View source for Depressant

{{Short description|Drugs that lower neurotransmission levels, reducing brain activity}}
{{Distinguish|depressogen}}
{{Multiple issues|{{Citations broken|date=April 2024}}
{{More citations needed|date=March 2025}}
{{Very long|date=March 2025}}}}
{{Use dmy dates|date=January 2024}}
{{Infobox drug class
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| Image               = File:Ethanol-2D-skeletal.svg
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| Caption             = [[Chemical structure]] of [[alcohol (drug)|alcohol]] (ethanol), among the most well-known and widely used central depressants.
| Width               = 150px
| Pronounce           = 
| Synonyms            = Central depressant; Central nervous system depressant; CNS depressant; Downer; Sedative; Tranquilizer
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| Use                 = [[Recreational drug use|Recreational]], [[medicine|medical]]
| ATC_prefix          = 
| Mode_of_action      = 
| Mechanism_of_action = Various
| Biological_target   = Various
| Chemical_class      = Various
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| Drugs.com           = <!-- {{Drugs.com|drug-class|?}} -->
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| MeshID              = 
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| legal_status        = Variable
}}

'''Depressants''', also known as '''central nervous system depressants''', or colloquially known as "'''downers'''", are a class of [[psychoactive drug]]s characterised by decreasing [[neurotransmission]] levels, decreasing the [[Action potential|electrical activity]] of [[Neuron|brain cells]], or reducing [[arousal]] or [[stimulation]] in various areas of the brain.<ref>{{cite encyclopedia |dictionary=Princeton WordNet |url=http://wordnetweb.princeton.edu/perl/webwn?s=depressant |title=Depressant – Definition |access-date=28 December 2013}}</ref> Commonly used depressants include [[alcohol (drug)|alcohol]], [[opioid]]s, and [[benzodiazepines]]. Some specific depressants influence mood, either positively (e.g., [[opioids]]) or negatively (e.g., [[Alcohol (drug)|alcohol]]), but depressants often have no clear impact on mood (e.g., most [[anticonvulsant]]s). In contrast, [[stimulant]]s, or "uppers", increase mental alertness, making stimulants the opposite [[drug class]] from depressants. [[Antidepressant]]s 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 [[sedative]]s 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 |date=June 2024}} Nearly all commonly used depressants are [[addiction|addictive]], and use of them carries the risk of death from [[respiratory depression]], especially in opioids.

Depressants are widely used throughout the world as [[prescription medicine]]s and [[Prohibition (drugs)|illicit substances]]. [[Alcohol (drug)|Alcohol]] is a very prominent depressant. When depressants are used, effects often include [[ataxia]], [[anxiolysis]], [[analgesia|pain relief]], [[sedation]] or [[somnolence]], [[cognitive deficit|cognitive]] or [[memory loss|memory impairment]], as well as, in some instances, [[euphoria]], [[Dissociation (psychology)|dissociation]], [[muscle relaxation]], lowered [[blood pressure]] or [[heart rate]], [[respiratory depression]], and [[anticonvulsant]] effects. Depressants sometimes also act to produce [[anesthesia]]. Other depressants can include drugs like [[benzodiazepine]]s (e.g., [[alprazolam]]) and a number of [[opioids]]. [[Gabapentinoid]]s like [[gabapentin]] and [[pregabalin]] are depressants and have anticonvulsant and [[anxiolytic]] effects. Most anticonvulsants, like [[lamotrigine]] and [[phenytoin]], are depressants. [[Carbamate]]s, such as [[meprobamate]], are depressants that are similar to [[barbiturate]]s. [[Anesthetic]]s are generally depressants; examples include [[ketamine]] and [[propofol]].

Depressants exert their effects through a number of different pharmacological mechanisms, the most prominent of which include facilitation of [[gamma-Aminobutyric acid|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 [[bromide]]s and [[channel blocker]]s.

== Indications ==
Depressants are used medicinally to relieve the following symptoms and disorders:{{Citation needed|date=March 2025}}
* [[Anxiety disorders]] such as:
** [[Generalized anxiety disorder]]
** [[Social anxiety disorder]]
** [[Panic attack]]s
* [[Insomnia]]
* [[Seizure]]s
* [[Convulsion]]s
* [[Depression (mood)|Depression]]
* [[Pain]]

== Types ==
[[Image:Alcoholic beverages.jpg|right|thumb|[[Distilled]] (concentrated) [[alcoholic beverage]]s, sometimes called "spirit" or "[[hard liquor]]", are roughly eight times more alcoholic than beer.]]

=== Alcohol ===
{{Main|Alcoholic beverage|Ethanol|Blood alcohol content}}
An [[alcoholic beverage]] is a drink that [[alcohol by volume|contains alcohol]] (known formally as [[ethanol]]), an [[anesthetic]] that has been used as a [[psychoactive drug]] for several [[millennia]]. Ethanol is the oldest [[recreational drug]] still used by humans. Ethanol can cause [[alcohol intoxication]] when consumed. Alcoholic beverages are divided into three general classes for [[Alcohol laws#Taxation and regulation of production|taxation and regulation of production]]: [[beer]]s, [[wine]]s, and [[Distilled beverage|spirits]] (distilled beverages). They are legally consumed in most countries around the world. More than 100 countries have laws regulating their production, sale, and consumption.<ref name="IARD">{{cite web|title=Minimum Legal Age Limits|url=http://www.iard.org/policy-tables/minimum-legal-age-limits/|website=IARD.org|publisher=International Alliance for Responsible Drinking|access-date=23 June 2016|archive-url=https://web.archive.org/web/20160504144607/http://www.iard.org/policy-tables/minimum-legal-age-limits/|archive-date=4 May 2016}}</ref>

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 [[Deciliter|dL]] of blood (i.e., mass per volume is used there).<ref>{{EMedicine|article|2090019|Ethanol Level}}</ref>

=== Barbiturates ===
{{Main|Barbiturate}}

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 [[Substance dependence|dependence]] and severe [[Drug withdrawal|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 [[seizure]]s or, in mild form, for relief from the symptoms of [[migraine]]s. One barbiturate that remains in use for seizure disorders is [[phenobarbital]].{{Citation needed|date=March 2025}}

=== Benzodiazepines ===
{{Main|Benzodiazepine}}
{{See also|Nonbenzodiazepine}}
A [[benzodiazepine]] is a drug whose core chemical structure is the fusion of a [[benzene]] ring and a [[diazepine]] ring. The first such drug, [[chlordiazepoxide]] (Librium), was [[Serendipity|discovered accidentally]] by [[Leo Sternbach]] in 1955 and made available in 1960 by [[Hoffmann–La Roche]], which has also marketed the benzodiazepine [[diazepam]] (Valium) since 1963.{{Citation needed|date=March 2025}}
[[File:Xanax 2 mg.jpg|thumb|Xanax ([[alprazolam]]) 2 mg tri-score tablets, a classical benzodiazepine sedative]]
Benzodiazepines enhance the effect of the [[neurotransmitter]] [[gamma-Aminobutyric acid|gamma-aminobutyric acid]] (GABA) at the [[GABAA receptor|GABA<sub>A</sub> 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, [[Psychomotor agitation|agitation]], seizures, [[Spasm|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.{{Citation needed|date=March 2025}}

In general, benzodiazepines are safe and effective in the short term, although cognitive impairments and [[paradoxical effect]]s 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 drug reaction|adverse effects]].{{Citation needed|date=March 2025}}

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 [[Neonatal withdrawal|withdrawal symptoms in the newborn]]. Benzodiazepines can be [[overdose]]d and cause dangerous [[coma|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 [[Alcoholic beverage|alcohol]] and [[Opioid|opioids]], 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 Criteria|Beers List]], which is significant in clinical practice.{{Citation needed|date=March 2025}}

===Cannabis===
{{Main|Cannabis (drug)|l1=Cannabis}}

[[cannabis (drug)|Cannabis]] is often considered either in its own unique category or as a mild [[psychedelic drug|psychedelic]].<ref name="WHO">{{Cite book|title=Clinical Guidelines for Withdrawal Management and Treatment of Drug Dependence in Closed Settings|author=World Health Organization|author-link=World Health Organization|date=31 August 2009|isbn= 978-92-9061-430-2|url=http://www.wpro.who.int/publications/docs/ClinicalGuidelines_forweb.pdf|archive-url=https://web.archive.org/web/20140312212437/http://www.wpro.who.int/publications/docs/ClinicalGuidelines_forweb.pdf|archive-date=12 March 2014|page=3|publisher=World Health Organization, Western Pacific Region |quote=Cannabis is a depressant drug, but it also has hallucinogenic effects.}}</ref><ref>{{cite journal|last1=Amsterdam|first1=Jan|last2=Nutt|first2=David|last3=Brink|first3=Wim|title=Generic legislation of new psychoactive drugs|journal=J Psychopharmacol |volume=27|issue=3|pages=317–324|date=23 January 2013|doi=10.1177/0269881112474525|pmid=23343598|s2cid=12288500|url=http://www.undrugcontrol.info/images/stories/documents/generic-legislation-nps.pdf|quote=Figure 1}}</ref> The chemical compound [[tetrahydrocannabinol]] (THC), which is found in cannabis, has many depressant effects, such as [[muscle relaxation]], [[sedation]], decreased [[alertness]], and [[drowsiness]].<ref>{{Cite web |last=Burgess |first=Lana |date=30 July 2019 |title=Is marijuana a depressant? Everything you need to know |url=https://www.medicalnewstoday.com/articles/325894 |access-date=19 August 2023 |website=www.medicalnewstoday.com |language=en |quote="They may reduce anxiety and muscle tension and make a person feel sleepy."}}</ref> Contrarily, activation of the [[CB1 receptor|CB<sub>1</sub> receptor]] by [[cannabinoids]] causes an inhibition of GABA, which is atypical to most other depressants.{{Citation needed|date=March 2025}}

=== Carbamates ===
{{Main|Carbamate}}
[[Carbamate]]s are a class of depressants, or "[[tranquilizer]]s", that are synthesized from [[urea]].<ref>{{Cite journal |last1=Jordan |first1=Allan M. |last2=Khan |first2=Tariq H. |last3=Malkin |first3=Hugh |last4=Osborn |first4=Helen M. I. |date=August 2002 |title=Synthesis and analysis of urea and carbamate prodrugs as candidates for melanocyte-directed enzyme prodrug therapy (MDEPT) |journal=Bioorganic & Medicinal Chemistry |volume=10 |issue=8 |pages=2625–2633 |doi=10.1016/s0968-0896(02)00097-4 |pmid=12057651}}</ref> Carbamates have [[anxiolytic]],<ref name="Conermann 2022">{{Citation |last1=Conermann |first1=Till |title=Carisoprodol |url=https://www.ncbi.nlm.nih.gov/books/NBK553077/ |work=StatPearls |place=Treasure Island (FL) |date=2022 |publisher=StatPearls Publishing |pmid=31971718 |access-date=30 November 2022 |last2=Christian |first2=Desirae}}</ref> [[muscle relaxant]],<ref name="Conermann 2022" /> [[anticonvulsant]],<ref>{{Cite journal |last1=Kulig |first1=Katarzyna |last2=Malawska |first2=Barbara |date=October 2007 |title=Carisbamate, a new carbamate for the treatment of epilepsy |journal=IDrugs |volume=10 |issue=10 |pages=720–727 |pmid=17899491}}</ref> [[hypnotic]],<ref name="Conermann 2022" /> [[Antihypertensive drug|antihypertensive]],<ref>{{Cite journal |last1=Kavelman |first1=D. A. |last2=Lewis |first2=J. A. |title=Clinical Evaluation of a New Antihypertensive Agent: W583 (Mebutamate) |date=9 November 1963 |journal=Canadian Medical Association Journal |volume=89 |issue=19 |pages=993–995 |pmc=1921904 |pmid=14076168}}</ref> and [[analgesic]] effects. They have other uses, like [[Tremor|muscle tremors]], [[Psychomotor agitation|agitation]], and [[Alcohol withdrawal syndrome|alcohol withdrawal]]. Their muscle relaxant effects are useful for [[Strain (injury)|strains]], [[sprain]]s, and muscle injuries combined with rest, physical therapy, and other measures.<ref name="Conermann 2022" /> The effects, synthesis, and mechanism of action of carbamates are very similar to those of barbiturates.<ref>{{Cite journal |last1=Rho |first1=J. M. |last2=Donevan |first2=S. D. |last3=Rogawski |first3=M. A. |date=March 1997 |title=Barbiturate-like actions of the propanediol dicarbamates felbamate and meprobamate |journal=The Journal of Pharmacology and Experimental Therapeutics |volume=280 |issue=3 |pages=1383–1391 |doi=10.1016/S0022-3565(24)36535-8 |pmid=9067327}}</ref>

[[File:Somadril Comp.JPG|thumb|upright|[[Carisoprodol]] tablets]]

Side effects of carbamates include [[Somnolence|drowsiness]], [[dizziness]], [[headache]], [[diarrhea]], [[nausea]], [[flatulence]], [[liver failure]], [[Ataxia|poor coordination]], [[nystagmus]], [[Substance abuse|abuse]], [[dizziness]], [[weakness]], [[Anxiety|nervousness]], [[euphoria]], [[overstimulation]], and [[Substance dependence|dependence]]. Uncommon but potentially [[Adverse effect|severe adverse reactions]] include hypersensitivity reactions such as [[Stevens–Johnson syndrome]], [[Developmental toxicity|embryo-fetal toxicity]], [[stupor]], and [[coma]]. It is not recommended to use most carbamates, like [[carisoprodol]], for a long time, as [[Physical dependence|physical]] and [[psychological dependence]] do occur.<ref>{{Citation |title=Meprobamate |date=2012 |url=https://www.ncbi.nlm.nih.gov/books/NBK548721/ |work=LiverTox: Clinical and Research Information on Drug-Induced Liver Injury |place=Bethesda (MD) |publisher=National Institute of Diabetes and Digestive and Kidney Diseases |pmid=31644030 |access-date=30 November 2022}}</ref>

[[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 [[Allosteric modulator|allosterically modulates]] and directly [[Agonist|activates]] the human [[GABAA receptor|α1β2γ2 GABAAR]] ([[GABAA receptor|GABA<sub>A</sub>]]) in the [[central nervous system]], similar to barbiturates. This causes [[chloride channel]]s to open, allowing [[chloride]] to flood into the neuron. This slows down [[Neurotransmission|communication between neurons]] and the [[nervous system]].<ref>{{Cite journal |last1=Gonzalez |first1=Lorie A. |last2=Gatch |first2=Michael B. |last3=Taylor |first3=Cynthia M. |last4=Bell-Horner |first4=Cathy L. |last5=Forster |first5=Michael J. |last6=Dillon |first6=Glenn H. |date=May 2009 |title=Carisoprodol-Mediated Modulation of GABAA Receptors: In Vitro and in Vivo Studies |journal=The Journal of Pharmacology and Experimental Therapeutics |volume=329 |issue=2 |pages=827–837 |doi=10.1124/jpet.109.151142 |pmc=2672873 |pmid=19244096}}</ref> Unlike benzodiazepines, which increase the frequency of the chloride channel opening, carisoprodol increases the duration of channel opening when GABA is bound.<ref>{{cite journal |last1=Twyman |first1=Roy E. |last2=Rogers |first2=Carl J. |last3=Macdonald |first3=Robert L. |title=Differential regulation of γ-aminobutyric acid receptor channels by diazepam and phenobarbital |journal=Annals of Neurology |date=March 1989 |volume=25 |issue=3 |pages=213–220 |doi=10.1002/ana.410250302 |pmid=2471436 |hdl=2027.42/50330 |s2cid=72023197 |hdl-access=free }}</ref><ref>{{Cite journal |last1=Twyman |first1=R. |last2=Rogers |first2=C. J. |last3=Macdonald |first3=R. |date=1989 |title=Differential regulation of γ-aminobutyric acid receptor channels by diazepam and phenobarbital |journal=Annals of Neurology |volume=25 |issue=3 |pages=213–220 |doi=10.1002/ANA.410250302 |pmid=2471436 |hdl=2027.42/50330 |s2cid=72023197 |hdl-access=free }}</ref> GABA is the main [[Inhibitory postsynaptic potential|inhibitory]] [[neurotransmitter]] in the [[nervous system]], which causes its depressant effects.

