Colloquially known as "downers", depressants or central nervous system (CNS) depressants are drugs that lower neurotransmission levels, decrease the electrical activity of brain cells, or reduce arousal or stimulation in various areas of the brain.[1] Some specific depressants do influence mood, either positively (e.g., opioids) or negatively, but depressants often have no clear impact on mood (e.g., most anticonvulsants). In contrast, stimulants, or "uppers", increase mental alertness, making stimulants the opposite drug class from depressants. Antidepressants are defined by their effect on mood, not on general brain activity, so they form an orthogonal category of drugs.
Depressants are closely related to sedatives as a category of drugs, with significant overlap. The terms may sometimes be used interchangeably or may be used in somewhat different contexts.[citation needed]
Depressants exert their effects through a number of different pharmacological mechanisms, the most prominent of which include facilitation of GABA and inhibition of glutamatergic or monoaminergic activity. Other examples are chemicals that modify the electrical signaling inside the body, the most prominent of which are bromides and channel blockers.
Indications
Depressants are used medicinally to relieve the following symptoms and disorders:
The most common way to measure intoxication for legal or medical purposes is through blood alcohol content (also called blood alcohol concentration or blood alcohol level). It is usually expressed as a percentage of alcohol in the blood in units of mass of alcohol per volume of blood, or mass of alcohol per mass of blood, depending on the country. For instance, in North America, a blood alcohol content of 0.10 g/dL means that there are 0.10 g of alcohol for every dL of blood (i.e., mass per volume is used there).[3]
Barbiturates were once popular treatments for insomnia, anxiety, and seizures, although their popularity has waned in recent decades. Barbiturates are sometimes used recreationally; they cause dependence and severe withdrawal, and they have a high risk of fatal overdose due to respiratory depression. By the late 1950s, concerns over the mounting social costs associated with barbiturates prompted a concerted effort to find alternative medications. Most people still using barbiturates today do so for the prevention of seizures or, in mild form, for relief from the symptoms of migraines. One barbiturate that remains in use for seizure disorders is phenobarbital.
Xanax (alprazolam) 2 mg tri-score tablets, a classical benzodiazepine sedative
Benzodiazepines enhance the effect of the neurotransmittergamma-aminobutyric acid (GABA) at the GABAA receptor, resulting in sedative, hypnotic (sleep-inducing), anxiolytic (anti-anxiety), anticonvulsant, and muscle relaxant properties. High doses of shorter-acting benzodiazepines induce anterograde amnesia, which may be helpful for surgical and procedural anesthesia to reduce patient recall. Midazolam is often used in anesthesiology. These properties make benzodiazepines useful in treating anxiety, insomnia, agitation, seizures, muscle spasms, alcohol withdrawal, and as a premedication for medical or dental procedures. Benzodiazepines are categorized as either short-, intermediate-, or long-acting. Short- and intermediate-acting benzodiazepines are preferred for the treatment of insomnia; longer-acting benzodiazepines are recommended for the treatment of anxiety.
In general, benzodiazepines are safe and effective in the short term, although cognitive impairments and paradoxical effects such as aggression or behavioral disinhibition occasionally occur. A minority of patients react to benzodiazepines with paradoxical agitation. Long-term use is controversial due to adverse psychological and cognitive effects, decreasing effectiveness, dependence, and benzodiazepine withdrawal syndrome, following withdrawal after long-term use. The elderly are at an increased risk of experiencing both short- and long-term adverse effects.
There is controversy concerning the safety of benzodiazepines in pregnancy. While they are not major teratogens, uncertainty remains as to whether they cause cleft palate in a small number of babies and whether neurobehavioral effects occur as a result of prenatal exposure; they are known to cause withdrawal symptoms in the newborn. Benzodiazepines can be overdosed and cause dangerous deep unconsciousness. However, they are much less toxic than their predecessors, barbiturates, and death rarely results when a benzodiazepine is the only drug taken; however, when combined with other central nervous system depressants such as alcohol and opiates, the potential for toxicity and fatal overdose increases. Benzodiazepines are commonly misused and taken in combination with other addictive drugs. In addition, all benzodiazepines are listed in the Beers List, which is significant in clinical practice.
