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Depressant

Article Discussion

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Depressants, also known as central nervous system depressants, or colloquially known as "downers", are drugs that lower neurotransmission levels, decrease the electrical activity of brain cells, or reduce arousal or stimulation in various areas of the brain.<ref>Template:Cite encyclopedia</ref> Some specific depressants do influence mood, either positively (e.g., opioids) or negatively, but depressants often have no clear impact on mood (e.g., most anticonvulsants). In contrast, stimulants, or "uppers", increase mental alertness, making stimulants the opposite drug class from depressants. Antidepressants are defined by their effect on mood, not on general brain activity, so they form an orthogonal category of drugs.

Depressants are closely related to sedatives as a category of drugs, with significant overlap. The terms may sometimes be used interchangeably or may be used in somewhat different contexts.Template:Citation needed

Depressants are widely used throughout the world as prescription medicines and illicit substances. Alcohol is a very prominent depressant. When depressants are used, effects often include ataxia, anxiolysis, pain relief, sedation or somnolence, cognitive or memory impairment, as well as, in some instances, euphoria, 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 benzodiazepines (e.g., alprazolam) and a number of opioids. Gabapentinoids like gabapentin and pregabalin are depressants and have anticonvulsant and anxiolytic effects. Most anticonvulsants, like lamotrigine and phenytoin, are depressants. Carbamates, such as meprobamate, are depressants that are similar to barbiturates. Anesthetics 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 GABA and inhibition of glutamatergic or monoaminergic activity. Other examples are chemicals that modify the electrical signaling inside the body, the most prominent of which are bromides and channel blockers.

IndicationsEdit

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

TypesEdit

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

AlcoholEdit

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} An alcoholic beverage is a drink that 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 taxation and regulation of production: beers, wines, and 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">{{#invoke:citation/CS1|citation |CitationClass=web }}</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 dL of blood (i.e., mass per volume is used there).<ref>Template:EMedicine</ref>

BarbituratesEdit

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Barbiturates were once popular treatments for insomnia, anxiety, and seizures, although their popularity has waned in recent decades. Barbiturates are sometimes used recreationally; they cause dependence and severe withdrawal, and they have a high risk of fatal overdose due to respiratory depression. By the late 1950s, concerns over the mounting social costs associated with barbiturates prompted a concerted effort to find alternative medications. Most people still using barbiturates today do so for the prevention of seizures or, in mild form, for relief from the symptoms of migraines. One barbiturate that remains in use for seizure disorders is phenobarbital.Template:Citation needed

BenzodiazepinesEdit

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} Template:See also 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 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.Template:Citation needed

File:Xanax 2 mg.jpg
Xanax (alprazolam) 2 mg tri-score tablets, a classical benzodiazepine sedative

Benzodiazepines enhance the effect of the neurotransmitter gamma-aminobutyric acid (GABA) at the GABAA receptor, resulting in sedative, hypnotic (sleep-inducing), anxiolytic (anti-anxiety), anticonvulsant, and muscle relaxant properties. High doses of shorter-acting benzodiazepines induce anterograde amnesia, which may be helpful for surgical and procedural anesthesia to reduce patient recall. Midazolam is often used in anesthesiology. These properties make benzodiazepines useful in treating anxiety, insomnia, agitation, seizures, muscle spasms, alcohol withdrawal, and as a premedication for medical or dental procedures. Benzodiazepines are categorized as either short-, intermediate-, or long-acting. Short- and intermediate-acting benzodiazepines are preferred for the treatment of insomnia; longer-acting benzodiazepines are recommended for the treatment of anxiety.Template:Citation needed

In general, benzodiazepines are safe and effective in the short term, although cognitive impairments and paradoxical effects such as aggression or behavioral disinhibition occasionally occur. A minority of patients react to benzodiazepines with paradoxical agitation. Long-term use is controversial due to adverse psychological and cognitive effects, decreasing effectiveness, dependence, and benzodiazepine withdrawal syndrome, following withdrawal after long-term use. The elderly are at an increased risk of experiencing both short- and long-term adverse effects.Template:Citation needed

