Wikipedia

Depressant

(Redirected fromDepressants)
Not to be confused withdepressogen.

Depressants,colloquially known as "downers"orcentral nervous system (CNS) depressants,aredrugsthat lowerneurotransmissionlevels, decrease theelectrical activityofbrain cells,or reducearousalorstimulationin various areas of the brain.[1]Some specific depressants do influence mood, either positively (e.g.,opioids) or negatively, but depressants often have no clear impact on mood (e.g., mostanticonvulsants). In contrast,stimulants,or "uppers", increase mental alertness, making stimulants the oppositedrug classfrom depressants.Antidepressantsare defined by their effect on mood, not on general brain activity, so they form anorthogonalcategory of drugs.

Depressants are closely related tosedativesas a category of drugs, with significant overlap. The terms may sometimes be used interchangeably or may be used in somewhat different contexts.[citation needed]

Depressants are widely used throughout the world asprescription medicinesandillicit substances.Alcoholis a very prominent depressant. When depressants are used, effects often includeataxia,anxiolysis,pain relief,sedationorsomnolence,cognitiveormemory impairment,as well as, in some instances,euphoria,dissociation,muscle relaxation,loweredblood pressureorheart rate,respiratory depression,andanticonvulsanteffects. Depressants sometimes also act to produceanesthesia.Other depressants can include drugs likeXanax(abenzodiazepine) and a number ofopioids.Gabapentinoidslikegabapentinandpregabalinare depressants and have anticonvulsant andanxiolyticeffects. Most anticonvulsants, likelamotrigineandphenytoin,are depressants.Carbamates,such asmeprobamate,are depressants that are similar tobarbiturates.Anestheticsare generally depressants; examples includeketamineandpropofol.

Depressants exert their effects through a number of different pharmacological mechanisms, the most prominent of which include facilitation ofGABAand inhibition ofglutamatergicormonoaminergicactivity. Other examples are chemicals that modify the electrical signaling inside the body, the most prominent of which arebromidesandchannel blockers.

Indications

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Depressants are used medicinally to relieve the following symptoms and disorders:

Types

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Distilled(concentrated)alcoholic beverages,sometimes called "spirit" or "hard liquor",are roughly eight times more alcoholic than beer.

Alcohol

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Main articles:Alcoholic beverage,Ethanol,andBlood alcohol content

Analcoholic beverageis a drink thatcontains alcohol(known formally asethanol), ananestheticthat has been used as apsychoactive drugfor severalmillennia.Ethanol is the oldestrecreational drugstill used by humans. Ethanol can causealcohol intoxicationwhen consumed. Alcoholic beverages are divided into three general classes fortaxation and regulation of production:beers,wines,andspirits(distilled beverages). They are legally consumed in most countries around the world. More than 100 countries have laws regulating their production, sale, and consumption.[2]

The most common way to measure intoxication for legal or medical purposes is throughblood alcohol content(also called blood alcohol concentration or blood alcohol level). It is usually expressed as apercentageof alcohol in thebloodin 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 everydLof blood (i.e., mass per volume is used there).[3]

Barbiturates

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Main article: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 causedependenceand severewithdrawal,and they have a high risk of fataloverdosedue 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 ofseizuresor, in mild form, for relief from the symptoms ofmigraines.One barbiturate that remains in use for seizure disorders isphenobarbital.

Benzodiazepines

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Main article:Benzodiazepine
See also:Nonbenzodiazepine

Abenzodiazepine(sometimes colloquially "benzo"; often abbreviated "BZD" ) is a drug whose core chemical structure is the fusion of abenzenering and adiazepinering. The first such drug,chlordiazepoxide(Librium), wasdiscovered accidentallybyLeo Sternbachin 1955 and made available in 1960 byHoffmann–La Roche,which has also marketed the benzodiazepinediazepam(Valium) since 1963.

Xanax (alprazolam) 2 mg tri-score tablets, a classical benzodiazepine sedative

Benzodiazepines enhance the effect of theneurotransmittergamma-aminobutyric acid(GABA) at theGABAAreceptor,resulting insedative,hypnotic(sleep-inducing), anxiolytic (anti-anxiety), anticonvulsant, andmuscle relaxantproperties. High doses of shorter-acting benzodiazepines induceanterograde amnesia,which may be helpful for surgical and procedural anesthesia to reduce patient recall.Midazolamis often used in anesthesiology. These properties make benzodiazepines useful in treating anxiety, insomnia,agitation,seizures,muscle spasms,alcohol withdrawal,and as apremedicationfor medical or dental procedures. Benzodiazepines are categorized as either short-, intermediate-, or long-acting. Short- and intermediate-acting benzodiazepines are preferred for the treatment of insomnia; longer-acting benzodiazepines are recommended for the treatment of anxiety.

In general, benzodiazepines are safe and effective in the short term, although cognitive impairments andparadoxical effectssuch as aggression or behavioraldisinhibitionoccasionally 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, andbenzodiazepine withdrawal syndrome,following withdrawal after long-term use. Theelderlyare at an increased risk of experiencing both short- and long-termadverse effects.