Cannabis is often considered either in its own unique category or as a mild psychedelic.[4][5] The chemical compound tetrahydrocannabinol (THC), which is found in cannabis, has many depressant effects, such as muscle relaxation, sedation, decreased alertness, and tiredness.[6] Contrary to the previous statement, activation of the CB1 receptor by cannabinoids causes an inhibition of GABA, the exact opposite of what CNS depressants do.
Meprobamate was launched in 1955. It quickly became the first popular psychotropic drug in America, becoming popular in Hollywood and gaining fame for its seemingly miraculous effects. It has since been marketed under more than 100 trade names, including Amepromat, Quivet, and Zirpon. Carisoprodol, which metabolizes into meprobamate and is still used mainly for its muscle relaxant effects, can potentially be abused. Its mechanism of action is very similar to that of barbiturates, alcohol, methaqualone, and benzodiazepines. Carisoprodol allosterically modulates and directly activates the human α1β2γ2 GABAAR (GABAA) in the central nervous system, similar to barbiturates. This causes chloride channels to open, allowing chloride to flood into the neuron. This slows down communication between neurons and the nervous system.[13] Unlike benzodiazepines, which increase the frequency of the chloride channel opening, carisoprodol increases the duration of channel opening when GABA is bound.[14][15] GABA is the main inhibitoryneurotransmitter in the nervous system, which causes its depressant effects.
Carbamates gained widespread use in the 1950s, alongside barbiturates. While their popularity has gradually waned due to concerns over overdose and dependence potential, newer derivatives of carbamates continue to be developed. Among these is Felbamate, an anticonvulsant that was approved in 1993 and is commonly used today. It is a GABAA positive allosteric modulator and blocks the NR2B subunit of the NMDA receptor. Other carbamates block sodium channels. Phenprobamate was used as an anxiolytic and is still sometimes used in Europe for general anesthesia and for treating muscle cramps and spasticity. Methocarbamol is a popular drug that is commonly known as Robaxin and is over-the-counter in some countries. It is a carbamate with muscle relaxant effects. Tetrabamate is a controversial drug that is a combination of febarbamate, difebarbamate, and phenobarbital. It is marketed in Europe and has been largely, but not completely, discontinued. On 4 April 1997, after over 30 years of use due to reports of hepatitis and acute liver failure, the use of the drug was restricted. Carisoprodol, known as "Soma", is still commonly used today for its muscle relaxant effects. It is also very commonly abused around the world. It is a Schedule IV substance in the United States. Famous martial artist and actor Bruce Lee died due to an allergic reaction to meprobamate.[citation needed]
Reuters reported on 25 March 2010 that "Pfizer Inc violated a United States racketeering law by improperly promoting the epilepsy drug Neurontin (gabapentin). Under the Racketeer Influenced and Corrupt Organizations Act, the penalty is automatically tripled, so the finding will cost Pfizer $141 million." The case stems from a claim from Kaiser Foundation Health Plan Inc. that "it was misled into believing Neurontin was effective for off-label treatment of migraines, bipolar disorder and other conditions. Pfizer argued that Kaiser physicians "still recommend the drug for those uses" and that "the insurer's website also still lists Neurontin as a drug for neuropathic pain."
