased and firing is less likely. As a result, the arousal of the cortical and limbic systems in the central nervous system is reduced.

The GABAA receptor is a heteromer composed of five subunits, the most common ones being two αs, two βs, and one γ (α2β2γ). For each subunit, many subtypes exist (α1–6, β1–3, and γ1–3). GABAA receptors containing the α1 subunit mediate the sedative, the anterograde amnesic, and partly the anticonvulsive effects of diazepam. GABAA receptors containing α2 mediate the anxiolytic actions and to a large degree the myorelaxant effects. GABAA receptors containing α3 and α5 also contribute to benzodiazepines myorelaxant actions, whereas GABAA receptors comprising the α5 subunit were shown to modulate the temporal and spatial memory effects of benzodiazepines. Diazepam is not the only drug to target these GABAA receptors. Drugs such as flumazenil also bind to GABAA to induce their effects.

Diazepam appears to act on areas of the limbic system, thalamus, and hypothalamus, inducing anxiolytic effects. Benzodiazepine drugs including diazepam increase the inhibitory processes in the cerebral cortex.

The anticonvulsant properties of diazepam and other benzodiazepines may be in part or entirely due to binding to voltage-dependent sodium channels rather than benzodiazepine receptors. Sustained repetitive firing seems limited by benzodiazepines’ effect of slowing recovery of sodium channels from inactivation.

The muscle relaxant properties of diazepam are produced via inhibition of polysynaptic pathways in the spinal cord.


Diazepam can be administered orally, intravenously (must be diluted, as it is painful and damaging to veins), intramuscularly (IM), or as a suppository.

The onset of action is one to five minutes for IV administration and 15-30 minutes for IM administration. The duration of diazepam’s peak pharmacological effects is 15 minutes to one hour for both routes of administration. The half-life of diazepam in general is 30-56 hours. Peak plasma levels occur between 30 and 90 minutes after oral administration and between 30 and 60 minutes after intramuscular administration; after rectal administration, peak plasma levels occur after 10 to 45 minutes. Diazepam is highly protein-bound, with 96 to 99% of the absorbed drug being protein-bound. The distribution half-life of diazepam is two to 13 minutes.

Diazepam is highly lipid-soluble, and is widely distributed throughout the body after administration. It easily crosses both the blood-brain barrier and the placenta, and is excreted into breast milk. After absorption, diazepam is redistributed into muscle and adipose tissue. Continual daily doses of diazepam quickly build to a high concentration in the body (mainly in adipose tissue), far in excess of the actual dose for any given day.

Diazepam is stored preferentially in some organs, including the heart. Absorption by any administered route and the risk of accumulation is significantly increased in the neonate, and withdrawal of diazepam during pregnancy and breast feeding is clinically justified.

Diazepam undergoes oxidative metabolism by demethylation (CYP 2C9, 2C19, 2B6, 3A4, and 3A5), hydroxylation (CYP 3A4 and 2C19) and glucuronidation in the liver as part of the cytochrome P450 enzyme system. It has several pharmacologically active metabolites. The main active metabolite of diazepam is desmethyldiazepam (also known as nordazepam or nordiazepam). Its other active metabolites include the minor active metabolites temazepam and oxazepam. These metabolites are conjugated with glucuronide, and are excreted primarily in the urine. Because of these active metabolites, the serum values of diazepam alone are not useful in predicting the effects of the drug. Diazepam has a biphasic half-life of about one to three days, and two to seven days for the active metabolite desmethyldiazepam. Most of the drug is metabolised; very little diazepam is excreted unchanged. The elimination half-life of diazepam and also the active metabolite desmethyldiazepam increases significantly in the elderly, which may result in prolonged action, as well as accumulation of the drug during repeated administration.