There is controversy concerning the safety of benzodiazepines in pregnancy. While they are not majorteratogens,uncertainty remains as to whether they causecleft palatein a small number of babies and whether neurobehavioral effects occur as a result of prenatal exposure; they are known to causewithdrawal symptoms in the newborn.Benzodiazepines can beoverdosedand cause dangerousdeep 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 othercentral nervous systemdepressants such asalcoholandopiates,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 theBeers List,which is significant in clinical practice.

Cannabis

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Main article:Cannabis

Cannabisis often considered either in its own unique category or as a mildpsychedelic.[4][5]The chemical compoundtetrahydrocannabinol (THC),which is found in cannabis, has many depressant effects, such asmuscle relaxation,sedation,decreasedalertness,andtiredness.[6]Contrary to the previous statement, activation of the CB1 receptor bycannabinoidscauses an inhibition of GABA, the exact opposite of what CNS depressants do.

Carbamates

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Main article:Carbamate

Carbamatesare a class of depressants, or "tranquilizers",that are synthesized fromurea.[7]Carbamates haveanxiolytic,[8]muscle relaxant,[8]anticonvulsant,[9]hypnotic,[8]antihypertensive,[10]andanalgesiceffects. They have other uses, likemuscle tremors,agitation,andalcohol withdrawal.Their muscle relaxant effects are useful forstrains,sprains,and muscle injuries combined with rest, physical therapy, and other measures.[8]The effects, synthesis, and mechanism of action of carbamates are very similar to those of barbiturates.[11]There are many different types of carbamates: some only produce anxiolytic and hypnotic effects, while others only have anticonvulsant effects.

Carisoprodoltablets

Side effectsof carbamates includedrowsiness,dizziness,headache,diarrhea,nausea,flatulence,liver failure,poor coordination,nystagmus,abuse,dizziness,weakness,nervousness,euphoria,overstimulation,anddependence.Uncommon but potentiallysevere adverse reactionsinclude hypersensitivity reactions such asStevens–Johnson syndrome,embryo-fetal toxicity,stupor,andcoma.It is not recommended to use most carbamates, likecarisoprodol,for a long time, asphysicalandpsychological dependencedo occur.[12]

Meprobamatewas 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. Carisoprodolallosterically modulatesand directlyactivatesthe humanα1β2γ2 GABAAR(GABAA) in thecentral nervous system,similar to barbiturates. This causeschloride channelsto open, allowingchlorideto flood into the neuron. This slows downcommunication between neuronsand thenervous system.[13]Unlike benzodiazepines, which increase the frequency of the chloride channel opening, carisoprodol increases the duration of channel opening when GABA is bound.[14][15]GABA is the maininhibitoryneurotransmitterin thenervous system,which causes its depressant effects.

Carbamates are fatal inoverdose,which is why many have been replaced with benzodiazepines. Symptoms are similar to a barbiturate overdose and typically includedifficulty thinking,poor coordination,decreasedlevels of consciousness,and a decreased effort to breathe (respiratory depression). An overdose is more likely to be fatal when mixed with another depressant thatsuppresses breathing.[citation needed]

Physical andpsychologicaldependence 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 resemblebarbiturate,alcohol,or benzodiazepine withdrawal, as they all have asimilar mechanism of action.Discontinuation symptoms includeconfusion,disorientation,delirium,hallucinations(auditoryandvisual),insomnia,decreased appetite,anxiety,psychomotor agitation,pressured speech,tremor,tachycardia,andseizures,which could be fatal.[16]

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 isFelbamate,an anticonvulsant that was approved in 1993 and is commonly used today. It is a GABAApositive allosteric modulator and blocks theNR2Bsubunit of theNMDA receptor.Other carbamates blocksodium channels.Phenprobamatewas used as an anxiolytic and is still sometimes used in Europe forgeneral anesthesiaand for treating muscle cramps and spasticity.Methocarbamolis a popular drug that is commonly known as Robaxin and isover-the-counterin some countries. It is a carbamate with muscle relaxant effects.Tetrabamateis a controversial drug that is a combination offebarbamate,difebarbamate,andphenobarbital.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 ofhepatitisandacute 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 aSchedule IVsubstance in the United States.

Approved:

Although a drug may be approved, that does not necessarily mean it is still being used today.

Not approved:

Gabapentinoids

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Main article:Gabapentinoids
GABAanalogues
Voltage gated calcium channel
Baclofentablets