In some cases, gabapentinoids are abused and provide similar effects to alcohol, benzodiazepines, and gamma-hydroxybutyric acid (GHB).[49][50][51] The FDA placed a black box warning on Neurontin (gabapentin) and Lyrica (pregabalin) for serious breathing problems.[52] Mixing gabapentinoids with opioids, benzodiazepines, barbiturates, GHB, alcohol, or any other depressant is potentially deadly.[53][54][55][56]
GHB is used illegally as an intoxicant, an aphrodisiac,[75][113] and an athletic-performance enhancer.[79] It is a popular club drug in some parts of the world due to its powerful aphrodisiac and euphoric effects. Similarly to phenibut and baclofen, it is used by bodybuilders to increase the human growth hormone due to GABAB activation.[114][115] It has also been reportedly used as a date-rape drug.[116][117] This caused it to be a Schedule I substance in the United States, Canada, and other countries. Xyrem, which is GHB in its sodium form, is Schedule III in the United States, Canada, and other countries.[90][103]
In low doses, GHB mainly binds to the GHB receptor and weakly binds to the GABAB receptor.[93][92][118] The GHB receptor is an excitatory G protein-coupled receptor (GPCR).[93][92] Its endogenous ligand is GHB, since GHB is also a neurotransmitter.[76] It is also a transporter for vitamin B2. The existence of a specific GHB receptor was predicted by observing the action of GHB and related compounds that primarily act on the GABAB receptor but also exhibit a range of effects that were found not to be produced by GABAB activity and so were suspected of being produced by a novel and, at the time, unidentified receptor target. At higher doses, seizures are very common.[111] This is thought to be mediated through an increased Na+/K+ current and the increased release of dopamine and glutamate.[94] GHB can also cause absence seizures;[111][119][120] the mechanism is currently not known but it is believed to be due to interactions with the GABAB receptor.[119] It is being investigated if endogenous GHB is responsible for non-convulsive seizures in humans.[111][121]
Nonbenzodiazepines, sometimes referred to as Z-drugs, are a class of hypnotic depressants that are mainly used to treat insomnia and sometimes anxiety.[129][130] They are structurally related to benzodiazepines. They positively modulate the benzodiazepine site of the GABAA receptor, the chief inhibitory receptor of the central nervous system, just like benzodiazepines, but at a molecular level, they are structurally unrelated.
Nonbenzodiazepines bind to the benzodiazepine at the GABAA receptor site to keep the chloride channel open.[131] This causes chloride in the intercellular area to flood into the neuron.[132] Since chloride has a negative charge, it causes the neuron to rest and cease firing. This results in a relaxing and depressant effect on the central nervous system.
Common nonbenzodiazepines like Zolpidem and Zopiclone are extremely effective for insomnia but carry many risks and side effects. Sleeping pills, including zopiclone, have been associated with an increased risk of death.
Adverse reactions are as follows: "taste disturbance (some report a metallic-like taste); less commonly, nausea, vomiting, dizziness, drowsiness, dry mouth, headache; rarely, amnesia, confusion, depression, hallucinations, nightmares; very rarely, lightheadedness, incoordination, paradoxical effects, and sleep-walking are also reported."[This quote needs a citation] Some users of nonbenzodiazepines have sleepwalked and committed murders or have been involved in motor vehicle accidents. Unlike benzodiazepines, nonbenzodiazepines have a risk of hallucinations and sleepwalking. Like benzodiazepines, they can cause anterograde amnesia.[citation needed]
Nonbenzodiazepines should not be discontinued abruptly if taken for more than a few weeks due to the risk of rebound withdrawal effects and acute withdrawal reactions, which may resemble those seen during benzodiazepine withdrawal. Treatment usually entails gradually reducing the dosage over a period of weeks or several months, depending on the individual, dosage, and length of time the drug has been taken. If this approach fails, a crossover to a benzodiazepine equivalent dose of a long-acting benzodiazepine (such as chlordiazepoxide or, more preferably, diazepam) can be tried, followed by a gradual reduction in dosage. In extreme cases and, in particular, where severe addiction and/or abuse are manifested, inpatient detoxification may be required, with flumazenil as a possible detoxification tool.[citation needed]
The rostromedial tegmental nucleus (RMTg) is located in the midbrain (pictured above) of the brainstem. The release of dopamine in the RMTg characterizes the euphoria and reinforcement of opioids.
Opioids are substances that act on opioid receptors to reduce pain.[133] Medically, they are primarily used for pain relief, including anesthesia. Opioids also cause euphoria and are highly abused.
Opioids and opiates are not the same. Opiates refer to natural opioids such as morphine and codeine. Opioids refer to all natural, semisynthetic, and synthetic opioids, like heroin and oxycodone.
Contrary to popular misconception, opioids are not depressants in the classical sense.[4] They do produce central nervous system depression, but they also excite certain areas of the central nervous system. To remain true to the term "depressant", opioids cannot be classified as such. For opioid agonists and opiumderivatives, these are classified differently. These drugs are more correctly identified as "analgesic" or "narcotic". However, they do have depressant actions nonetheless.