Physical and Chemical Properties

Diazepam is a 1,4-benzodiazepine. Diazepam occurs as solid white or yellow crystals with a melting point of 131.5 to 134.5 °C. It is odorless, and has a slightly bitter taste. The British Pharmacopoeia lists it as being very slightly soluble in water, soluble in alcohol, and freely soluble in chloroform. The United States Pharmacopoeia lists diazepam as soluble 1 in 16 ethyl alcohol, 1 in 2 of chloroform, 1 in 39 ether, and practically insoluble in water. The pH of diazepam is neutral (i.e., pH = 7). Due to additives such as benzoic acid/benzoate in the injectable form. Diazepam has a shelf life of five years for oral tablets and three years for IV/IM solutions. Diazepam should be stored at room temperature (15-30 °C). The solution for parenteral injection should be protected from light and kept from freezing. The oral forms should be stored in air-tight containers and protected from light.

Diazepam can absorb into plastics, so liquid preparations should not be kept in plastic bottles or syringes, etc. As such, it can leach into the plastic bags and tubing used for intravenous infusions. Absorption appears to depend on several factors, such as temperature, concentration, flow rates, and tube length. Diazepam should not be administered if a precipitate has formed and does not dissolve.

Detection in Body Fluids

Diazepam may be quantified in blood or plasma to confirm a diagnosis of poisoning in hospitalized patients, provide evidence in an impaired driving arrest, or to assist in a medicolegal death investigation. Blood or plasma diazepam concentrations are usually in a range of 0.1-1.0 mg/l in persons receiving the drug therapeutically. Most commercial immunoassays for the benzodiazepine class of drugs cross-react with diazepam, but confirmation and quantitation are usually performed using chromatographic techniques.

Society and Culture

Recreational Use

Diazepam is a medication with a high risk of misuse and can cause drug dependence. Urgent action by national governments has been recommended to improve prescribing patterns of benzodiazepines such as diazepam. A single dose of diazepam modulates the dopamine system in similar ways to how morphine and alcohol modulate the dopaminergic pathways. Between 50 and 64% of rats will self-administer diazepam. Diazepam has been shown to be able to substitute for the behavioural effects of barbiturates in a primate study. Diazepam has been found as an adulterant in heroin.

Diazepam drug misuse can occur either through recreational misuse where the drug is taken to achieve a high or when the drug is continued long term against medical advice.

Sometimes, it is used by stimulant users to “come down” and sleep and to help control the urge to binge. These users often escalate dosage from 2 to 25 times the therapeutic dose of 5 to 10 mg.

A large-scale study in the US, conducted by SAMHSA, using data from 2011, determined benzodiazepines were present in 28.7% of emergency department visits involving nonmedical use of pharmaceuticals. In this regard, benzodiazepines are second only to opiates, the study found in 39.2% of visits. About 29.3% of drug-related suicide attempts involve benzodiazepines, making them the most frequently represented class in drug-related suicide attempts. Males misuse benzodiazepines as commonly as females.

Benzodiazepines, including diazepam, nitrazepam, and flunitrazepam, account for the largest volume of forged drug prescriptions in Sweden, a total of 52% of drug forgeries being for benzodiazepines.

Diazepam was detected in 26% of cases of people suspected of driving under the influence of drugs in Sweden, and its active metabolite nordazepam was detected in 28% of cases. Other benzodiazepines and zolpidem and zopiclone also were found in high numbers. Many drivers had blood levels far exceeding the therapeutic dose range, suggesting a high degree of potential for misuse for benzodiazepines, zolpidem, and zopiclone. In Northern Ireland, in cases where drugs were detected in samples from impaired drivers who were not impaired by alcohol, benzodiazepines were found in 87% of cases. Diazepam was the most commonly detected benzodiazepine.

Legal Status

Diazepam is regulated in most countries as a prescription drug.