Gabapentinoidsare a unique and relatively novel class of depressants that selectivelybindto the auxiliaryα2δ subunit(CACNA2D1andCACNA2D2) site of certainVDCCsand thereby act asinhibitorsofα2δsubunit-containingvoltage-gated calcium channels.α2δ is nicknamed the "gabapentin receptor". Atphysiologicor restingmembrane potential,VDCCs are normallyclosed.They are activated (opened) atdepolarizedmembrane potentials,which is the source of the "voltage-gated"epithet.Gabapentinoids bind to theα1andα2sites of the α2δ subunit family. Gabapentin is theprototypicalgabapentinoid. The α2δ is found onL-type calcium channels,N-type calcium channels,P/Q-type calcium channels,andR-type calcium channelsthroughout the central andperipheral nervous systems.α2δ is located onpresynaptic neuronsand affectscalcium channeltrafficking and kinetics, initiatesextracellularsignaling cascadesandgene expression,and promotesexcitatorysynaptogenesisthroughthrombospondin 1.[17]Gabapentinoids are not directchannel blockers;rather, they disrupt the regulatory function of α2δ and its interactions with other proteins. Most of the effects of gabapentinoids are mediated by thehigh-voltage activatedN and P/Q-type calcium channels. P/Q-type calcium channels are mainly found in thecerebellum(Purkinje neurons), which may be responsible for theataxicadverse effect of gabapentinoids, while N-type calcium channels are located throughout the central and peripheral nervous systems.N-type calcium channelsare mainly responsible for theanalgesiceffects of gabapentinoids.Ziconotide,a non-gabapentinoid ω-conotoxinpeptide,binds to theN-type calcium channelsand has analgesic effects 1000 times stronger thanmorphine.Gabapentinoids are selective for the α2δ site butnon-selectivewhen they bind to the calcium channel complex. They act on the α2δ site to lower the release of manyexcitatoryand pro-nociceptiveneurochemicals,includingglutamate,substance P,calcitonin gene-related peptide(CGRP), and more.[18][19][20]

Gabapentinoids are absorbed from the intestines mainly by thelarge neutral amino acid transporter 1(LAT1, SLC7A5) and theexcitatory amino acid transporter 3(EAAT3). They are one of the few drugs that use theseamino acid transporters.Gabapentinoids are structurally similar to thebranched-chain amino acidsL-leucineandL-isoleucine,both of which also bind to the α2δ site.Branched-chain amino acidslike l-leucine, l-isoleucine, andl-valinehave many functions in the central nervous system. They modifylarge neutral amino acid(LNAA) transport at theblood–brain barrierand reduce the synthesis of neurotransmitters derived fromaromatic amino acids,notablyserotoninfromtryptophanandcatecholaminesfromtyrosineandphenylalanine.[21]This may be relevant to thepharmacologyof gabapentinoids.

Gabapentin was designed by researchers atParke-Davisto be ananalogueof theneurotransmitterGABA that could more easily cross theblood–brain barrierand was first described in 1975 by Satzinger and Hartenstein.[22][23]Gabapentin was first approved forepilepsy,mainly as an add-on treatment forpartial seizures.Gabapentinoids areGABA analogues,[24]but they do not bind to theGABA receptors,convert into GABA or anotherGABA receptor agonistin vivo,or directly modulate GABAtransportormetabolism.[25][26]Phenibutandbaclofen,two structurally related compounds, are exceptions, as they mainly act on theGABA B receptor.[27][28]Gabapentin, but not pregabalin, has been found to activatevoltage-gated potassium channels(KCNQ), which mightpotentiateits depressant qualities. Despite this, gabapentinoids mimicGABA activitybyinhibitingneurotransmission.[29]Gabapentinoids prevent delivery of the calcium channels to the cell membrane and disrupt interactions of α2δ withNMDA receptors,AMPA receptors,neurexins,andthrombospondins.Somecalcium channel blockersof thedihydropyridineclass are used forhypertensionto weakly blockα2δ.[30]

Gabapentinoids have anxiolytic,anticonvulsant,antiallodynic,antinociceptive,and possibly muscle relaxant properties.[19][31][32]Pregabalin and gabapentin are used inepilepsy,mainlypartial seizures(focal). Gabapentinoids are not effective forgeneralized seizures.They are also used forpostherpetic neuralgia,neuropathic painassociated withdiabetic neuropathy,fibromyalgia,generalized anxiety disorder,andrestless legs syndrome.[33][34][35][36][37][38]Pregabalin and gabapentin have manyoff-labeluses, includinginsomnia,[39]alcoholandopioid withdrawal,[40]smoking cessation,[41]social anxiety disorder,[42]bipolar disorder,[43][44]attention deficit hyperactivity disorder,[45]chronic pain,hot flashes,[46]tinnitus,migraines,and more. Baclofen is primarily used for the treatment ofspastic movementdisorders, especially in instances ofspinal cord injury,cerebral palsy,andmultiple sclerosis.[47]Phenibut is used in Russia, Ukraine, Belarus, and Latvia to treat anxiety and improve sleep, as in the treatment of insomnia.[48]It is also used for various other indications, including the treatment ofasthenia,depression,alcoholism,alcohol withdrawal syndrome,post-traumatic stress disorder,stuttering,tics,vestibular disorders,Ménière's disease,dizziness,and the prevention ofmotion sicknessand anxiety before or after surgical procedures or painful diagnostic tests.[48]Phenibut, like otherGABA Bagonists, is also sometimes used by bodybuilders to increase thehuman growth hormone.