Carbamates are fatal in [[Drug overdose|overdose]], which is why many have been replaced with benzodiazepines. Symptoms are similar to a barbiturate overdose and typically include [[Confusion|difficulty thinking]], [[Ataxia|poor coordination]], decreased [[levels of consciousness]], and a decreased effort to breathe ([[respiratory depression]]). An overdose is more likely to be fatal when mixed with another depressant that [[Hypoventilation|suppresses breathing]].{{fact|date=July 2024}}

Physical and [[psychological]] dependence does happen with long-term use of carbamates, particularly carisoprodol. Today, carisoprodol is only used in the short term for muscle pain, particularly back pain. Discontinuation after long-term use could be very intense and even possibly fatal. Withdrawal can resemble [[Barbiturate dependence|barbiturate]], [[Alcohol withdrawal syndrome|alcohol]], or benzodiazepine withdrawal, as they all have a [[GABAA receptor|similar mechanism of action]]. Discontinuation symptoms include [[confusion]], [[Orientation (mental)|disorientation]], [[delirium]], [[hallucination]]s ([[Auditory hallucination|auditory]] and [[Visual hallucinations in psychosis|visual]]), [[insomnia]], [[Anorexia (symptom)|decreased appetite]], [[anxiety]], [[psychomotor agitation]], [[Pressure of speech|pressured speech]], [[tremor]], [[tachycardia]], and [[seizure]]s, which could be fatal.<ref>{{Cite journal |last1=Ni |first1=Karen |last2=Cary |first2=Margaret |last3=Zarkowski |first3=Paul |date=October 2007 |title=Carisoprodol withdrawal induced delirium: A case study |journal=Neuropsychiatric Disease and Treatment |volume=3 |issue=5 |pages=679–682 |pmc=2656305 |pmid=19300598 }}</ref>

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 GABA<sub>A</sub> positive allosteric modulator and blocks the [[GRIN2B|NR2B]] subunit of the [[NMDA receptor]]. Other carbamates block [[sodium channel]]s. [[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 drug|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 controlled substance|Schedule IV]] substance in the United States.{{Citation needed|date=March 2025}}

Approved:{{Citation needed|date=March 2025}}
* [[Carisoprodol]]/[[Meprobamate]]/[[Tybamate]] (Soma/Miltown, Solacen) (muscle relaxant, anxiolytic)
* [[Difebarbamate]] (Atrium, Sevrium)
* [[Emylcamate]] (Striatran) (anxiolytic and muscle relaxant)
* [[Ethinamate]] (Valamin, Valmid) (sedative–hypnotic)
* [[Febarbamate]]/[[Febarbamate|Phenobamate]] (Solium, Tymium) (anxiolytic and sedative)
* [[Felbamate]] (Felbatol) (anticonvulsant)
* [[Hexapropymate]] (Merinax) (sedative–hypnotic)
* [[Mebutamate]] (Capla, Dormate) (anxiolytic, sedative, antihypertensive)
* [[Phenprobamate]] (Gamaquil, Isotonil) (muscle relaxant, sedative, anxiolytic, anticonvulsant, anesthesic)
* [[Procymate]] (Equipax) (sedative, anxiolytic)
* [[Styramate]] (Sinaxamol) (muscle relaxant, anticonvulsant)
* [[Tetrabamate]] ([[febarbamate]], [[difebarbamate]], [[phenobarbital]]) (Atrium, G Tril, Sevrium) (for anxiety, alcohol withdrawal, muscle tremors, agitation, and depression)

Not approved:{{Citation needed|date=March 2025}}

* [[Carisbamate]] (anticonvulsant)
* [[Clocental]] (hypnotic)
* [[Cyclarbamate]] (muscle relaxant and tranquilizer)
* [[Lorbamate]] (muscle relaxant and tranquilizer)
* [[Nisobamate]] (tranquilizer)
* [[Pentabamate]] (tranquilizer)

===Gabapentinoids===
{{Main|Gabapentinoids}}
{{multiple image
| align             = right
| total_width       = 500
| image1            = Phenibut and analogues.png
| alt1              = GABA analogues
| caption1          = [[GABA]] analogues
| image2            = Voltage gated calcium channel.jpg
| alt2              = Binding sites of [[pregabalin]] and the non-gabapentenoid [[ziconotide]] to the voltage-gated calcium channel complex.
| caption2          = [[Voltage gated calcium channel]]
| image3            = Baclosan.JPG
| caption3          = [[Baclofen]] tablets
}}
[[Gabapentinoid]]s are a unique and relatively novel class of depressants that selectively [[Binding site|bind]] to the auxiliary [[CACNA2D1|α<sub>2</sub>δ subunit]] ([[CACNA2D1]] and [[CACNA2D2]]) site of certain [[Voltage-dependent calcium channels|VDCCs]] and thereby act as [[Channel blocker|inhibitors]] of [[CACNA2D1|α<sub>2</sub>δ]] subunit-containing [[voltage-gated calcium channel]]s. α<sub>2</sub>δ is nicknamed the "gabapentin receptor". At [[physiologic]] or resting [[membrane potential]], VDCCs are normally [[Resting potential|closed]]. They are activated (opened) at [[Depolarization|depolarized]] [[membrane potential]]s, which is the source of the "[[Voltage-gated ion channel|voltage-gated]]" [[epithet]]. Gabapentinoids bind to the [[CACNA2D1|α1]] and [[CACNA2D2|α2]] sites of the α<sub>2</sub>δ subunit family. Gabapentin is the [[Prototype|prototypical]] gabapentinoid. The α<sub>2</sub>δ is found on [[L-type calcium channel]]s, [[N-type calcium channel]]s, [[P-type calcium channel|P/Q-type calcium channels]], and [[R-type calcium channel]]s throughout the central and [[peripheral nervous system]]s. α<sub>2</sub>δ is located on [[Chemical synapse|presynaptic neurons]] and affects [[calcium channel]] trafficking and kinetics, initiates [[extracellular]] [[Signal transduction|signaling cascades]] and [[gene expression]], and promotes [[Excitatory postsynaptic potential|excitatory]] [[synaptogenesis]] through [[thrombospondin 1]].<ref>{{Cite journal |last1=Spencer |first1=Sade |last2=Brown |first2=Robyn M. |last3=Quintero |first3=Gabriel C. |last4=Kupchik |first4=Yonatan M. |last5=Thomas |first5=Charles A. |last6=Reissner |first6=Kathryn J. |last7=Kalivas |first7=Peter W. |date=18 June 2014 |title=α2δ-1 signaling in nucleus accumbens is necessary for cocaine-induced relapse |journal=The Journal of Neuroscience|volume=34 |issue=25 |pages=8605–8611 |doi=10.1523/JNEUROSCI.1204-13.2014 |pmc=4061396 |pmid=24948814 }}</ref> Gabapentinoids are not direct [[channel blocker]]s; rather, they disrupt the regulatory function of α<sub>2</sub>δ and its interactions with other proteins. Most of the effects of gabapentinoids are mediated by the [[Voltage-gated calcium channel|high-voltage activated]] N and P/Q-type calcium channels. P/Q-type calcium channels are mainly found in the [[cerebellum]] ([[Purkinje neurons]]), which may be responsible for the [[Ataxia|ataxic]] adverse effect of gabapentinoids, while N-type calcium channels are located throughout the central and peripheral nervous systems. [[N-type calcium channel]]s are mainly responsible for the [[analgesic]] effects of gabapentinoids. [[Ziconotide]], a non-gabapentinoid ω-[[conotoxin]] [[peptide]], binds to the [[N-type calcium channel]]s and has analgesic effects 1000 times stronger than [[morphine]]. Gabapentinoids are selective for the α<sub>2</sub>δ site but [[non-selective]] when they bind to the calcium channel complex. They act on the α<sub>2</sub>δ site to lower the release of many [[Excitatory postsynaptic potential|excitatory]] and pro-[[Nociception|nociceptive]] [[neurochemical]]s, including [[Glutamic acid|glutamate]], [[substance P]], [[calcitonin gene-related peptide]] (CGRP), and more.<ref name="pmid172224652">{{cite journal |vauthors=Dooley DJ, Taylor CP, Donevan S, Feltner D |year=2007 |title=Ca2+ channel alpha2delta ligands: novel modulators of neurotransmission |journal=Trends Pharmacol. Sci. |volume=28 |issue=2 |pages=75–82 |doi=10.1016/j.tips.2006.12.006 |pmid=17222465}}</ref><ref name="WyllieCascino20123">{{cite book |author1=[[Elaine Wyllie]]  |url=https://books.google.com/books?id=j9t6Qg0kkuUC&pg=RA1-PA423 |title=Wyllie's Treatment of Epilepsy: Principles and Practice |author2=Gregory D. Cascino |author3=Barry E. Gidal |author4=Howard P. Goodkin |date=17 February 2012 |publisher=Lippincott Williams & Wilkins |isbn=978-1-4511-5348-4 |page=423}}</ref><ref name="BenzonRathmell20132">{{cite book |author1=Honorio Benzon |url=https://books.google.com/books?id=kfcDAQAAQBAJ&pg=PA1006 |title=Practical Management of Pain |author2=James P. Rathmell |author3=Christopher L. Wu |author4=Dennis C. Turk |author5=Charles E. Argoff |author6=Robert W Hurley |date=11 September 2013 |publisher=Elsevier Health Sciences |isbn=978-0-323-17080-2 |page=1006}}</ref>

Gabapentinoids are absorbed from the intestines mainly by the [[large neutral amino acid transporter 1]] (LAT1, SLC7A5) and the [[excitatory amino acid transporter 3]] (EAAT3). They are one of the few drugs that use these [[amino acid transporter]]s. Gabapentinoids are structurally similar to the [[branched-chain amino acid]]s [[Leucine|L-leucine]] and [[Isoleucine|L-isoleucine]], both of which also bind to the α<sub>2</sub>δ site. [[Branched-chain amino acid]]s like l-leucine, l-isoleucine, and [[Valine|l-valine]] have many functions in the central nervous system. They modify [[Large neutral amino acids transporter small subunit 1|large neutral amino acid]] (LNAA) transport at the [[blood–brain barrier]] and reduce the synthesis of neurotransmitters derived from [[aromatic amino acid]]s, notably [[serotonin]] from [[tryptophan]] and [[catecholamine]]s from [[tyrosine]] and [[phenylalanine]].<ref>{{Cite journal |last=Fernstrom |first=John D. |date=June 2005 |title=Branched-chain amino acids and brain function |journal=The Journal of Nutrition |volume=135 |issue=6 Suppl |pages=1539S–46S |doi=10.1093/jn/135.6.1539S |pmid=15930466 |doi-access=free }}</ref> This may be relevant to the [[pharmacology]] of gabapentinoids.

Gabapentin was designed by researchers at [[Parke-Davis]] to be an [[Structural analog|analogue]] of the [[neurotransmitter]] GABA that could more easily cross the [[blood–brain barrier]] and was first described in 1975 by Satzinger and Hartenstein.<ref>{{Cite book |last=Sneader |first=Walter |url=https://books.google.com/books?id=jglFsz5EJR8C&pg=PA219 |title=Drug Discovery: A History |date=31 October 2005 |publisher=John Wiley & Sons |isbn=978-0-470-01552-0 }}</ref><ref>{{cite journal |last1=Levandovskiy |first1=Igor A |last2=Sharapa |first2=Dmitry I |last3=Shamota |first3=Tatyana V |last4=Rodionov |first4=Vladimir N |last5=Shubina |first5=Tatyana E |title=Conformationally Restricted GABA Analogs: From Rigid Carbocycles to Cage Hydrocarbons |journal=Future Medicinal Chemistry |date=February 2011 |volume=3 |issue=2 |pages=223–241 |doi=10.4155/fmc.10.287 |pmid=21428817 }}</ref> Gabapentin was first approved for [[epilepsy]], mainly as an add-on treatment for [[Focal seizure|partial seizures]]. Gabapentinoids are [[GABA analogue]]s,<ref name="pmid101891762">{{Cite journal |last1=Bryans |first1=Justin S. |last2=Wustrow |first2=David J. |year=1999 |title=3-Substituted GABA analogs with central nervous system activity: A review |journal=Medicinal Research Reviews |volume=19 |issue=2 |pages=149–77 |doi=10.1002/(SICI)1098-1128(199903)19:2<149::AID-MED3>3.0.CO;2-B |pmid=10189176 |s2cid=38496241 }}</ref> but they do not bind to the [[GABA receptor]]s, convert into GABA or another [[GABA receptor agonist]] ''[[in vivo]]'', or directly modulate GABA [[neurotransmitter transport|transport]] or [[metabolism]].<ref name="Uch20102">{{Cite journal |last1=Uchitel |first1=O. D|last2=Di Guilmi|first2=M. N.|last3=Urbano|first3=F. J.|last4=Gonzalez-Inchauspe|first4=C. |year=2010 |title=Acute modulation of calcium currents and synaptic transmission by gabapentinoids |journal=Channels (Austin) |volume=4 |issue=6 |pages=490–496 |doi=10.4161/chan.4.6.12864 |pmid=21150315 |doi-access=free|hdl=11336/20897 |hdl-access=free }}</ref><ref name="pmid16376147">{{Cite journal |last=Sills, G. J. |year=2006 |title=The mechanisms of action of gabapentin and pregabalin |journal=Current Opinion in Pharmacology |volume=6 |issue=1 |pages=108–13 |doi=10.1016/j.coph.2005.11.003 |pmid=16376147}}</ref> [[Phenibut]] and [[baclofen]], two structurally related compounds, are exceptions, as they mainly act on the [[GABA B receptor]].<ref>{{Cite journal |last=Lapin |first=I. |date=2001 |title=Phenibut (beta-phenyl-GABA): a tranquilizer and nootropic drug |journal=CNS Drug Reviews |volume=7 |issue=4 |pages=471–481 |doi=10.1111/j.1527-3458.2001.tb00211.x |pmc=6494145 |pmid=11830761}}</ref><ref>{{Cite journal |last1=Abramets |first1=I. I. |last2=Komissarov |first2=I. V. |date=June 1985 |title=[Effect of fenibut on the GABA B receptors of the spinal motor neurons] |journal=Biulleten' Eksperimental'noi Biologii I Meditsiny |volume=99 |issue=6 |pages=698–700 |pmid=2861865}}</ref> Gabapentin, but not pregabalin, has been found to activate [[voltage-gated potassium channel]]s ([[KCNQ channels|KCNQ]]), which might [[Potentiator|potentiate]] its depressant qualities. Despite this, gabapentinoids mimic [[GABAergic|GABA activity]] by [[Inhibitory postsynaptic potential|inhibiting]] [[neurotransmission]].<ref>{{cite book |doi=10.1016/B978-0-12-415853-5.00050-9 |chapter=Anticonvulsant-Related Bone Disease |title=Osteoporosis |date=2013 |last1=Pack |first1=Alison M. |pages=1225–1238 |isbn=978-0-12-415853-5 }}</ref> Gabapentinoids prevent delivery of the calcium channels to the cell membrane and disrupt interactions of α<sub>2</sub>δ with [[NMDA receptor]]s, [[AMPA receptor]]s, [[neurexin]]s, and [[thrombospondin]]s. Some [[calcium channel blocker]]s of the [[dihydropyridine]] class are used for [[hypertension]] to weakly block [[CACNA2D1|α<sub>2</sub>δ]].<ref>{{Cite web |title=Target Information {{!}} Therapeutic Target Database |url=http://db.idrblab.net/ttd/data/target/details/t84316 |access-date=23 May 2022 |website=db.idrblab.net |language=en}}</ref>