There are three principal classes of opioid receptors: μ, κ, δ (mu, kappa, and delta),[134] although up to seventeen have been reported, and include the ε, ι, λ, and ζ (epsilon, iota, lambda, and zeta) receptors. Conversely, σ (sigma) receptors are no longer considered to be opioid receptors because their activation is not reversed by the opioid inverse-agonist naloxone. The nociception opioid peptide receptor (NOP) (ORL1) is an opioid receptor that is involved in pain responses, anxiety, movement, reward, hunger, memory, and much more. It plays a major role in the development of tolerance to μ-opioid agonists.[135]
When "pain" occurs, a signal gets sent from the site of possible injury. This signal goes up the spinal cord into the brain, where it is perceived as a negative emotion known as nociception or "hurt". In the central nervous system, the spine is connected to the brain by a structure called the brain stem.[136] The brain stem is the first part of the brain that develops in a mammal out of the neural crest. It is also the oldest part of the brain and controls many automatic functions such as consciousness, breathing, heart rate, digestion, and many more. Opioid receptors are specialized pain-blocking receptors. They bind a wide range of hormones, peptides, and much more. Although they are found everywhere in the central nervous system, they are highly concentrated in the brain stem. Depending on the receptor, activation of them has the ability to stop pain from making its way to the brain and being perceived as pain. Hence, opioids do not actually "stop" pain; they simply stop you from knowing you are in pain. Pain and the ability to modify it based on an organism's environment is an evolutionary advantage, and it has been shown that it can help an organism escape and survive certain situations where they may otherwise be immobilized due to pain and injury. The midbrain nuclei of the brain stem, with structures like the periaqueductal gray, reticular formation, and rostromedial tegmental nucleus, are responsible for the majority of the physical and psychological effects of endogenous and exogenous opioids.[citation needed]
The μ-opioid receptor is responsible for the analgesic, euphoric, and adverse effects of opioids. The μ-opioid receptor is a G protein-coupled receptor. When the μ-opioid receptor is activated, it causes pain relief, euphoria, constipation, constricted pupils, itching, and nausea.[137] The μ-opioid is located in the gastrointestinal tract, which controls peristalsis. This causes constipation, which can be extremely problematic and distressing. Activation of this receptor also causes relaxation of voluntary and involuntary muscles, which can cause side effects like trouble urinating and swallowing. The μ-opioid receptor can also reduce androgens, thus decreasing libido and sexual function. The receptor is also known to cause "musical anhedonia".[138]
The receptor plays a critical role in feeding. The palatability of food is determined by opioid receptor-related processes in the nucleus accumbens and ventral pallidum. The opioid processes involve mu opioid receptors and are present in the rostromedial shell of the nucleus accumbens on its spiny neurons. This area has been called the "opioid eating site".[This quote needs a citation]
The μ-opioid receptor has many endogenous ligands, including endorphin.[139]
The κ-opioid receptor (KOR) is a G protein-coupled receptor located in the central nervous system. KOR is also a G protein-coupled receptor.[141] Humans and some other primates have a higher density of kappa receptors than most other animals. KOR is responsible for nociception, consciousness, motor control, and mood. Dysregulation of this receptor system has been implicated in alcohol and drug addiction.[142] The endogenous ligand for KOR is dynorphin. The activation of KOR usually causes dysphoria, hence the name dynorphin. The intoxicating plant Salvia divinorum contains salvinorin A, an alkaloid that is a potent and selective κ-opioid receptor agonist. This causes powerful hallucinations. Antagonizing the κ-opioid receptor may be able to treat depression, anxiety, stress, addiction, and alcoholism.[143]
The third receptor is the δ-opioid receptor (DOR). The delta receptor is the least studied of the three main opioid receptors. It is a G protein-coupled receptor, and its endogenous ligand is deltorphin. The activation of DOR may have antidepressant effects. δ-opioid agonists can produce respiratory depression at very high doses; at lower doses, they have the opposite effect. High doses of a δ-opioid agonist can cause seizures, although not all delta agonists produce this effect.[144] Activation of the delta receptor is usually stimulating instead of sedating like most opioids.