Reutersreported on 25 March 2010 that "Pfizer Incviolated a United Statesracketeeringlaw by improperlypromotingthe epilepsy drug Neurontin (gabapentin). Under theRacketeer Influenced and Corrupt Organizations Act,the penalty is automatically tripled, so the finding will cost Pfizer $141 million. "The case stems from a claim fromKaiser Foundation Health Plan Inc.that "it was misled into believing Neurontin was effective for off-label treatment of migraines, bipolar disorder and other conditions. Pfizer argued that Kaiser physicians" still recommend the drug for those uses "and that" the insurer's website also still lists Neurontin as a drug for neuropathic pain. "

In some cases, gabapentinoids are abused and provide similar effects to alcohol, benzodiazepines, andgamma-hydroxybutyric acid(GHB).[49][50][51]TheFDAplaced ablack box warningon Neurontin (gabapentin) and Lyrica (pregabalin) for seriousbreathing problems.[52]Mixing gabapentinoids with opioids, benzodiazepines, barbiturates, GHB, alcohol, or any other depressant is potentially deadly.[53][54][55][56]

Commonside effectsof gabapentinoids includedrowsiness,dizziness,weakness,increased appetite,urinary retention,shortness of breath,involuntary eye movements (nystagmus),memory issues,uncontrollable jerking motions,auditory hallucinations,erectile dysfunction,andmyoclonic seizures.[57][58]

Anoverdoseof gabapentinoids usually consists ofsevere drowsiness,severe ataxia,blurred vision,slurred speech,severe uncontrollable jerking motions,and anxiety.[59][60]Like most anticonvulsants, pregabalin and gabapentin have an increased risk ofsuicidal thoughts and behaviors.[61][62]Gabapentinoids, like allcalcium channel blockers,are known to causeangioedema.[63]Taking them with anACE inhibitorcan increase the toxic effects of gabapentinoids.[64]They may also enhance thefluid-retainingeffect of certainanti-diabetic agents(thiazolidinediones). It is not known if they causegingival enlargementlike othercalcium channel blockers.Gabapentinoids areexcreted by the kidney,mostly in their original form. Gabapentinoids can build up in the body when someone hasrenal failure.This usually presents itself asmyoclonusand analtered mental state.It is unclear if it is safe to use gabapentinoids during pregnancy, with some studies showingpotential harm.[65]

Physicalorphysiological dependencedoes occur during the long-term use of gabapentinoids.[66]Following abrupt orrapid discontinuationof pregabalin and gabapentin, people reportwithdrawal symptomslike insomnia,headache,nausea,diarrhea,flu-like symptoms,anxiety,depression,pain,hyperhidrosis,seizures,psychomotor agitation,confusion,disorientation,andgastrointestinal complaints.[67][68]Acute withdrawal from baclofen and phenibut may also causeauditoryand visualhallucinations,as well as acutepsychosis.[69][70]Baclofen withdrawal can be more intense if it is administeredintrathecallyor for long periods of time. If baclofen or phenibut is used for long periods of time, it can resemble intensebenzodiazepine,GHB,or alcohol withdrawal. To minimizewithdrawal symptoms,baclofen or phenibut should be tapered down slowly.Abrupt withdrawalfrom phenibut or baclofen could possibly be life-threatening because of its mechanism of action. Abrupt withdrawal can causerebound seizuresandsevere agitation.[71][70]

Approved:

Not approved:

Endogenous(notgabapentinoids), endogenousBCAAamino acids that bind toα2δ):

Otherα2δligands:[72][73]

Gamma-hydroxybutyric acid

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Main article:Gamma-hydroxybutyric acid
GABA analogues
Severity of GHB withdrawal syndrome
GHB that is used to treatalcohol addictionin Italy.

Gamma-hydroxybutyric acid,or "GHB", is aGABA analoguethat is a naturally occurring neurotransmitter and depressant drug.[75][76][77]It is also naturally found in small amounts in somealcoholic beveragesalongside ethanol.[78]GHB is theprototypicalsubstance among a couple ofGHB receptor modulators.[79]

GHB has been used as ageneral anesthetic[80]and as a treatment forcataplexy,[81][82]narcolepsy,[81][83]andalcoholism.[84][85][86][87]The sodium salt of GHB,sodium oxybate,is commonly used today for narcolepsy,[88]sudden muscle weakness,[89]and excessive daytime sleepiness. It is sold under the brand name Xyrem.[90][91][88]

As a depressant, GHB would worsen narcolepsy andmuscle weakness.But in low doses, GHB mainly affects theGHB receptor,[92][93]anexcitatoryreceptor that releasesdopamineandglutamate,[94]giving GHBstimulanteffects, the opposite of a depressant. But in large doses, GHB activates theGABABreceptor,aninhibitory receptorin thecentral nervous system,which overpowers theexcitatory effects,thus causingcentral nervous system depression.[95][96]Someantipsychoticsare agonists of the GHB receptor.[97][98][99]

GHB can usually be found in eithersodium,potassium,magnesium,or calciumsalts.[100][101]Xywavis a medication that is a mixture of all GHB salts[102]and is used to treat the same conditions as Xyrem. Both Xywav and Xyrem areSchedule III[103][104]and have a black box warning[105]forcentral nervous system depressanteffects (hypoventilationandbradycardia) and for their very high potential forabuse.[106][79]Overdoseon GHB is fatal with or without mixing other CNS depressants.[107][108][109][110]Death from a GHB overdose is usually caused byrespiratory depression,seizures, orcoma.[95][111][112]