Gabapentinoids have anxiolytic, [[anticonvulsant]], [[Allodynia|antiallodynic]], [[Nociception|antinociceptive]], and possibly muscle relaxant properties.<ref name="WyllieCascino20123" /><ref name="Kirsch2013">{{cite book |author=Douglas Kirsch |url=https://books.google.com/books?id=Gf9QAQAAQBAJ&pg=PT241 |title=Sleep Medicine in Neurology |date=10 October 2013 |publisher=John Wiley & Sons |isbn=978-1-118-76417-6 |page=241}}</ref><ref name="SchatzbergNemeroff2009">{{cite book |last1=Frye |first1=Mark |title=The American Psychiatric Publishing Textbook of Psychopharmacology |last2=Moore |first2=Katherine |year=2009 |isbn=978-1-58562-309-9 |editor1-last=Schatzberg |editor1-first=Alan F. |pages=767–77 |chapter=Gabapentin and Pregabalin |doi=10.1176/appi.books.9781585623860.as38 |editor2-last=Nemeroff |editor2-first=Charles B. |chapter-url={{Google books|Xx7iNGdV25IC|page=767|plainurl=yes}}}}</ref> Pregabalin and gabapentin are used in [[epilepsy]], mainly [[Focal seizure|partial seizures]] (focal). Gabapentinoids are not effective for [[Generalized epilepsy|generalized seizures]]. They are also used for [[postherpetic neuralgia]], [[neuropathic pain]] associated with [[diabetic neuropathy]], [[fibromyalgia]], [[generalized anxiety disorder]], and [[restless legs syndrome]].<ref>{{Cite journal |last1=Garcia-Borreguero |first1=D. |last2=Larrosa |first2=O. |last3=de la Llave |first3=Y. |last4=Verger |first4=K. |last5=Masramon |first5=X. |last6=Hernandez |first6=G. |date=26 November 2002 |title=Treatment of restless legs syndrome with gabapentin: a double-blind, cross-over study |journal=Neurology |volume=59 |issue=10 |pages=1573–1579 |doi=10.1212/wnl.59.10.1573 |pmid=12451200 |s2cid=45436475 }}</ref><ref>{{Cite journal |last1=Derry |first1=Sheena |last2=Bell |first2=Rae Frances |last3=Straube |first3=Sebastian |last4=Wiffen |first4=Philip J. |last5=Aldington |first5=Dominic |last6=Moore |first6=R. Andrew |date=23 January 2019 |title=Pregabalin for neuropathic pain in adults |journal=The Cochrane Database of Systematic Reviews |volume=1 |issue=1 |article-number=CD007076 |doi=10.1002/14651858.CD007076.pub3 |pmc=6353204 |pmid=30673120 }}</ref><ref>{{Cite journal |last1=Ryvlin |first1=Philippe |last2=Perucca |first2=Emilio |last3=Rheims |first3=Sylvain |date=December 2008 |title=Pregabalin for the management of partial epilepsy |journal=Neuropsychiatric Disease and Treatment |volume=4 |issue=6 |pages=1211–1224 |doi=10.2147/ndt.s4716 |pmc=2646650 |pmid=19337461 |doi-access=free }}</ref><ref>{{Cite journal |last1=Derry |first1=Sheena |last2=Cording |first2=Malene |last3=Wiffen |first3=Philip J. |last4=Law |first4=Simon |last5=Phillips |first5=Tudor |last6=Moore |first6=R. Andrew |date=29 September 2016 |title=Pregabalin for pain in fibromyalgia in adults |journal=The Cochrane Database of Systematic Reviews |volume=9 |issue=5 |article-number=CD011790 |doi=10.1002/14651858.CD011790.pub2 |pmc=6457745 |pmid=27684492}}</ref><ref>{{Cite journal |last1=Baldwin |first1=David S |last2=Ajel |first2=Khalil |last3=Masdrakis |first3=Vasilios G |last4=Nowak |first4=Magda |last5=Rafiq |first5=Rizwan |date=2013 |title=Pregabalin for the treatment of generalized anxiety disorder: an update |journal=Neuropsychiatric Disease and Treatment |volume=9 |pages=883–892 |doi=10.2147/NDT.S36453 |pmc=3699256 |pmid=23836974 |doi-access=free }}</ref><ref>{{Cite journal |last=Cappuzzo |first=Kimberly A |date=2009 |title=Treatment of postherpetic neuralgia: focus on pregabalin |journal=Clinical Interventions in Aging |volume=4 |pages=17–23 |pmc=2685221 |pmid=19503762 }}</ref> Pregabalin and gabapentin have many [[Off-label use|off-label]] uses, including [[insomnia]],<ref>{{Cite journal |last1=Lo |first1=Hsiao-Sui |last2=Yang |first2=Chien-Ming |last3=Lo |first3=Helen G. |last4=Lee |first4=Chien-Ying |last5=Ting |first5=Hua |last6=Tzang |first6=Bor-Show |date=March 2010 |title=Treatment effects of gabapentin for primary insomnia |journal=Clinical Neuropharmacology |volume=33 |issue=2 |pages=84–90 |doi=10.1097/WNF.0b013e3181cda242 |pmid=20124884 |s2cid=4046961 }}</ref> [[Alcohol withdrawal syndrome|alcohol]] and [[opioid withdrawal]],<ref name="ReferenceA">{{Cite journal |last1=Freynhagen |first1=Rainer |last2=Backonja |first2=Miroslav |last3=Schug |first3=Stephan |last4=Lyndon |first4=Gavin |last5=Parsons |first5=Bruce |last6=Watt |first6=Stephen |last7=Behar |first7=Regina |date=2016 |title=Pregabalin for the Treatment of Drug and Alcohol Withdrawal Symptoms: A Comprehensive Review |journal=CNS Drugs |volume=30 |issue=12 |pages=1191–1200 |doi=10.1007/s40263-016-0390-z |pmc=5124051 |pmid=27848217}}</ref> [[smoking cessation]],<ref>{{Cite journal |last1=Sood |first1=Amit |last2=Ebbert |first2=Jon O. |last3=Wyatt |first3=Kirk D. |last4=Croghan |first4=Ivana T. |last5=Schroeder |first5=Darrell R. |last6=Sood |first6=Richa |last7=Hays |first7=J. Taylor |date=March 2010 |title=Gabapentin for smoking cessation |journal=Nicotine & Tobacco Research |volume=12 |issue=3 |pages=300–304 |doi=10.1093/ntr/ntp195 |pmc=2825098 |pmid=20081039 }}</ref> [[social anxiety disorder]],<ref>{{Cite journal |last1=Kawalec |first1=Paweł |last2=Cierniak |first2=Agnieszka |last3=Pilc |first3=Andrzej |last4=Nowak |first4=Gabriel |date=April 2015 |title=Pregabalin for the treatment of social anxiety disorder |journal=Expert Opinion on Investigational Drugs |volume=24 |issue=4 |pages=585–594 |doi=10.1517/13543784.2014.979283 |pmid=25361817 |s2cid=207477337 |url=http://ruj.uj.edu.pl/xmlui/handle/item/7876 }}</ref> [[bipolar disorder]],<ref>{{Cite journal |last1=Sokolski |first1=K. N. |last2=Green |first2=C. |last3=Maris |first3=D. E. |last4=DeMet |first4=E. M. |date=December 1999 |title=Gabapentin as an adjunct to standard mood stabilizers in outpatients with mixed bipolar symptomatology |journal=Annals of Clinical Psychiatry|volume=11 |issue=4 |pages=217–222 |doi=10.1023/a:1022361412956 |pmid=10596736 |s2cid=8468706 }}</ref><ref>{{Cite journal |last1=Conesa |first1=María-Llanos |last2=Rojo |first2=Luis-Miguel |last3=Plumed |first3=Javier |last4=Livianos |first4=Lorenzo |date=16 January 2012 |title=Pregabalin in the Treatment of Refractory Bipolar Disorders |journal=CNS Neuroscience & Therapeutics |volume=18 |issue=3 |pages=269–270 |doi=10.1111/j.1755-5949.2011.00289.x |pmc=6493626 |pmid=22449111}}</ref> [[attention deficit hyperactivity disorder]],<ref>{{Cite journal |last1=Hamrin |first1=V. |last2=Bailey |first2=K. |date=2001 |title=Gabapentin and methylphenidate treatment of a preadolescent with attention deficit hyperactivity disorder and bipolar disorder |journal=Journal of Child and Adolescent Psychopharmacology |volume=11 |issue=3 |pages=301–309 |doi=10.1089/10445460152595630 |pmid=11642481}}</ref> [[chronic pain]], [[hot flash]]es,<ref>{{Cite journal |last1=Pandya |first1=K J |last2=Morrow |first2=G R |last3=Roscoe |first3=J A |last4=Hickok |first4=J T |last5=Zhao |first5=H |last6=Pajon |first6=E |last7=Sweeney |first7=T J |last8=Banerjee |first8=T K |last9=Flynn |first9=P J |date=3 September 2005 |title=Gabapentin for hot flashes in 420 women with breast cancer: a randomised double-blind placebo-controlled trial |journal=Lancet |volume=366 |issue=9488 |pages=818–824 |doi=10.1016/S0140-6736(05)67215-7 |pmc=1627210 |pmid=16139656 }}</ref> [[tinnitus]], [[migraine]]s, and more. Baclofen is primarily used for the treatment of [[Spasticity|spastic movement]] disorders, especially in instances of [[spinal cord injury]], [[cerebral palsy]], and [[multiple sclerosis]].<ref name="AHFS">{{cite web |title=Baclofen |url=https://www.drugs.com/monograph/baclofen.html |access-date=6 December 2011 |work=The American Society of Health-System Pharmacists}}</ref> [[Phenibut]] is used in Russia, Ukraine, Belarus, and Latvia to treat anxiety and improve sleep, as in the treatment of insomnia.<ref name="pmid118307613">{{cite journal |vauthors=Lapin I |year=2001 |title=Phenibut (beta-phenyl-GABA): a tranquilizer and nootropic drug |journal=CNS Drug Reviews |volume=7 |issue=4 |pages=471–81 |doi=10.1111/j.1527-3458.2001.tb00211.x |pmc=6494145 |pmid=11830761}}</ref> It is also used for various other indications, including the treatment of [[asthenia]], depression, [[alcoholism]], alcohol withdrawal syndrome, [[post-traumatic stress disorder]], [[stuttering]], [[tic]]s, [[vestibular disorder]]s, [[Ménière's disease]], [[dizziness]], and the prevention of [[motion sickness]] and anxiety before or after surgical procedures or painful diagnostic tests.<ref name="pmid118307613"/> Phenibut, like other [[GABAB receptor|GABA<sub>B</sub> receptor]] agonists, is also sometimes used by bodybuilders to increase the [[Growth hormone|human growth hormone]].{{Citation needed|date=March 2025}}

In some cases, gabapentinoids are abused and provide similar effects to alcohol, benzodiazepines, and [[Gamma-Hydroxybutyric acid|gamma-hydroxybutyric acid]] (GHB).<ref>{{Cite journal |last1=Hägg |first1=Staffan |last2=Jönsson |first2=Anna K. |last3=Ahlner |first3=Johan |date=2020 |title=Current Evidence on Abuse and Misuse of Gabapentinoids |journal=Drug Safety |volume=43 |issue=12 |pages=1235–1254 |doi=10.1007/s40264-020-00985-6 |pmc=7686181 |pmid=32857333}}</ref><ref>{{Cite journal |last1=Smith |first1=Blair H |last2=Higgins |first2=Cassie |last3=Baldacchino |first3=Alex |last4=Kidd |first4=Brian |last5=Bannister |first5=Jonathan |date=August 2012 |title=Substance misuse of gabapentin |journal=The British Journal of General Practice |volume=62 |issue=601 |pages=406–407 |doi=10.3399/bjgp12X653516 |pmc=3404313 |pmid=22867659}}</ref><ref>{{Cite journal |last1=Althobaiti |first1=Yusuf S. |last2=Alghorabi |first2=Amal |last3=Alshehri |first3=Fahad S. |last4=Baothman |first4=Bandar |last5=Almalki |first5=Atiah H. |last6=Alsaab |first6=Hashem O. |last7=Alsanie |first7=Walaa |last8=Gaber |first8=Ahmed |last9=Almalki |first9=Hussam |last10=Alghamdi |first10=Abdulrahman S. |last11=Basfer |first11=Ahmad |date=26 June 2020 |title=Gabapentin-induced drug-seeking-like behavior: a potential role for the dopaminergic system |journal=Scientific Reports |volume=10 |issue=1 |page=10445 |doi=10.1038/s41598-020-67318-6 |pmc=7320158 |pmid=32591630 |bibcode=2020NatSR..1010445A }}</ref> The [[Food and Drug Administration|FDA]] placed a [[Boxed warning|black box warning]] on Neurontin (gabapentin) and Lyrica (pregabalin) for serious [[Shortness of breath|breathing problems]].<ref name="FDA breathing">{{cite web |date=19 December 2019 |title=FDA warns about serious breathing problems with seizure and nerve pain medicines gabapentin (Neurontin, Gralise, Horizant) and pregabalin (Lyrica, Lyrica CR) |url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-serious-breathing-problems-seizure-and-nerve-pain-medicines-gabapentin-neurontin |url-status=live |archive-url=https://web.archive.org/web/20191222091828/https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-serious-breathing-problems-seizure-and-nerve-pain-medicines-gabapentin-neurontin |archive-date=22 December 2019 |access-date=21 December 2019 |website=U.S. [[Food and Drug Administration]] (FDA)}} {{PD-notice}}</ref> Mixing gabapentinoids with opioids, benzodiazepines, barbiturates, GHB, alcohol, or any other depressant is potentially deadly.<ref>{{Cite journal |last1=Gomes |first1=Tara |last2=Juurlink |first2=David N. |last3=Antoniou |first3=Tony |last4=Mamdani |first4=Muhammad M. |last5=Paterson |first5=J. Michael |last6=van den Brink |first6=Wim |date=3 October 2017 |title=Gabapentin, opioids, and the risk of opioid-related death: A population-based nested case–control study |journal=PLOS Medicine |volume=14 |issue=10 |article-number=e1002396 |doi=10.1371/journal.pmed.1002396 |pmc=5626029 |pmid=28972983 |doi-access=free }}</ref><ref>{{Cite journal |last1=Kriikku |first1=Pirkko |last2=Ojanperä |first2=Ilkka |date=July 2021 |title=Pregabalin and gabapentin in non-opioid poisoning deaths |journal=Forensic Science International |volume=324 |article-number=110830 |doi=10.1016/j.forsciint.2021.110830 |pmid=34000615 |s2cid=234770186 |doi-access=free }}</ref><ref>{{Cite journal |last1=Elliott |first1=Simon P. |last2=Burke |first2=Timothy |last3=Smith |first3=Christopher |date=January 2017 |title=Determining the Toxicological Significance of Pregabalin in Fatalities |journal=Journal of Forensic Sciences |volume=62 |issue=1 |pages=169–173 |doi=10.1111/1556-4029.13263 |pmid=27864947|s2cid=39480384 }}</ref><ref>{{Cite journal |last1=Kalk |first1=Nicola J. |last2=Chiu |first2=Ching-Ting |last3=Sadoughi |first3=Rasa |last4=Baho |first4=Heli |last5=Williams |first5=Bryn D. |last6=Taylor |first6=David |last7=Copeland |first7=Caroline S. |date=18 April 2022 |title=Fatalities associated with gabapentinoids in England (2004–2020) |journal=British Journal of Clinical Pharmacology |volume=88 |issue=8 |pages=3911–3917 |doi=10.1111/bcp.15352 |pmid=35435281 |pmc=9543893 |s2cid=248228229 }}</ref>

Common [[side effects]] of gabapentinoids include [[Somnolence|drowsiness]], [[dizziness]], [[weakness]], [[Polyphagia|increased appetite]], [[urinary retention]], [[shortness of breath]], involuntary eye movements ([[nystagmus]]), [[Amnesia|memory issues]], [[Myoclonus|uncontrollable jerking motions]], [[auditory hallucination]]s, [[erectile dysfunction]], and [[Myoclonus|myoclonic seizures]].<ref>{{Cite book |url=https://www.ncbi.nlm.nih.gov/books/NBK304850/ |title=Gabapentin for Adults with Neuropathic Pain: A Review of the Clinical Efficacy and Safety |date=2015 |publisher=Canadian Agency for Drugs and Technologies in Health |series=CADTH Rapid Response Reports |location=Ottawa (ON) |pmid=26180879}}</ref><ref>{{Cite journal |last=Toth |first=Cory |date=February 2014 |title=Pregabalin: latest safety evidence and clinical implications for the management of neuropathic pain |journal=Therapeutic Advances in Drug Safety |volume=5 |issue=1 |pages=38–56 |doi=10.1177/2042098613505614 |pmc=4110876 |pmid=25083261}}</ref>