When the μ-opioid receptor is activated on a neuron, the voltage-gated calcium channel (green) closes and the voltage-gated potassium channel (blue) opens. Both of these individual actions make the presynaptic neuron less likely to release glutamate (red), leaving the neuron at rest longer. This slowing down of neurons via interactions with ion channels and receptors is a hallmark of a depressant. Without glutamate the pain signal gets "cut short" and cannot ascend a pathway and reach pain processing centers in the midbrain of the brainstem.
An opioid overdose is fatal.[147] A person overdosing on opioids or opiates is presented with respiratory depression, a lethal condition that can cause hypoxia from slow and shallow breathing.[148] Mixing opioids with another depressant, such as benzodiazepines or alcohol, increases the chance of an overdose and respiratory depression. Opioid overdose causes a decreased level of consciousness, pinpoint pupils, and respiratory depression. Other symptoms include seizures and muscle spasms. Opioids activate μ-opioid receptors in specific regions of the central nervous system associated with respiratory regulation. They activate μ-opioid receptors in the medulla and pons. They are located in the brain stem, which connects to the spine. This area has a high density of μ-opioid receptors as they block pain going up from the spine into the brain. These areas are the oldest and most primitive parts of the brain. They control automatic functions such as breathing and digestion. Opioids stop this process and cause respiratory depression and constipation. The brain stem no longer detects carbon dioxide in the blood, so it does not initiate the inhalation reflex, usually resulting in hypoxia. Some overdose victims, however, die from cardiovascular failure or asphyxiation from choking on their vomit.[citation needed]
Naloxone is a μ-opioid receptor antagonist,[149] meaning instead of activating the μ-opioid receptor, it disrupts the functioning of the receptor.[149] Since naloxone is powerful and highly selective for the μ-opioid receptor, it can knock powerful opioids like fentanyl off the receptor and block another ligand from binding to the receptor, thus stopping an overdose.[150] A person dependent on opioids may go into precipitated withdrawal when naloxone is used.[151] Since naloxone blocks any endogenous or exogenous opioids from binding to the μ-opioid receptor.[151] This may cause a person to immediately go into withdrawal after naloxone is used.[152] This can cause withdrawal symptoms like cold sweats and diarrhea.
Opioids activate μ-opioid receptors in the rostromedial tegmental nucleus (RMTg). The rostromedial tegmental nucleus is a GABAergic nucleus that functions as a "master brake" for the midbrain dopamine system.[153][154] The RMTg possesses robust functional and structural links to the dopamine pathways.[153][154] Opioids decrease the release of GABA, thus disinhibiting the GABAergic brake on dopamine networks.[153] GABA is an inhibitory neurotransmitter, meaning it either blocks or decreases the potential of neuron firing.[155] This causes large amounts of dopamine to be released, as it is no longer blocked by GABA.[153] Disinhibition of GABA may be responsible for causing seizures, an uncommon adverse effect of opioids. GABAergic disinhibition is also why opioids are not considered true depressants. This excitement of dopaminergic pathways causes the euphoria of opioids. This causes major positive reinforcing effects in the brain, instructing it to do it again. The RMTg is also responsible for the development of tolerance and addiction. Psychostimulants also excite this pathway.[153][154]
Fentanyl is very commonly cut into other substances sold on the street.[156] Fentanyl is used to increase the potency of substances, thus making the user spend more money on the laced substance.[157][158] Codeine is a weaker natural opiate that is usually used for bronchitis, diarrhea, and post-operative pain. It is very easy to overdose on these substances, especially if the user has no tolerance.