GHB is used illegally as anintoxicant,anaphrodisiac,[75][113]and an athletic-performance enhancer.[79]It is a popularclub drugin some parts of the world due to its powerful aphrodisiac andeuphoriceffects. Similarly to phenibut and baclofen, it is used by bodybuilders to increase thehuman growth hormonedue toGABABactivation.[114][115]It has also been reportedly used as adate-rape drug.[116][117]This caused it to be aSchedule Isubstance in theUnited States,Canada,and other countries. Xyrem, which is GHB in its sodium form, is Schedule III in the United States, Canada, and other countries.[90][103]

In low doses, GHB mainly binds to theGHB receptorand weakly binds to theGABABreceptor.[93][92][118]The GHB receptor is an excitatoryG protein-coupled receptor(GPCR).[93][92]Itsendogenous ligandis GHB, since GHB is also aneurotransmitter.[76]It is also a transporter for vitamin B2. The existence of a specific GHB receptor was predicted by observing the action of GHB and related compounds that primarily act on theGABABreceptorbut also exhibit a range of effects that were found not to be produced by GABABactivity and so were suspected of being produced by a novel and, at the time, unidentified receptor target. At higher doses, seizures are very common.[111]This is thought to be mediated through an increased Na+/K+current and the increased release ofdopamineandglutamate.[94]GHB can also causeabsence seizures;[111][119][120]the mechanism is currently not known but it is believed to be due to interactions with theGABABreceptor.[119]It is being investigated if endogenous GHB is responsible for non-convulsive seizures in humans.[111][121]

GHBwithdrawalis very intense.[122]Physical dependencedevelops quickly. It is also highly psychologically addictive. It shares some similarities with the withdrawal of gabapentinoids phenibut and baclofen due to the activation of theGABABreceptor. It features a typical depressant withdrawal syndrome that mimics alcohol withdrawal.[123]Symptoms includedelirium,tremor,anxiety,tachycardia,insomnia,hypertension,confusion,sweating,severe agitationwhich may require restraint,[124]auditory and visual hallucinations,and possibly death fromtonic-clonic seizures.[124][125][123][126][127][128]

Baclofen and phenibut are very effective for withdrawal and are preferred by patients over benzodiazepines for treatment of withdrawal.[126]

GHB receptor modulators:

GHB receptor agonists:

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

Prodrugs that metabolize into GHB:

  • γ-Hydroxyvaleric acid (GHV)

-gamma-Valerolactone, γ-Valerolactone(GVL) (prodrug to GHV)

GHB receptor antagonists:

Some GHB receptors modulators only bind to the GHB receptor, while others bind to both the GHB and GABABreceptors.

Nonbenzodiazepines

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Zolpidem
Zaleplon

Nonbenzodiazepines,sometimes referred to as Z-drugs, are a class of hypnotic depressants that are mainly used to treat insomnia and sometimes anxiety.[129][130]They are structurally related to benzodiazepines. They positively modulate thebenzodiazepine siteof the GABAAreceptor, the chief inhibitory receptor of thecentral nervous system,just like benzodiazepines, but at a molecular level, they are structurally unrelated.

Nonbenzodiazepines bind to the benzodiazepine at the GABAAreceptor site to keep thechloride channelopen.[131]This causeschloridein theintercellular areato flood into the neuron.[132]Since chloride has anegative charge,it causes the neuron to rest andcease firing.This results in a relaxing and depressant effect on the central nervous system.

Common nonbenzodiazepines likeZolpidemandZopicloneare extremely effective for insomnia but carry many risks and side effects. Sleeping pills, including zopiclone, have been associated with an increased risk of death.

Adverse reactions are as follows: "taste disturbance (some report a metallic-like taste); less commonly, nausea, vomiting, dizziness, drowsiness, dry mouth, headache; rarely, amnesia, confusion, depression, hallucinations, nightmares; very rarely, lightheadedness, incoordination, paradoxical effects, and sleep-walking are also reported."[This quote needs a citation]Some users of nonbenzodiazepines have sleepwalked and committed murders or have been involved in motor vehicle accidents. Unlike benzodiazepines, nonbenzodiazepines have a risk of hallucinations and sleepwalking. Like benzodiazepines, they can causeanterograde amnesia.[citation needed]

Nonbenzodiazepines should not be discontinued abruptly if taken for more than a few weeks due to the risk ofrebound withdrawal effectsand 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 abenzodiazepine equivalentdose of a long-acting benzodiazepine (such aschlordiazepoxideor, 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, withflumazenilas a possible detoxification tool.[citation needed]

Opioids/opiates

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Main article:Opioids
Oxycodoneis a semi-synthetic prescription opioid.
Papaver somniferum
Therostromedial tegmental nucleus(RMTg) is located in themidbrain(pictured above) of the brainstem. The release ofdopaminein the RMTg characterizes the euphoria and reinforcement of opioids.

Opioids are substances that act onopioid receptorsto reduce pain.[133]Medically, they are primarily used forpain relief,including anesthesia. Opioids also causeeuphoriaand are highly abused.

Opioids and opiates are not the same. Opiates refer to natural opioids such asmorphineandcodeine.Opioids refer to all natural, semisynthetic, and synthetic opioids, likeheroinandoxycodone.

Contrary to popular misconception, opioids are not depressants in the classical sense.[4]They do producecentral nervous system depression,but they also excite certain areas of the central nervous system. To remain true to the term "depressant", opioids cannot be classified as such. For opioid agonists andopiumderivatives,these are classified differently. These drugs are more correctly identified as "analgesic"or"narcotic".However, they do have depressant actions nonetheless.