An [[Drug overdose|overdose]] of gabapentinoids usually consists of [[Somnolence|severe drowsiness]], [[Ataxia|severe ataxia]], [[blurred vision]], [[Dysarthria|slurred speech]], [[Myoclonus|severe uncontrollable jerking motions]], and anxiety.<ref>{{Cite journal |last1=Desai |first1=Aaron |last2=Kherallah |first2=Yazan |last3=Szabo |first3=Cheryl |last4=Marawar |first4=Rohit |date=March 2019 |title=Gabapentin or pregabalin induced myoclonus: A case series and literature review |journal=Journal of Clinical Neuroscience |volume=61 |pages=225–234 |doi=10.1016/j.jocn.2018.09.019 |pmid=30381161 |s2cid=53165515 }}</ref><ref>{{Cite journal |last1=Isoardi |first1=Katherine Z. |last2=Polkinghorne |first2=Gregory |last3=Harris |first3=Keith |last4=Isbister |first4=Geoffrey K. |date=December 2020 |title=Pregabalin poisoning and rising recreational use: a retrospective observational series |journal=British Journal of Clinical Pharmacology |volume=86 |issue=12 |pages=2435–2440 |doi=10.1111/bcp.14348 |pmc=7688538 |pmid=32374500 }}</ref> Like most anticonvulsants, pregabalin and gabapentin have an increased risk of [[Suicidal ideation|suicidal thoughts and behaviors]].<ref>{{Cite journal |last1=Gibbons |first1=Robert D. |last2=Hur |first2=Kwan |last3=Brown |first3=C. Hendricks |last4=Mann |first4=J. John |date=December 2010 |title=Gabapentin and Suicide Attempts |journal=Pharmacoepidemiology and Drug Safety |volume=19 |issue=12 |pages=1241–1247 |doi=10.1002/pds.2036 |pmc=2992093 |pmid=20922708}}</ref><ref>{{Citation |last1=Cross |first1=Aaron L. |title=Pregabalin |date=2022 |url=https://www.ncbi.nlm.nih.gov/books/NBK470341/ |work=StatPearls |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=29261857 |access-date=21 May 2022 |last2=Viswanath |first2=Omar |last3=Sherman |first3=Andrew l}}</ref> Gabapentinoids, like all [[calcium channel blocker]]s, are known to cause [[angioedema]].<ref>{{Cite journal |last1=Read |first1=Stephanie H. |last2=Giannakeas |first2=Vasily |last3=Pop |first3=Paula |last4=Bronskill |first4=Susan E. |last5=Herrmann |first5=Nathan |last6=Chen |first6=Simon |last7=Luke |first7=Miles J. |last8=Wu |first8=Wei |last9=McCarthy |first9=Lisa M. |last10=Austin |first10=Peter C. |last11=Normand |first11=Sharon-Lise |date=October 2021 |title=Evidence of a gabapentinoid and diuretic prescribing cascade among older adults with lower back pain |journal=Journal of the American Geriatrics Society |volume=69 |issue=10 |pages=2842–2850 |doi=10.1111/jgs.17312 |pmid=34118076|s2cid=235412378 }}</ref> Taking them with an [[ACE inhibitor]] can increase the toxic effects of gabapentinoids.<ref>{{Cite journal |last=Quintero |first=Gabriel C |date=9 February 2017 |title=Review about gabapentin misuse, interactions, contraindications and side effects |journal=Journal of Experimental Pharmacology |volume=9 |pages=13–21 |doi=10.2147/JEP.S124391 |pmc=5308580 |pmid=28223849 |doi-access=free }}</ref> They may also enhance the [[Edema|fluid-retaining]] effect of certain [[Antidiabetic agent|anti-diabetic agents]] ([[thiazolidinedione]]s). It is not known if they cause [[gingival enlargement]] like other [[calcium channel blocker]]s. Gabapentinoids are [[Excretion|excreted by the kidney]], mostly in their original form. Gabapentinoids can build up in the body when someone has [[Kidney failure|renal failure]]. This usually presents itself as [[myoclonus]] and an [[Altered state of consciousness|altered mental state]]. It is unclear if it is safe to use gabapentinoids during pregnancy, with some studies showing [[Drugs in pregnancy|potential harm]].<ref>{{Cite web |title=Pregabalin Use During Pregnancy |url=https://www.drugs.com/pregnancy/pregabalin.html |access-date=11 June 2022 |website=Drugs.com |language=en}}</ref>

[[Physical dependence|Physical]] or [[Psychological dependence|physiological dependence]] does occur during the long-term use of gabapentinoids.<ref>{{Cite journal |last=Schifano |first=Fabrizio |date=June 2014 |title=Misuse and Abuse of Pregabalin and Gabapentin: Cause for Concern? |journal=CNS Drugs |volume=28 |issue=6 |pages=491–496 |doi=10.1007/s40263-014-0164-4 |pmid=24760436 |s2cid=4508086 |doi-access=free }}</ref> Following abrupt or [[Cold turkey|rapid discontinuation]] of pregabalin and gabapentin, people report [[Drug withdrawal|withdrawal symptoms]] like insomnia, [[headache]], [[nausea]], [[diarrhea]], [[Influenza-like illness|flu-like symptoms]], anxiety, [[Major depressive disorder|depression]], [[pain]], [[hyperhidrosis]], [[seizure]]s, [[psychomotor agitation]], [[confusion]], [[disorientation]], and [[Gastrointestinal tract|gastrointestinal complaints]].<ref>{{Cite journal |last1=Ishikawa |first1=Hayahito |last2=Takeshima |first2=Masahiro |last3=Ishikawa |first3=Hiroyasu |last4=Ayabe |first4=Naoko |last5=Ohta |first5=Hidenobu |last6=Mishima |first6=Kazuo |date=September 2021 |title=Pregabalin withdrawal in patients without psychiatric disorders taking a regular dose of pregabalin: A case series and literature review |journal=Neuropsychopharmacology Reports |volume=41 |issue=3 |pages=434–439 |doi=10.1002/npr2.12195 |pmc=8411313 |pmid=34382380 }}</ref><ref>{{Cite journal |last1=Hellwig |first1=Thaddaus R. |last2=Hammerquist |first2=Rhonda |last3=Termaat |first3=Jill |date=June 2010 |title=Withdrawal symptoms after gabapentin discontinuation |journal=American Journal of Health-System Pharmacy |volume=67 |issue=11 |pages=910–912 |doi=10.2146/ajhp090313 |pmid=20484214}}</ref> Acute withdrawal from baclofen and phenibut may also cause [[Auditory hallucination|auditory]] and visual [[hallucination]]s, as well as acute [[psychosis]].<ref>{{Cite journal |last1=Alvis |first1=Bret D. |last2=Sobey |first2=Christopher M. |date=January 2017 |title=Oral Baclofen Withdrawal Resulting in Progressive Weakness and Sedation Requiring Intensive Care Admission |journal=The Neurohospitalist |volume=7 |issue=1 |pages=39–40 |doi=10.1177/1941874416637404 |pmc=5167087 |pmid=28042369 }}</ref><ref name="Matthew I 2018">{{Cite journal |last1=Hardman |first1=Matthew I. |last2=Sprung |first2=Juraj |last3=Weingarten |first3=Toby N. |date=May 2019 |title=Acute phenibut withdrawal: A comprehensive literature review and illustrative case report |journal=Bosnian Journal of Basic Medical Sciences |volume=19 |issue=2 |pages=125–129 |doi=10.17305/bjbms.2018.4008 |pmc=6535394 |pmid=30501608}}</ref> Baclofen withdrawal can be more intense if it is administered [[intrathecally]] or for long periods of time. If baclofen or phenibut is used for long periods of time, it can resemble intense [[Benzodiazepine withdrawal syndrome|benzodiazepine]], [[Gamma-Hydroxybutyric acid|GHB]], or alcohol withdrawal. To minimize [[Drug withdrawal|withdrawal symptoms]], baclofen or phenibut should be tapered down slowly. [[Cold turkey|Abrupt withdrawal]] from phenibut or baclofen could possibly be life-threatening because of its mechanism of action. Abrupt withdrawal can cause [[Generalized tonic–clonic seizure|rebound seizures]] and [[Excited delirium|severe agitation]].<ref>{{Cite journal |last1=Mohammed |first1=Imran |last2=Hussain |first2=Asif |date=9 August 2004 |title=Intrathecal baclofen withdrawal syndrome- a life-threatening complication of baclofen pump: A case report |journal=BMC Clinical Pharmacology |volume=4 |page=6 |doi=10.1186/1472-6904-4-6 |pmid=15301690 |pmc=514562 |doi-access=free }}</ref><ref name="Matthew I 2018"/>

Approved:{{Citation needed|date=March 2025}}

* [[Gabapentin]] (Neurontin)
* [[Gabapentin enacarbil]] (Horizant, Regnite)
* Gabapentin Extended-Release (Gralise)
* [[Pregabalin]] (Lyrica)
* [[Phenibut]] (Anvifen, Fenibut, Noofen)
* [[Baclofen]] (Lioresal)
* [[Mirogabalin]] (Tarlige) (Japan only)
Not approved:{{Citation needed|date=March 2025}}

*[[Imagabalin]]
* [[Tolibut]]
* [[4-Fluorophenibut|4-Flurophenibut]]
* [[HSK16149]]
* Trans-4 and cis-4-[18F] fluorogabapentin (α2δ [[Positron emission tomography|PET Imaging]])
* [[4-Methylpregabalin]]
* [[PD-217,014]]
* [[Atagabalin]]
* [[Arbaclofen placarbil|Arbaclofen]]
* [[Saclofen]]
[[Endogeny (biology)|Endogenous]] (not [[gabapentinoid]]s), endogenous [[Branched-chain amino acid|BCAA]] amino acids that bind to [[CACNA2D1|α<sub>2</sub>δ]]):

* [[Calcium]]
* [[Isoleucine]]
* [[Leucine]]
* [[Valine]]
* [[Aspartic acid|Aspartate]]

Other [[CACNA2D1|α2δ]] ligands:<ref>{{Cite web |title=SwissTargetPrediction |url=http://www.swisstargetprediction.ch/molecules.php?job=2018037608&target=0&method=3D |access-date=21 December 2022 |website=www.swisstargetprediction.ch}}</ref><ref>{{Cite web |title=Target Report Card |url=https://www.ebi.ac.uk/chembl/target_report_card/CHEMBL2363032/ |access-date=21 December 2022 |website=www.ebi.ac.uk}}</ref>

* [[Phenylalanine]]
* NP-118809
* Gababutin
* [[Ziconotide]] (approved for pain)
* [[Alcohol (drug)|Ethanol]] 
* [[Dextrothyroxine]] ([[agonist]] of [[CACNA2D1|α2δ]] instead of [[Enzyme inhibitor|inhibiting]] it)<ref>{{Cite web |last=genophore |title=DEXTROTHYROXINE |url=https://genophore.com/app/drugs/small_molecule/9812/dextrothyroxine/ |access-date=21 December 2022 |website=genophore.com |language=en}}</ref>
* [[Ethionine|Ethioninie]]
* [[Suloctidil]]
* [[Terodiline]]
* [[Bepridil]]

=== Gamma-hydroxybutyric acid ===
{{Main|Gamma-hydroxybutyric acid}}
{{Multiple image
| image1            = Phenibut and analogues.png
| alt1              = [[GABA analogue]]s
| caption1          = [[GABA analogue]]s
| image2            = GHB withdrawal symptoms.png
| alt2              = Severity of GHB withdrawal syndrome
| caption2          = Severity of GHB withdrawal syndrome
| image3            = Alcover 17,5 - Gamma-Hydroxybutyric acid.JPG
| alt3              = GHB that is used to treat alcohol addiction in Italy.
| caption3          = GHB that is used to treat [[Alcoholism|alcohol addiction]] in Italy.
| direction         = horizontal
| total_width       = 500
}}
[[Gamma-hydroxybutyric acid]], or "GHB", is a [[GABA analogue]] that is a naturally occurring neurotransmitter and depressant drug.<ref name="O'connell 2478–2482">{{Cite journal |last1=O'connell |first1=Ted |last2=Kaye |first2=Lily |last3=Plosay |first3=John J. III |date=December 2000 |title=Gamma-Hydroxybutyrate (GHB): A Newer Drug of Abuse |journal=American Family Physician |volume=62 |issue=11 |pages=2478–2482 |pmid=11130233 |url= https://www.aafp.org/pubs/afp/issues/2000/1201/p2478.html}}</ref><ref name="Cash 291–304">{{Cite journal |last=Cash |first=Christopher D. |date=June 1994 |title=Gammahydroxybutyrate: An overview of the pros and cons for it being a neurotransmitter and/or a useful therapeutic agent |journal=Neuroscience & Biobehavioral Reviews |volume=18 |issue=2 |pages=291–304 |doi=10.1016/0149-7634(94)90031-0 |pmid=7914688 |s2cid=42104511 |doi-access=free }}</ref><ref>{{cite book |last1=Fait |first1=Aaron |date=2006 |work=Communication in Plants: Neuronal Aspects of Plant Life |pages=171–185 |editor-last=Baluška |editor-first=František |place=Berlin, Heidelberg |publisher=Springer |doi=10.1007/978-3-540-28516-8_12 |isbn=978-3-540-28516-8 |last2=Yellin |first2=Ayelet |last3=Fromm |first3=Hillel |title=Communication in Plants |chapter=GABA and GHB Neurotransmitters in Plants and Animals |editor2-last=Mancuso |editor2-first=Stefano |editor3-last=Volkmann |editor3-first=Dieter}}</ref> It is also naturally found in small amounts in some [[alcoholic beverage]]s alongside ethanol.<ref>{{Cite journal |last1=Elliott |first1=Simon |last2=Burgess |first2=Victoria |date=16 July 2005 |title=The presence of gamma-hydroxybutyric acid (GHB) and gamma-butyrolactone (GBL) in alcoholic and non-alcoholic beverages |journal=Forensic Science International |volume=151 |issue=2 |pages=289–292 |doi=10.1016/j.forsciint.2005.02.014 |pmid=15939164 }}</ref> GHB is the [[Prototype|prototypical]] substance among a couple of [[GHB receptor|GHB receptor modulators]].<ref name="Nicholson 1–22">{{Cite journal |last1=Nicholson |first1=Katherine L. |last2=Balster |first2=Robert L. |date=June 2001 |title=GHB: a new and novel drug of abuse |journal=Drug and Alcohol Dependence |volume=63 |issue=1 |pages=1–22 |doi=10.1016/S0376-8716(00)00191-5 |pmid=11297827 }}</ref>

GHB has been used as a [[General anaesthetic|general anesthetic]]<ref>{{cite journal |last1=Tunnicliff |first1=Godfrey |title=Sites of Action of Gamma-Hydroxybutyrate (GHB)–A Neuroactive Drug with Abuse Potential |journal=Journal of Toxicology: Clinical Toxicology |date=January 1997 |volume=35 |issue=6 |pages=581–590 |doi=10.3109/15563659709001236 |pmid=9365423 }}</ref> and as a treatment for [[cataplexy]],<ref name="Boscolo-Berto 431–443">{{Cite journal |last1=Boscolo-Berto |first1=Rafael |last2=Viel |first2=Guido |last3=Montagnese |first3=Sara |last4=Raduazzo |first4=Daniella I. |last5=Ferrara |first5=Santo D. |last6=Dauvilliers |first6=Yves |date=October 2012 |title=Narcolepsy and effectiveness of gamma-hydroxybutyrate (GHB): A systematic review and meta-analysis of randomized controlled trials |journal=Sleep Medicine Reviews |volume=16 |issue=5 |pages=431–443 |doi=10.1016/j.smrv.2011.09.001 |pmid=22055895 }}</ref><ref>{{Cite journal |last1=Xu |first1=Xiao-Min |last2=Wei |first2=You-Dong |last3=Liu |first3=Yang |last4=Li |first4=Zuo-Xiao |date=December 2019 |title=Gamma-hydroxybutyrate (GHB) for narcolepsy in adults: an updated systematic review and meta-analysis |journal=Sleep Medicine |volume=64 |pages=62–70 |doi=10.1016/j.sleep.2019.06.017 |pmid=31671326 |s2cid=198286153 }}</ref> [[narcolepsy]],<ref name="Boscolo-Berto 431–443"/><ref>{{cite journal |last1=Scharf |first1=Martin B. |last2=Lai |first2=Allen A. |last3=Branigan |first3=Barb |last4=Stover |first4=Robin |last5=Berkowitz |first5=David B. |title=Pharmacokinetics of Gammahydroxybutyrate (GHB) in Narcoleptic Patients |journal=Sleep |date=August 1998 |volume=21 |issue=5 |pages=507–514 |doi=10.1093/sleep/21.5.507 |pmid=9703591 }}</ref> and [[alcoholism]].<ref>{{cite journal |last1=Poldrugo |first1=F |title=Review. The role of gamma-hydroxybutyric acid in the treatment of alcoholism: from animal to clinical studies |journal=Alcohol and Alcoholism |date=January 1999 |volume=34 |issue=1 |pages=15–24 |doi=10.1093/alcalc/34.1.15 |pmid=10075397 }}</ref><ref>{{cite journal |last1=Sewell |first1=R. A. |last2=Petrakis |first2=I. L. |title=Does Gamma-Hydroxybutyrate (GHB) Have a Role in the Treatment of Alcoholism? |journal=Alcohol and Alcoholism |date=January 2011 |volume=46 |issue=1 |pages=1–2 |doi=10.1093/alcalc/agq086 |pmid=21156757 }}</ref><ref>{{Cite journal |last1=Maremmani |first1=Angelo Giovanni Icro |last2=Pani |first2=Pier Paolo |last3=Rovai |first3=Luca |last4=Pacini |first4=Matteo |last5=Dell'Osso |first5=Liliana |last6=Maremmani |first6=Icro |date=July 2011 |title=Long-Term γ-Hydroxybutyric Acid (GHB) and Disulfiram Combination Therapy in GHB Treatment-Resistant Chronic Alcoholics |journal=International Journal of Environmental Research and Public Health |language=en |volume=8 |issue=7 |pages=2816–2827 |doi=10.3390/ijerph8072816 |pmid=21845160 |pmc=3155331 |doi-access=free }}</ref><ref>{{Cite journal |last1=Caputo |first1=Fabio |last2=Vignoli |first2=Teo |last3=Maremmani |first3=Icro |last4=Bernardi |first4=Mauro |last5=Zoli |first5=Giorgio |date=June 2009 |title=Gamma Hydroxybutyric Acid (GHB) for the Treatment of Alcohol Dependence: A Review |journal=International Journal of Environmental Research and Public Health |language=en |volume=6 |issue=6 |pages=1917–1929 |doi=10.3390/ijerph6061917 |pmid=19578468 |pmc=2705225 |doi-access=free }}</ref> The sodium salt of GHB, [[sodium oxybate]], is commonly used today for narcolepsy,<ref name="Alshaikh 1">{{cite journal |last1=Alshaikh |first1=Mashael K. |last2=Gacuan |first2=Divine |last3=George |first3=Smitha |last4=Sharif |first4=Munir |last5=BaHammam |first5=Ahmed S. |title=Long-Term Follow-Up of Patients With Narcolepsy-Cataplexy Treated With Sodium Oxybate (Xyrem) |journal=Clinical Neuropharmacology |date=January 2011 |volume=34 |issue=1 |pages=1–4 |doi=10.1097/WNF.0b013e318203d415 |pmid=21206362 |s2cid=206127007 }}</ref> sudden muscle weakness,<ref>{{Cite journal |author=U. S. Xyrem Multicenter Study Group |date=March 2004 |title=Sodium oxybate demonstrates long-term efficacy for the treatment of cataplexy in patients with narcolepsy |journal=Sleep Medicine |volume=5 |issue=2 |pages=119–123 |doi=10.1016/j.sleep.2003.11.002 |pmid=15033130 }}</ref> and excessive daytime sleepiness. It is sold under the brand name Xyrem.<ref name="Carter 1–10">{{Cite journal |last1=Carter |first1=Lawrence P. |last2=Pardi |first2=Daniel |last3=Gorsline |first3=Jane |last4=Griffiths |first4=Roland R. |date=September 2009 |title=Illicit gamma-hydroxybutyrate (GHB) and pharmaceutical sodium oxybate (Xyrem®): Differences in characteristics and misuse |journal=Drug and Alcohol Dependence |volume=104 |issue=1 |pages=1–10 |doi=10.1016/j.drugalcdep.2009.04.012 |pmid=19493637 |pmc=2713368 }}</ref><ref>{{Cite journal |last1=Wang |first1=Y. Grace |last2=Swick |first2=Todd J. |last3=Carter |first3=Lawrence P. |last4=Thorpy |first4=Michael J. |last5=Benowitz |first5=Neal L. |date=15 August 2009 |title=Safety Overview of Postmarketing and Clinical Experience of Sodium Oxybate (Xyrem): Abuse, Misuse, Dependence, and Diversion |journal=Journal of Clinical Sleep Medicine |volume=05 |issue=4 |pages=365–371 |doi=10.5664/jcsm.27549 |doi-access=free }}</ref><ref name="Alshaikh 1"/>