There is controversy concerning the safety of benzodiazepines in pregnancy. While they are not major teratogens, uncertainty remains as to whether they cause cleft palate in a small number of babies and whether neurobehavioral effects occur as a result of prenatal exposure; they are known to cause withdrawal symptoms in the newborn. Benzodiazepines can be overdosed and cause dangerous deep unconsciousness. However, they are much less toxic than their predecessors, barbiturates, and death rarely results when a benzodiazepine is the only drug taken; however, when combined with other central nervous system depressants such as alcohol and 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 List, which is significant in clinical practice.Template:Citation needed

CannabisEdit

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Cannabis is often considered either in its own unique category or as a mild psychedelic.<ref name="WHO">Template:Cite book</ref><ref>Template:Cite journal</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>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Contrarily, activation of the CB1 receptor by cannabinoids causes an inhibition of GABA, which is atypical to most other depressants.Template:Citation needed

CarbamatesEdit

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} Carbamates are a class of depressants, or "tranquilizers", that are synthesized from urea.<ref>Template:Cite journal</ref> Carbamates have anxiolytic,<ref name="Conermann 2022">Template:Citation</ref> muscle relaxant,<ref name="Conermann 2022" /> anticonvulsant,<ref>Template:Cite journal</ref> hypnotic,<ref name="Conermann 2022" /> antihypertensive,<ref>Template:Cite journal</ref> and analgesic effects. They have other uses, like muscle tremors, agitation, and alcohol withdrawal. Their muscle relaxant effects are useful for strains, sprains, 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>Template:Cite journal</ref>

File:Somadril Comp.JPG
Carisoprodol tablets

Side effects of carbamates include drowsiness, dizziness, headache, diarrhea, nausea, flatulence, liver failure, poor coordination, nystagmus, abuse, dizziness, weakness, nervousness, euphoria, overstimulation, and dependence. Uncommon but potentially severe adverse reactions include hypersensitivity reactions such as Stevens–Johnson syndrome, embryo-fetal toxicity, stupor, and coma. It is not recommended to use most carbamates, like carisoprodol, for a long time, as physical and psychological dependence do occur.<ref>Template:Citation</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 allosterically modulates and directly activates the human α1β2γ2 GABAAR (GABAA) in the central nervous system, similar to barbiturates. This causes chloride channels to open, allowing chloride to flood into the neuron. This slows down communication between neurons and the nervous system.<ref>Template:Cite journal</ref> Unlike benzodiazepines, which increase the frequency of the chloride channel opening, carisoprodol increases the duration of channel opening when GABA is bound.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> GABA is the main inhibitory neurotransmitter in the nervous system, which causes its depressant effects.

Carbamates are fatal in overdose, which is why many have been replaced with benzodiazepines. Symptoms are similar to a barbiturate overdose and typically include difficulty thinking, 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 suppresses breathing.Template:Fact

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, alcohol, or benzodiazepine withdrawal, as they all have a similar mechanism of action. Discontinuation symptoms include confusion, disorientation, delirium, hallucinations (auditory and visual), insomnia, decreased appetite, anxiety, psychomotor agitation, pressured speech, tremor, tachycardia, and seizures, which could be fatal.<ref>Template:Cite journal</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 GABAA positive allosteric modulator and blocks the NR2B subunit of the NMDA receptor. Other carbamates block sodium channels. Phenprobamate was used as an anxiolytic and is still sometimes used in Europe for general anesthesia and for treating muscle cramps and spasticity. Methocarbamol is a popular drug that is commonly known as Robaxin and is over-the-counter in some countries. It is a carbamate with muscle relaxant effects. Tetrabamate is a controversial drug that is a combination of febarbamate, difebarbamate, and phenobarbital. It is marketed in Europe and has been largely, but not completely, discontinued. On 4 April 1997, after over 30 years of use due to reports of hepatitis and acute liver failure, the use of the drug was restricted. Carisoprodol, known as "Soma", is still commonly used today for its muscle relaxant effects. It is also very commonly abused around the world. It is a Schedule IV substance in the United States.Template:Citation needed