There are three principal classes of opioid receptors:μ,κ,δ(mu, kappa, and delta),[134]although up to seventeen have been reported, and include the ε, ι, λ, and ζ (epsilon, iota, lambda, and zeta) receptors. Conversely, σ (sigma) receptors are no longer considered to be opioid receptors because their activation is not reversed by the opioid inverse-agonistnaloxone.The nociception opioid peptide receptor (NOP) (ORL1) is an opioid receptor that is involved in pain responses, anxiety, movement, reward, hunger, memory, and much more. It plays a major role in the development of tolerance toμ-opioid agonists.[135]

When "pain" occurs, asignalgets sent from the site of possible injury. This signal goes up thespinal cordinto the brain, where it is perceived as anegative emotionknown asnociceptionor "hurt". In thecentral nervous system,the spine is connected to the brain by a structure called the brain stem.[136]The brain stem is the first part of the brain that develops in amammalout of theneural crest.It is also the oldest part of the brain and controls many automatic functions such asconsciousness,breathing,heart rate,digestion,and many more.Opioid receptorsare specialized pain-blocking receptors. They bind a wide range of hormones, peptides, and much more. Although they are found everywhere in thecentral 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. Themidbrainnuclei of the brain stem, with structures like theperiaqueductal gray,reticular formation,androstromedial tegmental nucleus,are responsible for the majority of the physical and psychological effects of endogenous and exogenous opioids.[citation needed]

Theμ-opioidreceptor is responsible for theanalgesic,euphoric, and adverse effects of opioids. The μ-opioid receptor is aG protein-coupled receptor.When the μ-opioid receptor is activated, it causes pain relief, euphoria, constipation, constricted pupils, itching, and nausea.[137]The μ-opioid is located in the gastrointestinal tract, which controlsperistalsis.This causesconstipation,which can be extremely problematic and distressing. Activation of this receptor also causes relaxation of voluntary and involuntary muscles, which can cause side effects liketrouble urinatingandswallowing.The μ-opioid receptor can also reduce androgens, thus decreasing libido and sexual function. The receptor is also known to cause "musical anhedonia".[138]

The receptor plays a critical role infeeding.Thepalatabilityof food is determined by opioid receptor-related processes in thenucleus accumbensand ventralpallidum.The opioid processes involve mu opioid receptors and are present in the rostromedial shell of the nucleus accumbens on itsspiny neurons.This area has been called the "opioid eating site".[This quote needs a citation]

The μ-opioid receptor has many endogenous ligands, includingendorphin.[139]

Adverse effects of opioids (μ-opioid receptor)

Common and short term

Other

The κ-opioid receptor (KOR) is aG protein-coupled receptorlocated in the central nervous system. KOR is also a G protein-coupled receptor.[141]Humans and some other primates have a higher density of kappa receptors than most other animals. KOR is responsible for nociception,consciousness,motor control,andmood.Dysregulation of this receptor system has been implicated in alcohol and drug addiction.[142]The endogenous ligand for KOR isdynorphin.The activation of KOR usually causesdysphoria,hence the name dynorphin. The intoxicating plantSalvia divinorumcontainssalvinorin A,an alkaloid that is a potent and selective κ-opioid receptoragonist.This causes powerfulhallucinations.Antagonizing the κ-opioid receptor may be able to treat depression, anxiety, stress, addiction, and alcoholism.[143]

The third receptor is theδ-opioid receptor(DOR). The delta receptor is the least studied of the three main opioid receptors. It is aG protein-coupled receptor,and its endogenous ligand isdeltorphin.The activation of DOR may haveantidepressanteffects.δ-opioid agonistscan producerespiratory depressionat very high doses; at lower doses, they have the opposite effect. High doses of a δ-opioid agonist can cause seizures, although not all delta agonists produce this effect.[144]Activation of the delta receptor is usually stimulating instead of sedating like most opioids.

Thenociception opioid peptide receptor(NOP) is involved in the regulation of numerous brain activities, particularly instinctive emotional behaviors and pain.[145]NOP is aG protein-coupled receptor.The nociception receptor controls a wide range of biological functions, including nociception, food intake,memoryprocesses,cardiovascularandrenalfunctions, spontaneouslocomotor activity,gastrointestinal motility,anxiety,and the control ofneurotransmitterrelease at peripheral and central sites.[146]

When theμ-opioid receptoris activated on aneuron,thevoltage-gated calcium channel(green) closes and thevoltage-gated potassium channel(blue) opens. Both of these individual actions make thepresynaptic neuronless likely to releaseglutamate(red), leaving the neuron at rest longer. This slowing down of neurons via interactions withion channelsand 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 thebrainstem.