Piperidinediones are a class of depressants that are not used anymore. There are piperidinediones that are used for other purposes, like breast cancer.[159][160][161] The piperidinedione class is very structurally similar to barbiturates. Some piperidinediones include glutethimide, methyprylon, pyrithyldione, glutarimide, and aminoglutethimide. The first three (glutethimide, methyprylon, and pyrithyldione) are central nervous depressants. The piperidinedione depressants, specifically glutethimide, are positive modulators of the GABAAanion channel. The drug increases inhibitory GABAergic tone and causes neuro-inhibition of the cortical and limbic systems, observed clinically as a sedative-hypnotic effect.[162] Glutethimide is also a potent inducer of the CYP 2D6 enzyme in the liver. This enzyme is responsible for converting many drugs, from beta blockers to antidepressants to opioids and opiates. Due to its effects on the conversion of opioids, it was highly abused and mixed with opioids like codeine. Codeine must be metabolized to morphine in the liver to have its psychoactive and analgesic effects. Mixing codeine with glutethimide allowed more codeine to be converted into morphine in the body, thus increasing its effect. These were known as "hits", "cibas and codeine", and "dors and 4s".[citation needed] Glutethimide was believed to be safer than barbiturates, but many people died from the drug. Demand was high in the United States at one point. Production of glutethimide was discontinued in the US in 1993 and in several eastern European countries, most notably Hungary, in 2006.[citation needed]
Quinazolinones are a class of depressants that are rarely used anymore. Quinazolinones have powerful sedative, hypnotic, and anxiolytic effects. Quinazolinone's structure is very similar to that of some antibiotics. Quinazolinone's main mechanism of action is binding to the GABAA receptor.[163] It does not bind to the ethanol, barbiturate, neurosteroid, or benzodiazepine site.[163] Instead, it binds on a site directly between the GABRB2 (β2) and (α1) GABRA1 proteins on the GABAA receptor.[163] The anestheticetomidate and anticonvulsant loreclezole may also bind to this site.[163]
Overdosing on quinazolinone sometimes causes effects that are the opposite of quinazolinone-like sedation. The overdose consists of hyperreflexia, vomiting, kidney failure, delirium, hypertonia, coma, myoclonic twitches, somnolence, euphoria, muscular hyperactivity, agitated delirium, tachycardia, and tonic-clonic seizures. In 1982, 2,764 people visited US emergency rooms after overdosing on quinazolinones, specifically methaqualone.[164] Mixing quinazolinones with another depressant is possibly fatal. Death from a quinazolinone overdose is usually caused by death through cardiac or respiratory arrest. An overdose resembles a barbiturate or carbamate overdose.
Methaqualone hydrochloride and quinazolinone anxiolytics and hypnotics are referred to as "quaaludes", "ludes", and "disco biscuits". Methaqualone was very commonly abused in the western world during the 1960s and 1970s. Methaqualone was mainly prescribed for insomnia, as it was thought to be safer than barbiturates and carbamates.[166] Methaqualone became highly abused by many, including celebrities, after its introduction in 1965.[164] Methaqualone was first synthesized in India in 1951 by Indra Kishore Kacker and Syed Husain Zaheer, who were conducting research on finding new antimalarial medications.[167][168] The drug name "Quaalude" (methaqualone) is a portmanteau, combining the words "quiet interlude". Methaqualone was discontinued in the United States in 1985, mainly due to its psychological addictiveness, widespread abuse, and illegal recreational use. Nonbenzodiazepines and benzodiazepines are now used to treat insomnia instead. Methaqualone is now a Schedule I substance. Some quinazolinone analogues are still sold online. They come with the risk of seizures.[citation needed]
Large doses of methaqualone can cause euphoria, disinhibition, increased sexuality and sociability, muscle relaxation, anxiolysis, and sedation. Today, methaqualone is widely abused in South Africa. Many celebrities have used quinazolinone, most notably methaqualone. Bill Cosby admitted to casual sex involving the recreational use of methaqualone.[169][170][171] 18-year-old actor Anissa Jones died from an overdose of cocaine, PCP, methaqualone, and the barbiturate Seconal. Billy Murcia, a drummer for the rock band New York Dolls, died at 21 when he drowned in a bathtub while overdosing on heroin and methaqualone.[172]
Cloroqualone was a quinazolinone that bound to the GABAA and sigma-1 receptors. It had useful cough suppressant effects and weaker sedative effects than methaqualone, but was ultimately withdrawn due to its potential for abuse and overdose.[173]
Etaqualone is a quinazolinone-class depressant. It has sedative, hypnotic, muscle relaxant, and central nervous system depressant properties. It was highly abused and had a high risk of overdose. Users would snort or smoke the free-base etaqualone hydrochloride salt.