Approved:Template:Citation needed

Not approved:Template:Citation needed

GabapentinoidsEdit

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} Template:Multiple image Gabapentinoids are a unique and relatively novel class of depressants that selectively bind to the auxiliary α2δ subunit (CACNA2D1 and CACNA2D2) site of certain VDCCs and thereby act as inhibitors of α2δ subunit-containing voltage-gated calcium channels. α2δ is nicknamed the "gabapentin receptor". At physiologic or resting membrane potential, VDCCs are normally closed. They are activated (opened) at depolarized membrane potentials, which is the source of the "voltage-gated" epithet. Gabapentinoids bind to the α1 and α2 sites of the α2δ subunit family. Gabapentin is the prototypical gabapentinoid. The α2δ is found on L-type calcium channels, N-type calcium channels, P/Q-type calcium channels, and R-type calcium channels throughout the central and peripheral nervous systems. α2δ is located on presynaptic neurons and affects calcium channel trafficking and kinetics, initiates extracellular signaling cascades and gene expression, and promotes excitatory synaptogenesis through thrombospondin 1.<ref>Template:Cite journal</ref> Gabapentinoids are not direct channel blockers; rather, they disrupt the regulatory function of α2δ and its interactions with other proteins. Most of the effects of gabapentinoids are mediated by the 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 ataxic adverse effect of gabapentinoids, while N-type calcium channels are located throughout the central and peripheral nervous systems. N-type calcium channels are mainly responsible for the analgesic effects of gabapentinoids. Ziconotide, a non-gabapentinoid ω-conotoxin peptide, binds to the N-type calcium channels and has analgesic effects 1000 times stronger than morphine. Gabapentinoids are selective for the α2δ site but non-selective when they bind to the calcium channel complex. They act on the α2δ site to lower the release of many excitatory and pro-nociceptive neurochemicals, including glutamate, substance P, calcitonin gene-related peptide (CGRP), and more.<ref name="pmid172224652">Template:Cite journal</ref><ref name="WyllieCascino20123">Template:Cite book</ref><ref name="BenzonRathmell20132">Template:Cite book</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 transporters. Gabapentinoids are structurally similar to the branched-chain amino acids L-leucine and L-isoleucine, both of which also bind to the α2δ site. Branched-chain amino acids like l-leucine, l-isoleucine, and l-valine have many functions in the central nervous system. They modify large neutral amino acid (LNAA) transport at the blood–brain barrier and reduce the synthesis of neurotransmitters derived from aromatic amino acids, notably serotonin from tryptophan and catecholamines from tyrosine and phenylalanine.<ref>Template:Cite journal</ref> This may be relevant to the pharmacology of gabapentinoids.

Gabapentin was designed by researchers at Parke-Davis to be an 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>Template:Cite book</ref><ref>Template:Cite journal</ref> Gabapentin was first approved for epilepsy, mainly as an add-on treatment for partial seizures. Gabapentinoids are GABA analogues,<ref name="pmid101891762">Template:Cite journal</ref> but they do not bind to the GABA receptors, convert into GABA or another GABA receptor agonist in vivo, or directly modulate GABA transport or metabolism.<ref name="Uch20102">Template:Cite journal</ref><ref name="pmid16376147">Template:Cite journal</ref> Phenibut and baclofen, two structurally related compounds, are exceptions, as they mainly act on the GABA B receptor.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Gabapentin, but not pregabalin, has been found to activate voltage-gated potassium channels (KCNQ), which might potentiate its depressant qualities. Despite this, gabapentinoids mimic GABA activity by inhibiting neurotransmission.<ref>Template:Cite book</ref> Gabapentinoids prevent delivery of the calcium channels to the cell membrane and disrupt interactions of α2δ with NMDA receptors, AMPA receptors, neurexins, and thrombospondins. Some calcium channel blockers of the dihydropyridine class are used for hypertension to weakly block α2δ.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Gabapentinoids have anxiolytic, anticonvulsant, antiallodynic, antinociceptive, and possibly muscle relaxant properties.<ref name="WyllieCascino20123" /><ref name="Kirsch2013">Template:Cite book</ref><ref name="SchatzbergNemeroff2009">Template:Cite book</ref> Pregabalin and gabapentin are used in epilepsy, mainly partial seizures (focal). Gabapentinoids are not effective for generalized seizures. They are also used for postherpetic neuralgia, neuropathic pain associated with diabetic neuropathy, fibromyalgia, generalized anxiety disorder, and restless legs syndrome.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Pregabalin and gabapentin have many off-label uses, including insomnia,<ref>Template:Cite journal</ref> alcohol and opioid withdrawal,<ref name="ReferenceA">Template:Cite journal</ref> smoking cessation,<ref>Template:Cite journal</ref> social anxiety disorder,<ref>Template:Cite journal</ref> bipolar disorder,<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> attention deficit hyperactivity disorder,<ref>Template:Cite journal</ref> chronic pain, hot flashes,<ref>Template:Cite journal</ref> tinnitus, migraines, and more. Baclofen is primarily used for the treatment of spastic movement disorders, especially in instances of spinal cord injury, cerebral palsy, and multiple sclerosis.<ref name="AHFS">{{#invoke:citation/CS1|citation |CitationClass=web }}</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">Template:Cite journal</ref> It is also used for various other indications, including the treatment of asthenia, depression, alcoholism, alcohol withdrawal syndrome, post-traumatic stress disorder, stuttering, tics, vestibular disorders, 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 agonists, is also sometimes used by bodybuilders to increase the human growth hormone.Template:Citation needed