Anopioid overdoseis fatal.[147]A person overdosing onopioidsoropiatesis presented withrespiratory depression,a lethal condition that can causehypoxiafrom slow and shallow breathing.[148]Mixing opioids with another depressant, such as benzodiazepines or alcohol, increases the chance of an overdose and respiratory depression. Opioid overdose causes a decreased level of consciousness,pinpoint pupils,and respiratory depression. Other symptoms include seizures and muscle spasms. Opioids activate μ-opioid receptors in specific regions of thecentral nervous systemassociated with respiratory regulation. They activate μ-opioid receptors in themedullaandpons.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 asbreathinganddigestion.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 theinhalation reflex,usually resulting in hypoxia. Some overdose victims, however, die fromcardiovascular failureor asphyxiation from choking on their vomit.[citation needed]

Naloxoneis a μ-opioid receptorantagonist,[149]meaning instead ofactivatingthe μ-opioid receptor, it disrupts the functioning of the receptor.[149]Since naloxone is powerful and highly selective for the μ-opioid receptor, it can knock powerful opioids likefentanyloff the receptor and block anotherligandfrom binding to the receptor, thus stopping anoverdose.[150]A person dependent on opioids may go intoprecipitated withdrawalwhen naloxone is used.[151]Since naloxone blocks any endogenous or exogenous opioids from binding to the μ-opioid receptor.[151]This may cause a person to immediately go into withdrawal after naloxone is used.[152]This can cause withdrawal symptoms likecold sweatsand diarrhea.

Opioids activate μ-opioid receptors in therostromedial tegmental nucleus(RMTg). Therostromedial tegmental nucleusis aGABAergicnucleus that functions as a "master brake" for themidbrain dopamine system.[153][154]The RMTg possesses robust functional and structural links to thedopamine pathways.[153][154]Opioids decrease the release of GABA, thus disinhibiting the GABAergic brake on dopamine networks.[153]GABA is aninhibitory neurotransmitter,meaning it either blocks or decreases the potential of neuron firing.[155]This causes large amounts ofdopamineto be released, as it is no longer blocked by GABA.[153]Disinhibition of GABA may be responsible for causing seizures, an uncommon adverse effect of opioids. GABAergic disinhibition is also why opioids are not considered true depressants. This excitement ofdopaminergic pathwayscauses the euphoria of opioids. This causes majorpositive reinforcing effectsin the brain, instructing it to do it again. The RMTg is also responsible for the development oftoleranceandaddiction.Psychostimulantsalso excite this pathway.[153][154]

Fentanylis very commonly cut into other substances sold on the street.[156]Fentanyl is used to increase the potency of substances, thus making the user spend more money on the laced substance.[157][158]Codeine is a weaker natural opiate that is usually used forbronchitis,diarrhea, and post-operative pain. It is very easy to overdose on these substances, especially if the user has no tolerance.

Natural opiates (derived frompapaver somniferumandopium)

Semi-syntheticmorphinanopioids (derived from thebaine):

Fully synthetic opioids:

Others:

Mitragyna speciosa(Kratom) (indole alkaloid)

Piperidinediones

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Main article:Glutarimide
The structure ofglutethimideis very similar to that ofbarbiturates.

Piperidinedionesare a class of depressants that are not used anymore. There are piperidinediones that are used for other purposes, likebreast cancer.[159][160][161]The piperidinedione class is very structurally similar to barbiturates. Some piperidinediones includeglutethimide,methyprylon,pyrithyldione,glutarimide,andaminoglutethimide.The first three (glutethimide, methyprylon, and pyrithyldione) arecentral nervous depressants.The piperidinedione depressants, specifically glutethimide, are positive modulators of the GABAAanion channel.The drug increases inhibitoryGABAergic toneand causesneuro-inhibitionof thecorticalandlimbic systems,observed clinically as asedative-hypnoticeffect.[162]Glutethimide is also a potent inducer of theCYP 2D6enzyme in the liver. This enzyme is responsible for converting many drugs, frombeta blockersto 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 tomorphinein the liver to have itspsychoactiveandanalgesiceffects. Mixing codeine with glutethimide allowed more codeine to be converted into morphine in the body, thus increasing its effect. These were known as "hits", "cibas and codeine", and "dors and 4s".[citation needed]Glutethimide was believed to be safer than barbiturates, but many people died from the drug. Demand was high in the United States at one point. Production of glutethimide was discontinued in the US in 1993 and in several eastern European countries, most notably Hungary, in 2006.[citation needed]

Glutethimide withdrawal is intense and resembles barbiturate withdrawal. It features hallucinations and delirium typical of a depressant withdrawal. In the 1970s, there were reports ofneonatal withdrawalfrom glutethimide. Infants born to mothers addicted to glutethimide responded well initially, then had a recurrence of symptoms about 5 days later, includingoveractivity,restlessness,tremors,hyperreflexia,hypotonia,vasomotor instability,incessant crying,andgeneral irritability.[citation needed]

Glutethimide withdrawal featured severe agitation,tremors,and seizures, which could be fatal.[citation needed]

Overdose causesstupor,coma, and/or respiratory depression.[citation needed]

  • Methyprylon (Dimerin,Methyprylone,Noctan,Noludar)
  • Pyrithyldione (Presidon,Pyridion,Pyridione,Pyrithyldion,Pyrithyldione)
  • Piperidione (Ascron,Dihyprylon,Dihyprylone,Sedulon,Tusseval) (withdrawn before approval)
  • Glutethimide (Doriden)

Quinazolinone

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Main article:Quinazolinone
Methaqualonetablets
Nitromethaqualonestructure