GHB mainly affects the [[GHB receptor]],<ref name="Bay 220–228">{{Cite journal |last1=Bay |first1=Tina |last2=Eghorn |first2=Laura F. |last3=Klein |first3=Anders B. |last4=Wellendorph |first4=Petrine |date=15 January 2014 |title=GHB receptor targets in the CNS: Focus on high-affinity binding sites |journal=Biochemical Pharmacology |volume=87 |issue=2 |pages=220–228 |doi=10.1016/j.bcp.2013.10.028 |pmid=24269284 }}</ref><ref name="Carter 100–114">{{Cite journal |last1=Carter |first1=Lawrence P. |last2=Koek |first2=Wouter |last3=France |first3=Charles P. |date=January 2009 |title=Behavioral analyses of GHB: Receptor mechanisms |journal=Pharmacology & Therapeutics |volume=121 |issue=1 |pages=100–114 |doi=10.1016/j.pharmthera.2008.10.003 |pmid=19010351 |pmc=2631377 }}</ref> an [[Excitatory postsynaptic potential|excitatory]] receptor that releases [[dopamine]] and [[Glutamic acid|glutamate]],<ref name="Kamal 2016 65–80">{{cite journal |last1=Kamal |first1=Rama M. |last2=van Noorden |first2=Martijn S. |last3=Franzek |first3=Ernst |last4=Dijkstra |first4=Boukje A.G. |last5=Loonen |first5=Anton J.M. |last6=De Jong |first6=Cornelius A.J. |title=The Neurobiological Mechanisms of Gamma-Hydroxybutyrate Dependence and Withdrawal and Their Clinical Relevance: A Review |journal=Neuropsychobiology |date=2016 |volume=73 |issue=2 |pages=65–80 |doi=10.1159/000443173 |pmid=27003176 |s2cid=33389634 |doi-access=free |hdl=2066/158441 |hdl-access=free }}</ref> giving GHB [[stimulant]] effects, the opposite of a depressant. But in large doses, GHB activates the [[GABAB receptor|GABA<sub>B</sub> receptor]], an [[Inhibitory postsynaptic potential|inhibitory receptor]] in the [[central nervous system]], which overpowers the [[Excitatory postsynaptic potential|excitatory effects]], thus causing [[central nervous system depression]].<ref name="Ingels 47–50">{{Cite journal |last1=Ingels |first1=Marianne |last2=Rangan |first2=Cyrus |last3=Bellezzo |first3=Joseph |last4=Clark |first4=Richard F |date=July 2000 |title=Coma and respiratory depression following the ingestion of GHB and its precursors: Three cases11Selected Topics: Toxicology is coordinated by Kenneth Kulig, MD, of Denver, Colorado |journal=The Journal of Emergency Medicine |volume=19 |issue=1 |pages=47–50 |doi=10.1016/S0736-4679(00)00188-8 |pmid=10863118 }}</ref><ref>{{Cite journal |last1=Roth |first1=R. H. |last2=Giarman |first2=N. J. |date=May 1968 |title=Evidence that central nervous system depression by 1,4-butanediol is mediated through a metabolite, gamma-hydroxybutyrate |journal=Biochemical Pharmacology |volume=17 |issue=5 |pages=735–739 |doi=10.1016/0006-2952(68)90010-5 |pmid=5649891 }}</ref> Some [[antipsychotic]]s are agonists of the GHB receptor.<ref>{{Cite journal |last1=Maitre |first1=Michel |last2=Ratomponirina |first2=Charline |last3=Gobaille |first3=Serge |last4=Hodé |first4=Yann |last5=Hechler |first5=Viviane |date=21 April 1994 |title=Displacement of [3H]γ-hydroxybutyrate binding by benzamide neuroleptics and prochlorperazine but not by other antipsychotics |journal=European Journal of Pharmacology |language=en |volume=256 |issue=2 |pages=211–214 |doi=10.1016/0014-2999(94)90248-8 |pmid=7914168 }}</ref><ref>{{Cite journal |last1=Ratomponirina |first1=Charline |last2=Gobaille |first2=Serge |last3=Hodé |first3=Yann |last4=Kemmel |first4=Véronique |last5=Maitre |first5=Michel |date=10 April 1998 |title=Sulpiride, but not haloperidol, up-regulates γ-hydroxybutyrate receptors in vivo and in cultured cells |journal=European Journal of Pharmacology |language=en |volume=346 |issue=2 |pages=331–337 |doi=10.1016/S0014-2999(98)00068-5 |pmid=9652377 }}</ref><ref>{{Cite journal |last1=Viviani |first1=Roberto |last2=Graf |first2=Heiko |last3=Wiegers |first3=Maike |last4=Abler |first4=Birgit |date=September 2013 |title=Effects of amisulpride on human resting cerebral perfusion |journal=Psychopharmacology |volume=229 |issue=1 |pages=95–103 |doi=10.1007/s00213-013-3091-z |pmid=23584671 |s2cid=253740656 }}</ref>

GHB can usually be found in either [[sodium]], [[potassium]], [[magnesium]], or calcium [[Salt (chemistry)|salts]].<ref>{{Cite journal |last1=Ferris |first1=Trevor J. |last2=Went |first2=Michael J. |date=10 March 2012 |title=Synthesis, characterisation and detection of gamma-hydroxybutyrate salts |journal=Forensic Science International |volume=216 |issue=1 |pages=158–162 |doi=10.1016/j.forsciint.2011.09.014 |pmid=22014974 |url=https://kar.kent.ac.uk/29249/4/Revised%20Paper_with_authors%20for%20KAR.pdf }}</ref><ref>{{cite journal |last1=Wolnik |first1=Karen A. |last2=Heitkemper |first2=Douglas T. |last3=Crowe |first3=John B. |last4=Barnes |first4=Barbara S. |last5=Brueggemeyer |first5=Thomas W. |title=Application of inductively coupled plasma atomic emission and mass spectrometry to forensic analysis of sodium gamma hydroxy butyrate and ephedrine hydrochloride. Invited lecture |journal=Journal of Analytical Atomic Spectrometry |date=1995 |volume=10 |issue=3 |page=177 |doi=10.1039/JA9951000177 }}</ref> [[Xywav]] is a medication that is a mixture of all GHB salts<ref>{{Cite journal |last=Heo |first=Young-A |date=May 2022 |title=Calcium, Magnesium, Potassium and Sodium Oxybates (Xywav®) in Sleep Disorders: A Profile of Its Use |journal=CNS Drugs |volume=36 |issue=5 |pages=541–549 |doi=10.1007/s40263-022-00912-6 |pmc=9095545 |pmid=35357671 }}</ref> and is used to treat the same conditions as Xyrem. Both Xywav and Xyrem are [[Controlled Substances Act#Schedule III controlled substances|Schedule III]]<ref name="Tunnicliff 278–283">{{cite journal |last1=Tunnicliff |first1=Godfrey |last2=Raess |first2=Beat U. |title=Gamma-Hydroxybutyrate (orphan medical) |journal=Current Opinion in Investigational Drugs |date=February 2002 |volume=3 |issue=2 |pages=278–283 |pmid=12020060 }}</ref><ref>{{Cite journal |last1=Strunc |first1=Michael J. |last2=Black |first2=Jed |last3=Lillaney |first3=Prasheel |last4=Profant |first4=Judi |last5=Mills |first5=Sherice |last6=Bujanover |first6=Shay |last7=Thorpy |first7=Michael J. |date=March 2021 |title=The Xyrem® (Sodium Oxybate) Risk Evaluation and Mitigation Strategy (REMS) Program in the USA: Results From 2016 to 2017 |journal=Drugs - Real World Outcomes |volume=8 |issue=1 |pages=15–28 |doi=10.1007/s40801-020-00223-6 |pmc=7984153 |pmid=33439474}}</ref> and have a black box warning<ref>{{cite journal |last1=Yan |first1=Han Helen |title=Off-Label Promotion Is Protected Speech: Second Circuit Sweeps Away Pharmaceutical Representative's Misbranding Conviction Under the First Amendment – United States v. Caronia |journal=American Journal of Law & Medicine |date=March 2013 |volume=39 |issue=1 |pages=189–192 |doi=10.1017/S0098858800000150 |s2cid=203716949 }}</ref> for [[Central nervous system depression|central nervous system depressant]] effects ([[hypoventilation]] and [[bradycardia]]) and for their very high potential for [[Drug abuse|abuse]].<ref>{{Cite journal |last1=Tay |first1=Emma |last2=Lo |first2=Wing Kwan Winky |last3=Murnion |first3=Bridin |date=31 December 2022 |title=Current Insights on the Impact of Gamma-Hydroxybutyrate (GHB) Abuse |journal=Substance Abuse and Rehabilitation |volume=13 |pages=13–23 |doi=10.2147/SAR.S315720 |pmc=8843350 |pmid=35173515 |doi-access=free }}</ref><ref name="Nicholson 1–22" /> [[Drug overdose|Overdose]] on GHB is fatal with or without mixing other CNS depressants.<ref>{{Cite journal |last1=Zvosec |first1=Deborah L. |last2=Smith |first2=Stephen W. |last3=Hall |first3=Brad J. |date=April 2009 |title=Three deaths associated with use of Xyrem® |journal=Sleep Medicine |volume=10 |issue=4 |pages=490–493 |doi=10.1016/j.sleep.2009.01.005 |pmid=19269893 }}</ref><ref>{{cite journal |last1=Couper |first1=F. J. |last2=Thatcher |first2=J. E. |last3=Logan |first3=B. K. |title=Suspected GHB Overdoses in the Emergency Department |journal=Journal of Analytical Toxicology |date=September 2004 |volume=28 |issue=6 |pages=481–484 |doi=10.1093/jat/28.6.481 |pmid=15516299 }}</ref><ref>{{Cite journal |last1=Degenhardt |first1=Louisa |last2=Darke |first2=Shane |last3=Dillon |first3=Paul |date=February 2003 |title=The prevalence and correlates of gamma-hydroxybutyrate (GHB) overdose among Australian users: GHB overdose among Australian users |journal=Addiction |language=en |volume=98 |issue=2 |pages=199–204 |doi=10.1046/j.1360-0443.2003.00265.x |pmid=12534425 }}</ref><ref>{{Cite journal |last1=van Amsterdam |first1=Jan G. C. |last2=Brunt |first2=Tibor M. |last3=McMaster |first3=Minni T. B. |last4=Niesink |first4=Raymond J. M. |date=April 2012 |title=Possible long-term effects of γ-hydroxybutyric acid (GHB) due to neurotoxicity and overdose |journal=Neuroscience & Biobehavioral Reviews |volume=36 |issue=4 |pages=1217–1227 |doi=10.1016/j.neubiorev.2012.02.002 |pmid=22342779 |s2cid=207089557 }}</ref> Death from a GHB overdose is usually caused by [[respiratory depression]], seizures, or [[coma]].<ref name="Ingels 47–50"/><ref name="Venzi 123–140">{{Cite journal |last1=Venzi |first1=Marcello |last2=Di Giovanni |first2=Giuseppe |last3=Crunelli |first3=Vincenzo |date=February 2015 |title=A Critical Evaluation of the Gamma-Hydroxybutyrate (GHB) Model of Absence Seizures |journal=CNS Neuroscience & Therapeutics |language=en |volume=21 |issue=2 |pages=123–140 |doi=10.1111/cns.12337 |pmc=4335601 |pmid=25403866 }}</ref><ref>{{cite journal |last1=Steele |first1=M. T. |last2=Watson |first2=W. A. |title=Acute poisoning from gamma hydroxybutyrate (GHB) |journal=Missouri Medicine |date=July 1995 |volume=92 |issue=7 |pages=354–357 |pmid=7651315 }}</ref>