Methylmethaqualone is an analogue of methaqualone with similar hypnotic and sedative effects. Methylmethaqualone differs from methaqualone by 4-methylation on the phenyl ring. It produces convulsions at only slightly above the effective sedative dose. It would appear that this compound was sold on the black market in Germany as a designer druganalogue of methaqualone.[174]
Combining multiple depressants can be very dangerous because the central nervous system's depressive properties have been proposed to increase exponentially instead of linearly.[176] This characteristic makes depressants a common choice for deliberate overdoses in the case of suicide. The use of alcohol or benzodiazepines along with the usual dose of heroin is often the cause of overdose deaths in opiate addicts.
An anxiolytic is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxiety disorders and their related psychological and physical symptoms.
gamma-Hydroxybutyric acid (GHB), also known as 4-hydroxybutanoic acid is a naturally occurring neurotransmitter and a depressant drug. It is a precursor to GABA, glutamate, and glycine in certain brain areas. It acts on the GHB receptor and is a weak agonist at the GABAB receptor. GHB has been used in the medical setting as a general anesthetic and as treatment for cataplexy, narcolepsy, and alcoholism. The substance is also used illicitly for various reasons, including as a performance-enhancing drug, date rape drug, and as a recreational drug.
A sedative or tranquilliser is a substance that induces sedation by reducing irritability or excitement. They are CNS depressants and interact with brain activity causing its deceleration. Various kinds of sedatives can be distinguished, but the majority of them affect the neurotransmitter gamma-aminobutyric acid (GABA). In spite of the fact that each sedative acts in its own way, most produce relaxing effects by increasing GABA activity.
Gabapentin, sold under the brand name Neurontin among others, is an anticonvulsant medication primarily used to treat partial seizures and neuropathic pain. It is a commonly used medication for the treatment of neuropathic pain caused by diabetic neuropathy, postherpetic neuralgia, and central pain. It is moderately effective: about 30–40% of those given gabapentin for diabetic neuropathy or postherpetic neuralgia have a meaningful benefit.
Baclofen, sold under the brand name Lioresal among others, is a medication used to treat muscle spasticity such as from a spinal cord injury or multiple sclerosis. It may also be used for hiccups and muscle spasms near the end of life, and off-label to treat alcohol use disorder or opioid withdrawal symptoms. It is taken orally or by intrathecal pump. It is also sometimes used transdermally in combination with gabapentin and clonidine prepared at a compounding pharmacy.
Physical dependence is a physical condition caused by chronic use of a tolerance-forming drug, in which abrupt or gradual drug withdrawal causes unpleasant physical symptoms. Physical dependence can develop from low-dose therapeutic use of certain medications such as benzodiazepines, opioids, stimulants, antiepileptics and antidepressants, as well as the recreational misuse of drugs such as alcohol, opioids and benzodiazepines. The higher the dose used, the greater the duration of use, and the earlier age use began are predictive of worsened physical dependence and thus more severe withdrawal syndromes. Acute withdrawal syndromes can last days, weeks or months. Protracted withdrawal syndrome, also known as post-acute-withdrawal syndrome or "PAWS", is a low-grade continuation of some of the symptoms of acute withdrawal, typically in a remitting-relapsing pattern, often resulting in relapse and prolonged disability of a degree to preclude the possibility of lawful employment. Protracted withdrawal syndrome can last for months, years, or depending on individual factors, indefinitely. Protracted withdrawal syndrome is noted to be most often caused by benzodiazepines. To dispel the popular misassociation with addiction, physical dependence to medications is sometimes compared to dependence on insulin by persons with diabetes.
Gamma-butyrolactone (GBL) or γ-butyrolactone is an organic compound with the formula O=CO(CH2)3. It is hygroscopic, colorless, water-miscible liquid with a weak, characteristic odor. It is the simplest 4-carbon lactone. It is mainly used as an intermediate in the production of other chemicals, such as N-methyl-2-pyrrolidone.
Cross-tolerance is a phenomenon that occurs when tolerance to the effects of a certain drug produces tolerance to another drug. It often happens between two drugs with similar functions or effects—for example, acting on the same cell receptor or affecting the transmission of certain neurotransmitters. Cross-tolerance has been observed with pharmaceutical drugs such as anti-anxiety agents and illicit substances, and sometimes the two of them together. Often, a person who uses one drug can be tolerant to a drug that has a completely different function. This phenomenon allows one to become tolerant to a drug that they have never used before.