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 GABAAreceptor.[163]It does not bind to the ethanol, barbiturate,neurosteroid,orbenzodiazepine site.[163]Instead, it binds on a site directly between the GABRB2 (β2) and (α1)GABRA1proteins on the GABAAreceptor.[163]Theanestheticetomidateandanticonvulsantloreclezole may also bind to this site.[163]

Overdosing on quinazolinone sometimes causes effects that are the opposite of quinazolinone-like sedation. The overdose consists ofhyperreflexia,vomiting,kidney failure,delirium,hypertonia,coma,myoclonic twitches,somnolence,euphoria, muscular hyperactivity,agitated delirium,tachycardia,andtonic-clonic seizures.In 1982, 2,764 people visited US emergency rooms after overdosing on quinazolinones, specifically methaqualone.[164]Mixing quinazolinones with another depressant ispossibly fatal.Death from a quinazolinone overdose is usually caused by death throughcardiacorrespiratory arrest.An overdose resembles a barbiturate or carbamate overdose.

Quinazolinonewithdrawaloccurs when someone who has become dependent on a quinazolinone ceases usage. Quinazolinone withdrawal resembles ethanol, barbiturate, benzodiazepine, and carbamate withdrawal. It usually consists ofrestlessness,nausea and vomiting,decreased appetite,tachycardia,insomnia, tremor, hallucinations, delirium, confusion, and seizures; and, which are possibly fatal:EEG photoparoxysmal response,myoclonic twitches,fever,muscle spasms,andirritability.[165]

Methaqualone hydrochlorideand quinazolinone anxiolytics andhypnoticsare referred to as "quaaludes", "ludes", and "disco biscuits". Methaqualone was very commonly abused in the western world during the 1960s and 1970s. Methaqualone was mainly prescribed for insomnia, as it was thought to be safer than barbiturates and carbamates.[166]Methaqualone became highly abused by many, including celebrities, after its introduction in 1965.[164]Methaqualone was first synthesized in India in 1951 by Indra Kishore Kacker andSyed Husain Zaheer,who were conducting research on finding newantimalarial medications.[167][168]The drug name "Quaalude" (methaqualone) is aportmanteau,combining the words "quiet interlude". Methaqualone was discontinued in the United States in 1985, mainly due to itspsychological addictiveness,widespread abuse, and illegal recreational use. Nonbenzodiazepines and benzodiazepines are now used to treat insomnia instead. Methaqualone is now a Schedule I substance. Some quinazolinone analogues are still sold online. They come with the risk of seizures.[citation needed]

Large doses of methaqualone can cause euphoria,disinhibition,increased sexualityandsociability,muscle relaxation, anxiolysis, and sedation. Today, methaqualone is widely abused inSouth Africa.Many celebrities have used quinazolinone, most notably methaqualone. Bill Cosby admitted to casual sex involving the recreational use of methaqualone.[169][170][171]18-year-old actor Anissa Jones died from an overdose ofcocaine,PCP,methaqualone, and the barbiturateSeconal.Billy Murcia,a drummer for the rock bandNew York Dolls,died at 21 when hedrowned in a bathtubwhile overdosing onheroinand methaqualone.[172]

Cloroqualonewas a quinazolinone that bound to the GABAAandsigma-1 receptors.It had useful cough suppressant effects and weaker sedative effects than methaqualone, but was ultimately withdrawn due to its potential for abuse and overdose.[173]

Diproqualoneis a quinazolinone that is still used today. Diproqualone hassedative,anxiolytic,antihistamine,andanalgesicproperties, resulting from its agonist activity at the β subtype of the GABAareceptor, antagonist activity at allhistamine receptors,inhibition of thecyclooxygenase-1enzyme, and possibly its agonist activity at both theSigma-1 receptorandSigma-2 receptor.Diproqualone is used primarily for the treatment ofinflammatory painassociated withosteoarthritisandrheumatoid arthritis;it is used more rarely for treatinginsomnia,anxiety,andneuralgia.Diproqualone is the only analogue ofmethaqualonethat is still in widespread clinical use due to its usefulanti-inflammatoryandanalgesiceffects, 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 andoverdose;it is sold not as a pure drug but as thecamphosulfonatesalt in combination mixtures with other medicines such asethenzamide.[citation needed]

Etaqualoneis aquinazolinone-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.

Methylmethaqualoneis an analogue of methaqualone with similarhypnoticandsedativeeffects. Methylmethaqualone differs from methaqualone by 4-methylation on the phenyl ring. It producesconvulsionsat only slightly above the effective sedative dose. It would appear that this compound was sold on the black market in Germany as adesigner druganalogueof methaqualone.[174]

Nitromethaqualoneis a quinazolinone depressant with ten times morehypnoticandsedativeeffects than methaqualone.[175]

Quinazolinones:

Miscellaneous

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Combining multiple depressants

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Combining multiple depressants can be very dangerous because the central nervous system's depressive properties have been proposed to increase exponentially instead of linearly.[176]This characteristic makes depressants a common choice for deliberate overdoses in the case ofsuicide.The use of alcohol or benzodiazepines along with the usual dose of heroin is often the cause of overdose deaths in opiate addicts.

See also

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References

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