GHB is used illegally as an [[Psychoactive drug|intoxicant]], an [[aphrodisiac]],<ref name="O'connell 2478–2482"/><ref>{{Cite journal |last1=Degenhardt |first1=Louisa |last2=Darke |first2=Shane |last3=Dillon |first3=Paul |date=June 2002 |title=GHB use among Australians: characteristics, use patterns and associated harm |journal=Drug and Alcohol Dependence |volume=67 |issue=1 |pages=89–94 |doi=10.1016/S0376-8716(02)00017-0 |pmid=12062782 }}</ref> and an athletic-performance enhancer.<ref name="Nicholson 1–22"/> It is a popular [[club drug]] in some parts of the world due to its powerful aphrodisiac and [[Euphoria|euphoric]] effects. Similarly to phenibut and baclofen, it is used by bodybuilders to increase the [[Growth hormone|human growth hormone]] due to [[GABAB receptor|GABA<sub>B</sub>]] activation.<ref>{{Cite journal |last1=Davis |first1=Lori L. |last2=Trivedi |first2=Madhukar |last3=Choate |first3=Amy |last4=Kramer |first4=Gerald L. |last5=Petty |first5=Frederick |date=April 1997 |title=Growth hormone response to the GABAB agonist baclofen in major depressive disorder |journal=Psychoneuroendocrinology |volume=22 |issue=3 |pages=129–140 |doi=10.1016/S0306-4530(96)00048-0 |pmid=9203224 |s2cid=29674330 }}</ref><ref>{{cite journal |last1=Gamel-Didelon |first1=Katia |last2=Corsi |first2=Claudia |last3=Pepeu |first3=Giancarlo |last4=Jung |first4=Heike |last5=Gratzl |first5=Manfred |last6=Mayerhofer |first6=Artur |title=An Autocrine Role for Pituitary GABA: Activation of GABA-B Receptors and Regulation of Growth Hormone Levels |journal=Neuroendocrinology |date=2002 |volume=76 |issue=3 |pages=170–177 |doi=10.1159/000064523 |pmid=12218349 |s2cid=18676115 |url=https://epub.ub.uni-muenchen.de/16580/1/10_1159_000064523.pdf }}</ref> It has also been reportedly used as a [[Date rape drug|date-rape drug]].<ref>{{Cite journal |last1=Son |first1=Seong Uk |last2=Jang |first2=Soojin |last3=Kang |first3=Byunghoon |last4=Kim |first4=Junseok |last5=Lim |first5=Jaewoo |last6=Seo |first6=Seungbeom |last7=Kang |first7=Taejoon |last8=Jung |first8=Juyeon |last9=Lee |first9=Kyu-Sun |last10=Kim |first10=Hyungjun |last11=Lim |first11=Eun-Kyung |date=15 November 2021 |title=Colorimetric paper sensor for visual detection of date-rape drug γ-hydroxybutyric acid (GHB) |journal=Sensors and Actuators B: Chemical |volume=347 |article-number=130598 |doi=10.1016/j.snb.2021.130598 |bibcode=2021SeAcB.34730598S }}</ref><ref>{{cite journal |last1=Zhai |first1=Duanting |last2=Tan |first2=Yong Qiao Elton |last3=Xu |first3=Wang |last4=Chang |first4=Young-Tae |title=Development of a fluorescent sensor for illicit date rape drug GHB |journal=Chemical Communications |date=2014 |volume=50 |issue=22 |pages=2904–2906 |doi=10.1039/C3CC49603A |pmid=24492471 }}</ref> This caused it to be a [[Schedule I chemical|Schedule I]] substance in the [[Controlled Substances Act|United States]], [[Controlled Drugs and Substances Act|Canada]], and other countries. Xyrem, which is GHB in its sodium form, is Schedule III in the United States, Canada, and other countries.<ref name="Carter 1–10"/><ref name="Tunnicliff 278–283"/>

In low doses, GHB mainly binds to the [[GHB receptor]] and weakly binds to the [[GABAB receptor|GABA<sub>B</sub>]] receptor.<ref name="Carter 100–114"/><ref name="Bay 220–228"/><ref>{{cite journal |last1=Carter |first1=Lawrence P. |last2=Wu |first2=Huifang |last3=Chen |first3=Weibin |last4=Cruz |first4=Christopher M. |last5=Lamb |first5=R. J. |last6=Koek |first6=Wouter |last7=Coop |first7=Andy |last8=France |first8=Charles P. |title=Effects of γ-Hydroxybutyrate (GHB) on Schedule-Controlled Responding in Rats: Role of GHB and GABA B Receptors |journal=Journal of Pharmacology and Experimental Therapeutics |date=January 2004 |volume=308 |issue=1 |pages=182–188 |doi=10.1124/jpet.103.058909 |pmid=14569056 |s2cid=753852 }}</ref> The GHB receptor is an excitatory [[G protein-coupled receptor]] (GPCR).<ref name="Carter 100–114"/><ref name="Bay 220–228"/> Its [[endogenous ligand]] is GHB, since GHB is also a [[neurotransmitter]].<ref name="Cash 291–304"/> 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|GABA<sub>B</sub> receptor]] but also exhibit a range of effects that were found not to be produced by GABA<sub>B</sub> 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.<ref name="Venzi 123–140"/> This is thought to be mediated through an increased Na<sup>+</sup>/K<sup>+</sup> current and the increased release of [[dopamine]] and [[glutamate]].<ref name="Kamal 2016 65–80"/> GHB can also cause [[absence seizure]]s;<ref name="Venzi 123–140"/><ref name="Hu 427–439">{{Cite journal |last1=Hu |first1=R. Q |last2=Banerjee |first2=P. K |last3=Snead III |first3=O. C |date=March 2000 |title=Regulation of γ-aminobutyric acid (GABA) release in cerebral cortex in the γ-hydroxybutyric acid (GHB) model of absence seizures in rat |journal=Neuropharmacology |volume=39 |issue=3 |pages=427–439 |doi=10.1016/S0028-3908(99)00152-5 |pmid=10698009 |s2cid=54323081 }}</ref><ref>{{cite journal |last1=Iii |first1=O. Carter Snead |title=γ-Hydroxybutyrate Model of Generalized Absence Seizures: Further Characterization and Comparison with Other Absence Models |journal=Epilepsia |date=August 1988 |volume=29 |issue=4 |pages=361–368 |doi=10.1111/j.1528-1157.1988.tb03732.x |pmid=3391142 |s2cid=221733630 }}</ref> the mechanism is currently not known but it is believed to be due to interactions with the [[GABAB receptor|GABA<sub>B</sub>]] receptor.<ref name="Hu 427–439"/> It is being investigated if endogenous GHB is responsible for non-convulsive seizures in humans.<ref name="Venzi 123–140"/><ref>{{cite journal |last1=Mamelak |first1=Mortimer |title=Gammahydroxybutyrate: An endogenous regulator of energy metabolism |journal=Neuroscience & Biobehavioral Reviews |date=December 1989 |volume=13 |issue=4 |pages=187–198 |doi=10.1016/S0149-7634(89)80053-3 |pmid=2691926 |s2cid=20217078 }}</ref>

[[Physical dependence]] develops quickly and is highly addictive. It shares some similarities, when suddenly discontinued, with the [[Drug withdrawal|withdrawal]] symptoms of gabapentinoids phenibut and baclofen due to the activation of the [[GABAB receptor|GABA<sub>B</sub>]] receptor. It features a typical depressant withdrawal syndrome that mimics alcohol withdrawal.<ref name="van Noorden A1286">{{cite journal |last1=van Noorden |first1=Martijn S. |last2=Kamal |first2=Rama |last3=de Jong |first3=Cor A. J. |last4=Vergouwen |first4=A. C. M. Ton |last5=Zitman |first5=Frans G. |title=STAND VAN ZAKEN GHB-afhankelijkheid en-onthoudingssyndroom |trans-title=Gamma-hydroxybutyric acid (GHB) dependence and the GHB withdrawal syndrome: diagnosis and treatment |language=nl |journal=Nederlands Tijdschrift voor Geneeskunde |date=2010 |volume=154 |pages=A1286 |pmid=21040601 |url=https://www.ntvg.nl/system/files/publications/a1286.pdf }}</ref> Symptoms include [[delirium]], [[tremor]], anxiety, [[tachycardia]], insomnia, [[hypertension]], [[confusion]], [[Perspiration|sweating]], [[Psychomotor agitation|severe agitation]] which may require restraint,<ref name="Dyer Roth Hyma 2001">{{cite journal |last1=Dyer |first1=Jo Ellen |last2=Roth |first2=Brett |last3=Hyma |first3=Bruce A. |title=Gamma-hydroxybutyrate withdrawal syndrome |journal=Annals of Emergency Medicine |date=February 2001 |volume=37 |issue=2 |pages=147–153 |doi=10.1067/mem.2001.112985 |pmid=11174231 }}</ref> [[Psychosis|auditory and visual hallucinations]], and possibly death from [[Generalized tonic–clonic seizure|tonic-clonic seizures]].<ref name="Dyer Roth Hyma 2001"/><ref>{{Cite journal |last1=Wolf |first1=Casper J. H. |last2=Beurmanjer |first2=Harmen |last3=Dijkstra |first3=Boukje A. G. |last4=Geerlings |first4=Alexander C. |last5=Spoelder |first5=Marcia |last6=Homberg |first6=Judith R. |last7=Schellekens |first7=Arnt F. A. |date=January 2021 |title=Characterization of the GHB Withdrawal Syndrome |journal=Journal of Clinical Medicine |language=en |volume=10 |issue=11 |page=2333 |doi=10.3390/jcm10112333 |pmid=34073640 |pmc=8199158 |doi-access=free }}</ref><ref name="van Noorden A1286"/><ref name="Lingford-Hughes 472">{{Cite journal |last1=Lingford-Hughes |first1=Anne |last2=Patel |first2=Yash |last3=Bowden-Jones |first3=Owen |last4=Crawford |first4=Mike J. |last5=Dargan |first5=Paul I. |last6=Gordon |first6=Fabiana |last7=Parrott |first7=Steve |last8=Weaver |first8=Tim |last9=Wood |first9=David M. |date=27 September 2016 |title=Improving GHB withdrawal with baclofen: study protocol for a feasibility study for a randomised controlled trial |journal=Trials |volume=17 |issue=1 |page=472 |doi=10.1186/s13063-016-1593-9 |pmc=5039898 |pmid=27677382 |doi-access=free }}</ref><ref>{{Cite journal |last1=Bennett |first1=W. R. Murray |last2=Wilson |first2=Lawrence G. |last3=Roy-Byrne |first3=Peter P. |date=September 2007 |title=Gamma-Hydroxybutyric Acid (GHB) Withdrawal: A Case Report |journal=Journal of Psychoactive Drugs |volume=39 |issue=3 |pages=293–296 |doi=10.1080/02791072.2007.10400616 |pmid=18159783 |s2cid=44864947 }}</ref><ref name="van Noorden 394–396">{{Cite journal |last1=van Noorden |first1=Martijn S. |last2=van Dongen |first2=Lieselotte C. A. M. |last3=Zitman |first3=Frans G. |last4=Vergouwen |first4=Ton (A. )C. M. |date=July 2009 |title=Gamma-hydroxybutyrate withdrawal syndrome: dangerous but not well-known |journal=General Hospital Psychiatry |language=en |volume=31 |issue=4 |pages=394–396 |doi=10.1016/j.genhosppsych.2008.11.001 |pmid=19555805 }}</ref>

Baclofen and phenibut are very effective for withdrawal and are preferred by patients over benzodiazepines for treatment of withdrawal.<ref name="Lingford-Hughes 472"/>

'''GHB receptor agonists''':{{Citation needed|date=March 2025}}
* [[Gamma-hydroxybutyric acid]] (GHB, Xyrem)

- Calcium oxybate, magnesium oxybate, sodium oxybate (Xyrem), potassium oxybate (Xywav is a mixture of all these salts.)

* [[HOCPCA|3-hydroxycyclopent-1-enecarboxylic acid]] (HOCPCA)
* [[T-HCA|γ-hydroxycrotonic acid, trans-4-Hydroxycrotonic acid]] (GHC, T-HCA)
* [[Amisulpride]], [[levosulpiride]], [[sulpiride]], [[sultopride]] (antipsychotic GHB receptor ligands)
* 3-Chloropropanoic acid (UMB66)
* 3-phenylpropyloxybutyric acid (UMB72)
* 4-benzyloxybutyric acid (UMB73)
* 4-hydroxy-4-napthylbutanoic acid (UMB86)
* 5-Hydroxypentanoate (UMB58)
* gamma-(4-methoxybenzyl)-gamma-hydroxybutyric acid (NCS-435)
* 4-(4-chlorophenyl)-4-hydroxy-2-butanoic acid (NCS-356)
* 3-hydroxyphenylacetic acid (3-HPA)
* [[Catechin]], [[monastrol]] (positive allosteric modulators)
'''Prodrugs that metabolize into GHB''':{{Citation needed|date=March 2025}}
* γ-Hydroxyvaleric acid (GHV)

- [[Gamma-Valerolactone|gamma-Valerolactone, γ-Valerolactone]] (GVL) (prodrug to GHV)

* [[1,4-Butanediol]] (1,4-BD)
* 1,4-Butanediol acetate (DABD)
* [[Ethyl acetoxy butanoate]] (EAB)
* [[Aceburic acid]] (GHB acetate)
* [[gamma-Butyrolactone]], γ-Butyrolactone (GBL)
* [[2-Furanone|2-Furanone, γ-crotonolactone]] (GCL)
* [[Gamma-Hydroxybutyraldehyde|Gamma-Hydroxybutyraldehyde, γ-Hydroxybutyraldehyde]] (GHBAL)
* [[Gamma-Hydroxyvaleric acid|Gamma-Hydroxyvaleric acid, γ-Hydroxyvaleric acid]] (GHV)

'''GHB receptor antagonists''':{{Citation needed|date=March 2025}}

* [[NCS-382]]
* [[Gabazine]]

''Some GHB receptors modulators only bind to the GHB receptor, while others bind to both the GHB and GABA<sub>B</sub> receptors.''

=== Nonbenzodiazepines ===
{{multiple image
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| total_width       = 300
| image1            = Zolpidem.svg
| alt1              = [[Zolpidem]]
| caption1          = [[Zolpidem]]
| image2            = Sonata10mg.JPG
| alt2              = [[Zaleplon]]
| caption2          = [[Zaleplon]]
| direction         = horizontal
}}
[[Nonbenzodiazepine]]s, sometimes referred to as Z-drugs, are a class of hypnotic depressants that are mainly used to treat insomnia and sometimes anxiety.<ref>{{Cite journal |last1=Dang |first1=Amit |last2=Garg |first2=Amit |last3=Rataboli |first3=Padmanabh V. |date=October 2011 |title=Role of Zolpidem in the Management of Insomnia: Role of Zolpidem |journal=CNS Neuroscience & Therapeutics |language=en |volume=17 |issue=5 |pages=387–397 |doi=10.1111/j.1755-5949.2010.00158.x |pmc=6493830 |pmid=20553305}}</ref><ref>{{cite journal |last1=Greenblatt |first1=David J |last2=Roth |first2=Thomas |title=Zolpidem for insomnia |journal=Expert Opinion on Pharmacotherapy |date=April 2012 |volume=13 |issue=6 |pages=879–893 |doi=10.1517/14656566.2012.667074 |pmid=22424586 }}</ref> They are structurally related to benzodiazepines. They positively modulate the [[benzodiazepine site]] of the GABA<sub>A</sub> receptor, the chief inhibitory receptor of the [[central nervous system]], just like benzodiazepines, but at a molecular level, they are structurally unrelated.{{Citation needed|date=March 2025}}

Nonbenzodiazepines bind to the benzodiazepine site on the GABA<sub>A</sub> receptor to keep the [[chloride channel]] open.<ref>{{cite journal |last1=Casida |first1=John E. |title=Insecticide action at the GABA-gated chloride channel: Recognition, progress, and prospects |journal=Archives of Insect Biochemistry and Physiology |date=January 1993 |volume=22 |issue=1–2 |pages=13–23 |doi=10.1002/arch.940220104 |pmid=7679302 }}</ref> This causes [[chloride]] in the [[Intercellular cleft|intercellular area]] to flood into the neuron.<ref>{{cite journal |last1=Sigel |first1=Erwin |title=Mapping of the Benzodiazepine Recognition Site on GABA-A Receptors |journal=Current Topics in Medicinal Chemistry |date=2002 |volume=2 |issue=8 |pages=833–839 |doi=10.2174/1568026023393444 |pmid=12171574 }}</ref> Since chloride has a [[Electric charge|negative charge]], it causes the neuron to rest and [[Action potential|cease firing]]. This results in a relaxing and depressant effect on the central nervous system.{{Citation needed|date=March 2025}}

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.{{Citation needed|date=March 2025}}

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.{{fact|date=July 2024}}

=== Opioids ===
{{Main|Opioids}}
{{multiple image
| align             = left
| total_width       = 180
| image1            = OnyNorm förpackning.jpg
| alt1              = 5mg [[Oxycodone]] hard capsules
| caption1          = [[Oxycodone]] is a semi-synthetic prescription opioid.
| image2            = Oriental poppies gone wild - geograph.org.uk - 1397319.jpg
| alt2              = [[Papaver somniferum]]
| caption2          = [[Papaver somniferum]]
| image3            = Midbrain small.gif
| caption3          = 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.
| direction         = vertical
| alt3              = 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.
}}

[[Opioid|Opioids]] are substances that act on [[opioid receptor]]s to reduce pain.<ref>{{Cite book |author1=Hugh C. Hemmings |url=https://books.google.com/books?id=s8CXrbimviMC&pg=PA268 |title=Pharmacology and Physiology for Anesthesia: Foundations and Clinical Application |author2=Talmage D. Egan |date=25 January 2013 |publisher=Elsevier Health Sciences |isbn=978-1-4377-1679-5 |language=en}}</ref> Medically, they are primarily used for [[pain relief]], including anesthesia. Opioids also cause [[euphoria]] and are highly abused.{{Citation needed|date=March 2025}}