  • International: Diazepam is a Schedule IV controlled drug under the Convention on Psychotropic Substances.
  • UK: Classified as a controlled drug, listed under Schedule IV, Part I (CD Benz POM) of the Misuse of Drugs Regulations 2001, allowing possession with a valid prescription. The Misuse of Drugs Act 1971 makes it illegal to possess the drug without a prescription, and for such purposes it is classified as a Class C drug.
  • Germany: Classified as a prescription drug, or in high dosage as a restricted drug (Betäubungsmittelgesetz, Anlage III).
  • Australia: Diazepam is Schedule 4 substance under the Poisons Standard (June 2018). A schedule 4 drug is outlined in the Poisons Act 1964 as, “Substances, the use or supply of which should be by or on the order of persons permitted by State or Territory legislation to prescribe and should be available from a pharmacist on prescription.”
  • United States: Diazepam is controlled as a Schedule IV substance under the Controlled Substances Act of 1970.

Judicial Executions

The states of California and Florida offer diazepam to condemned inmates as a pre-execution sedative as part of their lethal injection program, although the state of California has not executed a prisoner since 2006. In August 2018, Nebraska used diazepam as part of the drug combination used to execute Carey Dean Moore, the first death row inmate executed in Nebraska in over 21 years.

Veterinary Uses

Diazepam is used as a short-term sedative and anxiolytic for cats and dogs, sometimes used as an appetite stimulant. It can also be used to stop seizures in dogs and cats.

On This Day … 03 June

People (Births)

  • 1873 – Otto Loewi, German-American pharmacologist and psychobiologist, Nobel Prize laureate (d. 1961).

Otto Loewi

Otto Loewi (03 June 1873 to 25 December 1961) was a German-born pharmacologist and psychobiologist who discovered the role of acetylcholine as an endogenous neurotransmitter. For his discovery he was awarded the Nobel Prize in Physiology or Medicine in 1936, which he shared with Sir Henry Dale, who was a lifelong friend that helped to inspire the neurotransmitter experiment. Loewi met Dale in 1902 when spending some months in Ernest Starling’s laboratory at University College, London.

GABA and Mental Disorders

Research Paper Title

Development and validation of a UPLC-MS/MS method for the simultaneous determination of gamma-aminobutyric acid and glutamic acid in human plasma.


Gamma-aminobutyric acid (GABA) and its precursor glutamic acid are important neurotransmitters. Both are also present in peripheral tissues and the circulation, where abnormal plasma concentrations have been linked to specific mental disorders. In addition to endogenous synthesis, GABA and glutamic acid can be obtained from dietary sources.

An increasing number of studies suggest beneficial cardio-metabolic effects of GABA intake, and therefore GABA is being marketed as a food supplement.

The need for further research into their health effects merits accurate and sensitive methods to analyse GABA and glutamic acid in plasma.


To this end, an ultra-pressure liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the quantification of GABA and glutamic acid in human plasma.

Samples were prepared by a protein precipitation step and subsequent solid phase extraction using acetonitrile.


Chromatographic separation was achieved on an Acquity UPLC HSS reversed phase C18 column using gradient elution. Analytes were detected using electrospray ionisation and selective reaction monitoring. Standard curve concentrations for GABA ranged from 3.4 to 2500 ng/mL and for glutamic acid from 30.9 ng/mL to 22,500 ng/mL. Within- and between-day accuracy and precision were <10% in quality control samples at low, medium and high concentrations for both GABA and glutamic acid. GABA and glutamic acid were found to be stable in plasma after freeze-thaw cycles and up to 12 months of storage. The validated method was applied to human plasma from 17 volunteers. The observed concentrations ranged between 11.5 and 20.0 ng/ml and 2269 and 7625 ng/ml for respectively GABA and glutamic acid.


The reported method is well suited for the measurement of plasma GABA and glutamic acid in pre-clinical or clinical studies.


de Bie, T.H., Witkamp, R.F., Jongsma, M.A. & Balvers, M.G.J. (2021) Development and validation of a UPLC-MS/MS method for the simultaneous determination of gamma-aminobutyric acid and glutamic acid in human plasma. Journal of Chromatography. doi: 10.1016/j.jchromb.2020.122519. Online ahead of print.