Pregabalin, sold under the brand name Lyrica among others, is an anticonvulsant, analgesic, and anxiolytic amino acid medication used to treat epilepsy, neuropathic pain, fibromyalgia, restless legs syndrome, opioid withdrawal, and generalized anxiety disorder (GAD). Pregabalin also has antiallodynic properties. Its use in epilepsy is as an add-on therapy for partial seizures. It is a gabapentinoid medication which are drugs that are derivatives of γ-aminobutyric acid (GABA), an inhibitory neurotransmitter. Pregabalin acts by inhibiting certain calcium channels. When used before surgery, it reduces pain but results in greater sedation and visual disturbances. It is taken by mouth.
Central nervous system (CNS) depression is a physiological state that can result in a decreased rate of breathing, decreased heart rate, and loss of consciousness, possibly leading to coma or death.
Sodium oxybate, sold under the brand name Xyrem among others, is a medication used to treat symptoms of narcolepsy: sudden muscle weakness and excessive daytime sleepiness. It is used sometimes in France and Italy as an anesthetic given intravenously; it is also approved and used in Italy and in Austria to treat alcohol dependence and alcohol withdrawal syndrome.
Phenibut, sold under the brand names Anvifen, Fenibut, and Noofen among others, is a central nervous system depressant with anxiolytic effects, and is used to treat anxiety, insomnia, and for a variety of other indications. It is usually taken by mouth as a tablet, but may be given intravenously.
Etaqualone is a quinazolinone-class GABAergic and is an analogue of methaqualone that was developed in the 1960s and marketed mainly in France and some other European countries. It has sedative, hypnotic, muscle relaxant and central nervous system depressant properties resulting from its agonist activity at the β-subtype of the GABAA receptor, and was used for the treatment of insomnia.
Ro15-4513(IUPAC: Ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo-1,4-benzodiazepine-3-carboxylate) is a weak partial inverse agonist of the benzodiazepine class of drugs, developed by Hoffmann–La Roche in the 1980s. It acts as an inverse agonist, and can therefore be an antidote to the acute impairment caused by alcohols, including ethanol, isopropanol, tert-butyl alcohol, tert-amyl alcohol, 3-methyl-3-pentanol, methylpentynol and ethchlorvynol.
A GABA receptor agonist is a drug that is an agonist for one or more of the GABA receptors, producing typically sedative effects, and may also cause other effects such as anxiolytic, anticonvulsant, and muscle relaxant effects. There are three receptors of the gamma-aminobutyric acid. The two receptors GABA-α and GABA-ρ are ion channels that are permeable to chloride ions which reduces neuronal excitability. The GABA-β receptor belongs to the class of G-Protein coupled receptors that inhibit adenylyl cyclase, therefore leading to decreased cyclic adenosine monophosphate (cAMP). GABA-α and GABA-ρ receptors produce sedative and hypnotic effects and have anti-convulsion properties. GABA-β receptors also produce sedative effects. Furthermore, they lead to changes in gene transcription.
Barbiturates are a class of depressant drugs that are chemically derived from barbituric acid. They are effective when used medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological addiction potential as well as overdose potential among other possible adverse effects. They have been used recreationally for their anti-anxiety and sedative effects, and are thus controlled in most countries due to the risks associated with such use.
Barbiturate overdose is poisoning due to excessive doses of barbiturates. Symptoms typically include difficulty thinking, poor coordination, decreased level of consciousness, and a decreased effort to breathe. Complications of overdose can include noncardiogenic pulmonary edema. If death occurs this is typically due to a lack of breathing.
SKF-97,541 is a compound used in scientific research which acts primarily as a selective GABAB receptor agonist. It has sedative effects in animal studies and is widely used in research into potential treatment of various types of drug addiction.
Gabapentinoids, also known as α2δ ligands, are a class of drugs that are derivatives of the inhibitory neurotransmitter gamma-Aminobutyric acid (GABA) which block α2δ subunit-containing voltage-dependent calcium channels (VDCCs). This site has been referred to as the gabapentin receptor, as it is the target of the drugs gabapentin and pregabalin.
A GABA analogue is a compound which is an analogue or derivative of the neurotransmitter gamma-Aminobutyric acid (GABA).
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