There are three principal classes of opioid receptors: [[Mu opioid receptor|μ]], [[Kappa opioid receptor|κ]], [[Delta opioid receptor|δ]] (mu, kappa, and delta),<ref>{{Citation |last1=Dhaliwal |first1=Armaan |title=Physiology, Opioid Receptor |date=2022 |url=https://www.ncbi.nlm.nih.gov/books/NBK546642/ |work=StatPearls |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=31536249 |access-date=10 February 2023 |last2=Gupta |first2=Mohit}}</ref> although up to seventeen have been reported, and include the ε, ι, λ, and ζ (epsilon, iota, lambda, and zeta) receptors. Conversely, σ ([[Sigma receptor|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) ([[Nociceptin receptor|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 receptor|μ-opioid receptor agonists]].<ref>{{Cite journal |last1=New |first1=David C. |last2=Wong |first2=Yung H. |date=2002 |title=The ORL1 receptor: molecular pharmacology and signalling mechanisms |journal=Neuro-Signals |volume=11 |issue=4 |pages=197–212 |doi=10.1159/000065432 |pmid=12393946 |s2cid=38056310 |doi-access=free }}</ref>

When pain occurs, a [[Action potential|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 affectivity|negative emotion]] known as [[nociception]]. In the [[central nervous system]], the spine is connected to the brain by a structure called the brain stem.<ref>{{Cite journal |last1=Purves |first1=Dale |last2=Augustine |first2=George J. |last3=Fitzpatrick |first3=David |last4=Katz |first4=Lawrence C. |last5=LaMantia |first5=Anthony-Samuel |last6=McNamara |first6=James O. |last7=Williams |first7=S. Mark |date=2001 |title=Nociceptors |url=https://www.ncbi.nlm.nih.gov/books/NBK10965/ |journal=Neuroscience. 2nd Edition |language=en}}</ref> 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.{{fact|date=July 2024}}

The [[Μ-opioid receptor|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.<ref>{{Citation |last1=Herman |first1=Timothy F. |title=Mu Receptors |date=2024 |work=StatPearls |url=https://www.ncbi.nlm.nih.gov/books/NBK551554/ |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=31855381 |last2=Cascella |first2=Marco |last3=Muzio |first3=Maria Rosaria}}</ref> 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 [[Urinary retention|trouble urinating]] and [[Dysphagia|swallowing]]. The μ-opioid receptor can also reduce androgens, thus decreasing libido and sexual function. The receptor is also known to cause "musical anhedonia".<ref>{{Cite journal |last1=Mallik |first1=Adiel |last2=Chanda |first2=Mona Lisa |last3=Levitin |first3=Daniel J. |date=8 February 2017 |title=Anhedonia to music and mu-opioids: Evidence from the administration of naltrexone |journal=Scientific Reports |volume=7 |issue=1 |article-number=41952 |doi=10.1038/srep41952 |pmid=28176798 |pmc=5296903 |bibcode=2017NatSR...741952M }}</ref>

The μ-opioid receptor has many endogenous ligands, including [[Endorphins|endorphin]].<ref>{{Citation |last1=Chaudhry |first1=Shazia R. |title=Biochemistry, Endorphin |date=2022 |url=https://www.ncbi.nlm.nih.gov/books/NBK470306/ |work=StatPearls |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=29262177 |access-date=10 February 2023 |last2=Gossman |first2=William}}</ref>

{{quote box
| title = Adverse effects of opioids
(μ-opioid receptor)|'''Common and short term'''
* [[Itch]]ing<ref name="Furlan">{{cite journal | vauthors = Furlan AD, Sandoval JA, Mailis-Gagnon A, Tunks E | title = Opioids for chronic noncancer pain: a meta-analysis of effectiveness and side effects | journal = CMAJ | volume = 174 | issue = 11 | pages = 1589–94 | date = May 2006 | pmid = 16717269 | pmc = 1459894 | doi = 10.1503/cmaj.051528 }}</ref>
* [[Nausea]]<ref name="Furlan"/>
* Vomiting<ref name="Furlan"/>
* [[Constipation]]<ref name="Furlan"/>
* [[Miosis]]<ref name="Furlan"/>
* [[Somnolence|Drowsiness]]<ref name="Furlan"/>
* [[Xerostomia|Dry mouth]]<ref name="Furlan"/>
'''Other'''
* Cognitive effects
* [[Opioid dependence]]
* [[Dizziness]]
* [[Anorexia (symptom)|Loss of appetite]]
* [[Gastroparesis|Delayed gastric emptying]]
* Decreased sex drive
* [[Sexual dysfunction|Impaired sexual function]]
* [[hypogonadism|Decreased testosterone levels]]
* Depression
* [[Immunodeficiency]]
* [[Opioid-induced hyperalgesia|Increased pain sensitivity]]
* [[Irregular menstruation]]
* Increased risk of [[Falling (accident)|falls]]
* [[hypoventilation|Slowed breathing]]
* Coma
| width = 180
}}

The κ-opioid receptor ([[Κ-opioid receptor|KOR]]) is a [[G protein-coupled receptor]] located in the central nervous system. KOR is also a G protein-coupled receptor.<ref>{{Cite journal |last1=Ho |first1=Jo-Hao |last2=Stahl |first2=Edward L. |last3=Schmid |first3=Cullen L. |last4=Scarry |first4=Sarah M. |last5=Aubé |first5=Jeffrey |last6=Bohn |first6=Laura M. |date=7 August 2018 |title=G protein signaling–biased agonism at the κ-opioid receptor is maintained in striatal neurons |journal=Science Signaling |volume=11 |issue=542 |article-number=eaar4309 |doi=10.1126/scisignal.aar4309 |pmc=6373773 |pmid=30087177}}</ref> 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 (psychology)|mood]]. Dysregulation of this receptor system has been implicated in alcohol and drug addiction.<ref>{{cite journal |last1=Anderson |first1=Rachel I. |last2=Becker |first2=Howard C. |title=Role of the Dynorphin/Kappa Opioid Receptor System in the Motivational Effects of Ethanol |journal=Alcoholism: Clinical and Experimental Research |date=August 2017 |volume=41 |issue=8 |pages=1402–1418 |doi=10.1111/acer.13406 |pmc=5522623 |pmid=28425121 }}</ref> 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 [[hallucination]]s. Antagonizing the κ-opioid receptor may be able to treat depression, anxiety, stress, addiction, and alcoholism.<ref>{{Cite journal |last=Chavkin |first=Charles |date=August 2018 |title=Kappa-opioid antagonists as stress resilience medications for the treatment of alcohol use disorders |journal=Neuropsychopharmacology |volume=43 |issue=9 |pages=1803–1804 |doi=10.1038/s41386-018-0046-4 |pmc=6046055 |pmid=29752444 }}</ref>

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 receptor|δ-opioid agonists]] can produce [[Hypoventilation|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.<ref>{{Cite journal |last1=Jutkiewicz |first1=Emily M. |last2=Baladi |first2=Michelle G. |last3=Folk |first3=John E. |last4=Rice |first4=Kenner C. |last5=Woods |first5=James H. |date=June 2006 |title=The Convulsive and Electroencephalographic Changes Produced by Nonpeptidic δ-Opioid Agonists in Rats: Comparison with Pentylenetetrazol |journal=Journal of Pharmacology and Experimental Therapeutics |volume=317 |issue=3 |pages=1337–1348 |doi=10.1124/jpet.105.095810 |pmid=16537798 |s2cid=21838231 }}</ref> Activation of the δ-opioid receptor is usually stimulating instead of sedating like most opioids.{{Citation needed|date=March 2025}}

The [[Nociceptin receptor|nociception opioid peptide receptor]] (NOP) is involved in the regulation of numerous brain activities, particularly instinctive emotional behaviors and pain.<ref>{{EntrezGene|4987}} OPRL1 opioid related nociceptin receptor 1</ref> NOP is a [[G protein-coupled receptor]]. The nociception receptor controls a wide range of biological functions, including nociception, food intake, [[memory]] processes, [[cardiovascular]] and [[renal]] functions, spontaneous [[locomotor activity]], [[gastrointestinal motility]], [[anxiety]], and the control of [[neurotransmitter]] release at peripheral and central sites.<ref>{{Cite journal |last1=Calo' |first1=Girolamo |last2=Guerrini |first2=Remo |last3=Rizzi |first3=Anna |last4=Salvadori |first4=Severo |last5=Regoli |first5=Domenico |date=April 2000 |title=Pharmacology of nociceptin and its receptor: a novel therapeutic target |journal=British Journal of Pharmacology |volume=129 |issue=7 |pages=1261–1283 |doi=10.1038/sj.bjp.0703219 |pmc=1571975 |pmid=10742280 }}</ref>

{{multiple image
| align             = left
| total_width       = 280
| image1            = Mu opioid receptor.svg
| alt1              = 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]].
| caption1          = 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]] can be fatal.<ref>{{cite journal |last1=Rosenblum |first1=Andrew |last2=Marsch |first2=Lisa A. |last3=Joseph |first3=Herman |last4=Portenoy |first4=Russell K. |title=Opioids and the treatment of chronic pain: Controversies, current status, and future directions. |journal=Experimental and Clinical Psychopharmacology |date=October 2008 |volume=16 |issue=5 |pages=405–416 |doi=10.1037/a0013628 |pmc=2711509 |pmid=18837637 }}</ref> A person overdosing on [[opioid]]s presents with [[Hypoventilation|respiratory depression]], a potentially lethal condition that can cause [[Hypoxia (medical)|hypoxia]] from slow and shallow breathing.<ref>{{cite journal |last1=Boyer |first1=Edward W. |title=Management of Opioid Analgesic Overdose |journal=New England Journal of Medicine |date=12 July 2012 |volume=367 |issue=2 |pages=146–155 |doi=10.1056/NEJMra1202561 |pmid=22784117 |pmc=3739053 }}</ref> 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 pupil]]s, 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 oblongata|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|inhalation reflex]], usually resulting in hypoxia. Some overdose victims, however, die from [[Cardiac arrest|cardiovascular failure]] or asphyxiation from choking on their vomit.{{fact|date=July 2024}}

[[Naloxone]] is a μ-opioid receptor [[Receptor antagonist|antagonist]],<ref name="Theriot 2022">{{Citation |last1=Theriot |first1=Jonathan |title=Opioid Antagonists |date=2022 |url=https://www.ncbi.nlm.nih.gov/books/NBK537079/ |work=StatPearls |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=30725764 |access-date=11 February 2023 |last2=Sabir |first2=Sarah |last3=Azadfard |first3=Mohammadreza}}</ref> meaning instead of [[Agonist|activating]] the μ-opioid receptor, it disrupts the functioning of the receptor.<ref name="Theriot 2022" /> 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 [[Drug overdose|overdose]].<ref>{{Cite journal |last1=Rzasa Lynn |first1=Rachael |last2=Galinkin |first2=JL |date=January 2018 |title=Naloxone dosage for opioid reversal: current evidence and clinical implications |journal=Therapeutic Advances in Drug Safety |volume=9 |issue=1 |pages=63–88 |doi=10.1177/2042098617744161 |pmc=5753997 |pmid=29318006}}</ref> A person dependent on opioids may go into [[Drug withdrawal|precipitated withdrawal]] when naloxone is used.<ref name="Sun 544">{{Cite journal |last=Sun |first=Hsiao Lun |date=March 1998 |title=Naloxone-Precipitated Acute Opioid Withdrawal Syndrome After Epidural Morphine |journal=Anesthesia & Analgesia |volume=86 |issue=3 |pages=544–545 |doi=10.1213/00000539-199803000-00019 |pmid=9495411 |doi-access=free }}</ref> Since naloxone blocks any endogenous or exogenous opioids from binding to the μ-opioid receptor.<ref name="Sun 544" /> This may cause a person to immediately go into withdrawal after naloxone is used.<ref>[https://cpsm.mb.ca/assets/PrescribingPracticesProgram/Introduction%20Pharmacology,%20Precipitated%20Withdrawal%20&%20Management%20of%20Adverse%20Effects.pdf Introduction: The Pharmacology of Buprenorphine, Precipitated Withdrawal & Management of Adverse Effects]{{full|date=July 2024}}</ref> This can cause withdrawal symptoms like [[Diaphoresis|cold sweat]]s 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|midbrain dopamine system]].<ref name="Bourdy 681–690">{{Cite journal |last1=Bourdy |first1=Romain |last2=Barrot |first2=Michel |date=November 2012 |title=A new control center for dopaminergic systems: pulling the VTA by the tail |journal=Trends in Neurosciences |language=English |volume=35 |issue=11 |pages=681–690 |doi=10.1016/j.tins.2012.06.007 |pmid=22824232 |s2cid=43434322 }}</ref><ref name="Barrot 14094–14101">{{Cite journal |last1=Barrot |first1=Michel |last2=Sesack |first2=Susan R. |last3=Georges |first3=François |last4=Pistis |first4=Marco |last5=Hong |first5=Simon |last6=Jhou |first6=Thomas C. |date=10 October 2012 |title=Braking Dopamine Systems: A New GABA Master Structure for Mesolimbic and Nigrostriatal Functions |journal=The Journal of Neuroscience |volume=32 |issue=41 |pages=14094–14101 |doi=10.1523/JNEUROSCI.3370-12.2012 |pmc=3513755 |pmid=23055478 }}</ref> The RMTg possesses robust functional and structural links to the [[dopamine pathways]].<ref name="Bourdy 681–690" /><ref name="Barrot 14094–14101" /> Opioids decrease the release of GABA, thus disinhibiting the GABAergic brake on dopamine networks.<ref name="Bourdy 681–690" /> GABA is an [[inhibitory neurotransmitter]], meaning it either blocks or decreases the potential of neuron firing.<ref>{{Citation |title=γ-Aminobutyric acid |date=6 February 2023 |url=https://en.wikipedia.org/w/index.php?title=%CE%93-Aminobutyric_acid&oldid=1137889503 |work=Wikipedia |language=en |access-date=11 February 2023}}</ref> This causes large amounts of [[dopamine]] to be released, as it is no longer blocked by GABA.<ref name="Bourdy 681–690" /> 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 [[Reinforcement|positive reinforcing effects]] in the brain, instructing it to do it again. The RMTg is also responsible for the development of [[Drug tolerance|tolerance]] and [[addiction]]. [[Psychostimulants]] also excite this pathway.<ref name="Bourdy 681–690" /><ref name="Barrot 14094–14101" />

[[Fentanyl]] is very commonly cut into other substances sold on the street.<ref>{{Citation |last1=Ramos-Matos |first1=Carlos F. |title=Fentanyl |date=2024 |work=StatPearls |url=https://www.ncbi.nlm.nih.gov/books/NBK459275/ |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=29083586 |last2=Bistas |first2=Karlyle G. |last3=Lopez-Ojeda |first3=Wilfredo}}</ref> Fentanyl is used to increase the potency of substances, thus making the user spend more money on the laced substance.<ref>{{Cite journal |last1=Mars |first1=Sarah G |last2=Ondocsin |first2=Jeff |last3=Ciccarone |first3=Daniel |date=2018 |title=Sold As Heroin: Perceptions and Use of an Evolving Drug in Baltimore, MD |journal=Journal of Psychoactive Drugs |volume=50 |issue=2 |pages=167–176 |doi=10.1080/02791072.2017.1394508 |pmc=6114137 |pmid=29211971}}</ref><ref>{{Cite journal |last1=Misailidi |first1=Nektaria |last2=Papoutsis |first2=Ioannis |last3=Nikolaou |first3=Panagiota |last4=Dona |first4=Artemisia |last5=Spiliopoulou |first5=Chara |last6=Athanaselis |first6=Sotiris |date=2018 |title=Fentanyls continue to replace heroin in the drug arena: the cases of ocfentanil and carfentanil |journal=Forensic Toxicology |volume=36 |issue=1 |pages=12–32 |doi=10.1007/s11419-017-0379-4 |pmc=5754389 |pmid=29367860}}</ref> 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.{{Citation needed|date=March 2025}}

Natural opiates (derived from [[papaver somniferum]] and [[opium]]):{{Citation needed|date=March 2025}}
* [[Morphine]] (MS Contin)
* [[Codeine]] (Tylenol No. 3)
* [[Papaverine]] (Pavabid)
* [[Noscapine]] (Narcotine)
* [[Thebaine]]
* [[Oripavine]]
* [[Narceine]]

Semi-synthetic [[morphinan]] opioids (derived from thebaine):{{Citation needed|date=March 2025}}
* [[Oxycodone]] (Roxicodone)
* [[Heroin]]
* [[Hydrocodone]] (Vicodin)
* [[Oxymorphone]] (Opana)
* [[Hydromorphone]] (Dilaudid)
* [[Buprenorphine]] (Suboxone)
Fully synthetic opioids:
* [[Fentanyl]] (Duragesic)
* [[Tramadol]] (Ultram)
* [[Methadone]] (Dolophine)
* [[Pethidine]] (Demerol)
* [[Ketobemidone]] (Ketogan)
* [[Pentazocine]] (Talwin)
* [[Carfentanil]] (Wildnil)
* [[Loperamide]] (Imodium)
* [[Dextropropoxyphene]] (Darvocet)
* [[Tapentadol]] (Nucynta)
* [[Dextropropoxyphene]] (Darvocet)
Others:{{Citation needed|date=March 2025}}

* [[Mitragynine]] (derived from ''[[Mitragyna speciosa]]'' [Kratom])
* [[7-Hydroxymitragynine]] (derived from ''Mitragyna speciosa'' [Kratom])

=== Piperidinediones ===
{{Main|Glutarimide}}
[[File:Glutethimide.svg|thumb|upright=0.8|The structure of [[glutethimide]] is very similar to that of [[barbiturates]].]]
[[Piperidinedione]]s are a class of depressants that are not used anymore. There are piperidinediones that are used for other purposes, like [[breast cancer]].<ref>{{Cite book |last=Milne |first=George W. A. |url=https://books.google.com/books?id=xUlaDwAAQBAJ&pg=PT1182 |title=Drugs: Synonyms and Properties: Synonyms and Properties |date=2018-05-08 |publisher=Routledge |isbn=978-1-351-78989-9 |language=en}}</ref><ref>{{Cite book |last1=Morton |first1=I. K. |url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA14 |title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms |last2=Hall |first2=Judith M. |date=2012-12-06 |publisher=Springer Science & Business Media |isbn=978-94-011-4439-1 |language=en}}{{pn|date=July 2024}}</ref><ref>{{cite book |doi=10.1007/978-1-60327-829-4_8 |chapter=Adrenal Androgen Synthesis Inhibitor Therapies in Castration-Resistant Prostate Cancer |title=Drug Management of Prostate Cancer |date=2010 |last1=Friedlander |first1=Terence W. |last2=Ryan |first2=Charles J. |pages=91–100 |isbn=978-1-60327-831-7 }}</ref> 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 [[Depressants|central nervous depressants]]. The piperidinedione depressants, specifically glutethimide, are positive modulators of the GABA<sub>A</sub> [[Chloride channel|anion channel]]. The drug increases inhibitory [[GABAergic|GABAergic tone]] and causes [[Ligand (biochemistry)|neuro-inhibition]] of the [[Cerebral cortex|cortical]] and [[limbic system]]s, observed clinically as a [[Sedative|sedative-hypnotic]] effect.<ref>{{Cite web |title=glutethimide {{!}} Ligand page {{!}} IUPHAR/BPS Guide to PHARMACOLOGY |url=https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=clinical&ligandId=7192 |website=www.guidetopharmacology.org}}</ref> Glutethimide is also a potent inducer of the [[CYP2D6|CYP 2D6]] enzyme in the liver. This enzyme is responsible for converting many drugs, from [[beta blocker]]s 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 drug|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".{{fact|date=July 2024}} 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.{{fact|date=July 2024}}

Glutethimide withdrawal is intense and resembles barbiturate withdrawal. It features hallucinations and delirium typical of a depressant withdrawal. In the 1970s, there were reports of [[neonatal withdrawal]] from glutethimide. Infants born to mothers addicted to glutethimide responded well initially, then had a recurrence of symptoms about 5 days later, including [[Hyperactivity|overactivity]], [[Psychomotor agitation|restlessness]], [[tremor]]s, [[hyperreflexia]], [[hypotonia]], [[vasomotor instability]], [[Crying|incessant crying]], and [[Irritability|general irritability]].{{fact|date=July 2024}}

Glutethimide withdrawal featured severe agitation, [[tremor]]s, and seizures, which could be fatal.{{fact|date=July 2024}}

List of piperidinediones:{{Citation needed|date=March 2025}}

* [[Methyprylon]] (Dimerin, Methyprylone, Noctan, Noludar)
* [[Pyrithyldione]] (Presidon, Pyridion, Pyridione, Pyrithyldion, Pyrithyldione)
* [[Piperidione]] (Ascron, Dihyprylon, Dihyprylone, Sedulon, Tusseval)
* [[Glutethimide]] (Doriden)

=== Quinazolinone ===
{{Main|Quinazolinone}}
{{Multiple image
| image1            = Метаквалон.jpg
| caption1          = [[Methaqualone]] tablets
| image2            = Nitromethaqualone.svg
| caption2          = [[Nitromethaqualone]] structure
| direction         = vertical
}}

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 GABA<sub>A</sub> receptor.<ref name="Hammer 401–420">{{Cite journal |last1=Hammer |first1=Harriet |last2=Bader |first2=Benjamin M. |last3=Ehnert |first3=Corina |last4=Bundgaard |first4=Christoffer |last5=Bunch |first5=Lennart |last6=Hoestgaard-Jensen |first6=Kirsten |last7=Schroeder |first7=Olaf H.-U. |last8=Bastlund |first8=Jesper F. |last9=Gramowski-Voß |first9=Alexandra |last10=Jensen |first10=Anders A. |date=August 2015 |title=A Multifaceted GABAA Receptor Modulator: Functional Properties and Mechanism of Action of the Sedative-Hypnotic and Recreational Drug Methaqualone (Quaalude) |journal=Molecular Pharmacology |volume=88 |issue=2 |pages=401–420 |doi=10.1124/mol.115.099291 |pmc=4518083 |pmid=26056160 }}</ref> It does not bind to the ethanol, barbiturate, [[neurosteroid]], or [[benzodiazepine site]].<ref name="Hammer 401–420"/> Instead, it binds on a site directly between the GABRB2 (β2) and (α1) [[GABRA1]] proteins on the GABA<sub>A</sub> receptor.<ref name="Hammer 401–420"/> The [[anesthetic]] [[etomidate]] and [[anticonvulsant]] loreclezole may also bind to this site.<ref name="Hammer 401–420"/>

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, [[Myoclonus|myoclonic twitches]], [[somnolence]], euphoria, muscular hyperactivity, [[Excited delirium|agitated delirium]], [[tachycardia]], and [[Generalized tonic–clonic seizure|tonic-clonic seizures]]. In 1982, 2,764 people visited US emergency rooms after overdosing on quinazolinones, specifically methaqualone.<ref name="web.archive.org">{{Cite web |date=23 February 2012 |title=Methaqualone (Encyclopedia of Drugs and Addictive Substances) - eNotes.com |url=http://www.enotes.com/methaqualone-reference/methaqualone |access-date=1 December 2022 |archive-url=https://web.archive.org/web/20120223014958/http://www.enotes.com/methaqualone-reference/methaqualone |archive-date=23 February 2012 }}</ref> Mixing quinazolinones with another depressant is [[Drug overdose|possibly fatal]]. Death from a quinazolinone overdose is usually caused by death through [[Cardiac arrest|cardiac]] or [[respiratory arrest]]. An overdose resembles a barbiturate or carbamate overdose.{{Citation needed|date=March 2025}}

Quinazolinone [[Drug withdrawal|withdrawal]] occurs when someone who has become dependent on a quinazolinone ceases usage. Quinazolinone withdrawal resembles ethanol, barbiturate, benzodiazepine, and carbamate withdrawal. It usually consists of [[Psychomotor agitation|restlessness]], nausea and vomiting, [[decreased appetite]], [[tachycardia]], insomnia, tremor, hallucinations, delirium, confusion, and seizures; and, which are possibly fatal: [[Photosensitive epilepsy|EEG photoparoxysmal response]], [[Myoclonus|myoclonic twitches]], [[fever]], [[muscle spasms]], and [[irritability]].<ref>{{Cite web |title=Quaaludes Addiction and Abuse, Statistics, Signs, Symptoms & Side Effects |website=Addiction Hope |url=https://www.addictionhope.com/quaaludes/ |access-date=1 December 2022 |language=en-US}}</ref>

[[Methaqualone|Methaqualone hydrochloride]] and quinazolinone anxiolytics and [[hypnotic]]s 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.<ref>{{Cite web |date= |title=Methaqualone (Encyclopedia of Drugs and Addictive Substances) |url=http://www.enotes.com/methaqualone-reference/methaqualone |archive-url=https://web.archive.org/web/20120223014958/http://www.enotes.com/methaqualone-reference/methaqualone |archive-date=2012-02-23 |website=eNotes.com}}</ref> Methaqualone became highly abused by many, including celebrities, after its introduction in 1965.<ref name="web.archive.org" /> Methaqualone was first synthesized in India in 1951 by Indra Kishore Kacker and [[Syed Husain Zaheer]], who were conducting research on finding new [[antimalarial medication]]s.<ref>{{Cite web |title=Lawrence Journal-World - Google News Archive Search |url=https://news.google.com/newspapers?nid=2199&dat=19810528&id=VpkyAAAAIBAJ&pg=4915,6415336 |access-date=1 December 2022 |website=news.google.com}}</ref><ref>{{Cite journal |last=van Zyl |first=Etienne F. |date=1 November 2001 |title=A survey of reported synthesis of methaqualone and some positional and structural isomers |journal=Forensic Science International |language=en |volume=122 |issue=2 |pages=142–149 |doi=10.1016/S0379-0738(01)00484-4 |pmid=11672968 }}</ref> 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 dependence|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.{{fact|date=July 2024}}

Large doses of methaqualone can cause euphoria, [[disinhibition]], [[Human sexuality|increased sexuality]] and [[Social behavior|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.<ref>{{Cite web |last=Moghe |first=Sonia |date=25 July 2015 |title=Cosby deposition: Quaaludes came from L.A. gynecologist |url=https://www.cnn.com/2015/07/24/us/cosby-deposition-quaaludes/index.html |access-date=1 December 2022 |website=CNN |language=en}}</ref><ref>{{cite news |last1=Bowley |first1=Graham |last2=Ember |first2=Sydney |title=Bill Cosby, in Deposition, Said Drugs and Fame Helped Him Seduce Women |url=https://www.nytimes.com/2015/07/19/arts/bill-cosby-deposition-reveals-calculated-pursuit-of-young-women-using-fame-drugs-and-deceit.html |work=The New York Times |date=19 July 2015 }}</ref><ref>{{Cite web |date=11 September 2016 |title=Gloria Allred wins Cobb Energy Bill Cosby concert protest case {{!}} Radio & TV Talk |url=http://radiotvtalk.blog.myajc.com/2016/09/09/gloria-allred-wins-cobb-energy-bill-cosby-concert-protest-case/ |access-date=1 December 2022 |archive-url=https://web.archive.org/web/20160911013439/http://radiotvtalk.blog.myajc.com/2016/09/09/gloria-allred-wins-cobb-energy-bill-cosby-concert-protest-case/ |archive-date=11 September 2016 }}</ref> 18-year-old actor Anissa Jones died from an overdose of [[cocaine]], [[Phencyclidine|PCP]], methaqualone, and the barbiturate [[Seconal]]. [[Billy Murcia]], a drummer for the rock band [[New York Dolls]], died at 21 when he [[Drowning|drowned in a bathtub]] while overdosing on [[heroin]] and methaqualone.<ref>{{Cite web |title=New York Doll Murcia died here |url=http://shadyoldlady.com/location.php?loc=1588 |access-date=1 December 2022 |website=shadyoldlady.com}}</ref>

[[Cloroqualone]] was a quinazolinone that bound to the GABA<sub>A</sub> and [[sigma-1 receptor]]s. It had useful cough suppressant effects and weaker sedative effects than methaqualone, but was ultimately withdrawn due to its potential for abuse and overdose.<ref>{{Cite web |last=PubChem |title=Cloroqualone |url=https://pubchem.ncbi.nlm.nih.gov/compound/63338 |access-date=1 December 2022 |website=pubchem.ncbi.nlm.nih.gov |language=en}}</ref>

[[Diproqualone]] is a quinazolinone that is still used today. Diproqualone has [[sedative]], [[anxiolytic]], [[antihistamine]], and [[analgesic]] properties, resulting from its agonist activity at the β subtype of the GABA<sub>a</sub> receptor, antagonist activity at all [[histamine receptor]]s, inhibition of the [[PTGS1|cyclooxygenase-1]] enzyme, and possibly its agonist activity at both the [[Sigma-1 receptor]] and [[Sigma-2 receptor]]. Diproqualone is used primarily for the treatment of [[Inflammation|inflammatory pain]] associated with [[osteoarthritis]] and [[rheumatoid arthritis]]; it is used more rarely for treating [[insomnia]], [[anxiety]], and [[neuralgia]]. Diproqualone is the only analogue of [[methaqualone]] that is still in widespread clinical use due to its useful [[anti-inflammatory]] and [[analgesic]] effects, along with the sedative and anxiolytic actions common to other drugs of this class. There are still some concerns about the potential of diproqualone for abuse and [[Drug overdose|overdose]]; it is sold not as a pure drug but as the [[Camphorsulfonic acid|camphosulfonate]] salt in combination mixtures with other medicines such as [[ethenzamide]].{{fact|date=July 2024}}

[[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.{{Citation needed|date=March 2025}}

[[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 drug]] [[Analog (chemistry)|analogue]] of methaqualone.<ref>{{Cite web |date=19 July 2011 |title=Microgram Journal  |url=http://www.justice.gov/dea/programs/forensicsci/microgram/journal_v1/2003_1-2.pdf |access-date=1 December 2022 |archive-url=https://web.archive.org/web/20110719112749/http://www.justice.gov/dea/programs/forensicsci/microgram/journal_v1/2003_1-2.pdf |archive-date=19 July 2011 }}</ref>

[[Nitromethaqualone]] is a quinazolinone depressant with ten times more [[hypnotic]] and [[sedative]] effects than methaqualone.<ref>{{cite journal |last1=Szirmai |first1=A. |title=Pharmacological and Therapeutic Studies with a New Quinazolone Derivative, Nitromethaqualone |language=de |journal=Therapeutische Umschau. Revue Therapeutique |date=November 1963 |volume=20 |pages=542–546 |pmid=14101319 }}</ref>

Quinazolinones:{{Citation needed|date=March 2025}}

* [[Afloqualone|Alfoqualone]] (Arofuto)
* [[Cloroqualone]]
* [[Diproqualone]]
* [[Etaqualone]] (Aolan, Athinazone, Ethinazone)
* [[Mebroqualone]] (MBQ)
* [[Mecloqualone]] (Nubarene, Casfen)
* [[Methaqualone]] (Quaalude, Sopor, Mandrax)
* [[Methylmethaqualone]]
* [[Nitromethaqualone]]
* [[SL-164]] (Dicloqualone, DCQ)

=== Miscellaneous ===
* [[Alpha blocker|Alpha]] and [[beta blocker]]s ([[carvedilol]], [[propranolol]], [[atenolol]]){{Citation needed|date=March 2025}}
* [[Anticholinergic]]s ([[atropine]], [[hyoscyamine]], [[Hyoscine hydrobromide|scopolamine]]){{Citation needed|date=March 2025}}
* [[Anticonvulsant]]s ([[topiramate]], [[carbamazepine]], [[lamotrigine]]){{Citation needed|date=March 2025}}
* [[Antihistamine]]s ([[diphenhydramine]], [[doxylamine]], [[promethazine]]){{Citation needed|date=March 2025}}
* [[Antipsychotic]]s ([[haloperidol]], [[chlorpromazine]], [[clozapine]]){{Citation needed|date=March 2025}}
* [[Hypnotic]]s ([[zolpidem]], [[zopiclone]], [[chloral hydrate]], [[eszopiclone]]){{Citation needed|date=March 2025}}
* [[Muscle relaxants]] ([[baclofen]], [[phenibut]], [[carisoprodol]], [[cyclobenzaprine]]){{Citation needed|date=March 2025}}
* [[Sedative]]s ([[gamma-hydroxybutyrate]]){{Citation needed|date=March 2025}}

== Combining multiple depressants ==
Combining multiple depressants can be very dangerous because the central nervous system's depressive properties have been proposed to increase exponentially instead of linearly.<ref>{{cite journal |last1=Avery |first1=S N |last2=Clauss |first2=J A |last3=Blackford |first3=J U |title=The Human BNST: Functional Role in Anxiety and Addiction |journal=Neuropsychopharmacology |date=January 2016 |volume=41 |issue=1 |pages=126–141 |doi=10.1038/npp.2015.185 |pmid=26105138 |pmc=4677124 }}</ref> 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.{{Citation needed|date=March 2025}}

== See also ==
* [[Central nervous system depression]]
* [[Inhalant]]

== References ==
{{Reflist}}

{{Depressants}}
{{Major Drug Groups}}
{{Chemical classes of psychoactive drugs}}
{{Recreational drug use}}

[[Category:Drugs by psychological effects]]
[[Category:Drugs acting on the nervous system]]
[[Category:Health effects of alcohol]]