In some cases, gabapentinoids are abused and provide similar effects to alcohol, benzodiazepines, and gamma-hydroxybutyric acid (GHB).<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> The FDA placed a black box warning on Neurontin (gabapentin) and Lyrica (pregabalin) for serious breathing problems.<ref name="FDA breathing">{{#invoke:citation/CS1|citation |CitationClass=web }} Template:PD-notice</ref> Mixing gabapentinoids with opioids, benzodiazepines, barbiturates, GHB, alcohol, or any other depressant is potentially deadly.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Common side effects of gabapentinoids include drowsiness, dizziness, weakness, increased appetite, urinary retention, shortness of breath, involuntary eye movements (nystagmus), memory issues, uncontrollable jerking motions, auditory hallucinations, erectile dysfunction, and myoclonic seizures.<ref>Template:Cite book</ref><ref>Template:Cite journal</ref>

An overdose of gabapentinoids usually consists of severe drowsiness, severe ataxia, blurred vision, slurred speech, severe uncontrollable jerking motions, and anxiety.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Like most anticonvulsants, pregabalin and gabapentin have an increased risk of suicidal thoughts and behaviors.<ref>Template:Cite journal</ref><ref>Template:Citation</ref> Gabapentinoids, like all calcium channel blockers, are known to cause angioedema.<ref>Template:Cite journal</ref> Taking them with an ACE inhibitor can increase the toxic effects of gabapentinoids.<ref>Template:Cite journal</ref> They may also enhance the fluid-retaining effect of certain anti-diabetic agents (thiazolidinediones). It is not known if they cause gingival enlargement like other calcium channel blockers. Gabapentinoids are excreted by the kidney, mostly in their original form. Gabapentinoids can build up in the body when someone has renal failure. This usually presents itself as myoclonus and an altered mental state. It is unclear if it is safe to use gabapentinoids during pregnancy, with some studies showing potential harm.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Physical or physiological dependence does occur during the long-term use of gabapentinoids.<ref>Template:Cite journal</ref> Following abrupt or rapid discontinuation of pregabalin and gabapentin, people report withdrawal symptoms like insomnia, headache, nausea, diarrhea, flu-like symptoms, anxiety, depression, pain, hyperhidrosis, seizures, psychomotor agitation, confusion, disorientation, and gastrointestinal complaints.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Acute withdrawal from baclofen and phenibut may also cause auditory and visual hallucinations, as well as acute psychosis.<ref>Template:Cite journal</ref><ref name="Matthew I 2018">Template:Cite journal</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, GHB, or alcohol withdrawal. To minimize withdrawal symptoms, baclofen or phenibut should be tapered down slowly. Abrupt withdrawal from phenibut or baclofen could possibly be life-threatening because of its mechanism of action. Abrupt withdrawal can cause rebound seizures and severe agitation.<ref>Template:Cite journal</ref><ref name="Matthew I 2018"/>

Approved:Template:Citation needed

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Endogenous (not gabapentinoids), endogenous BCAA amino acids that bind to α2δ):

Other α2δ ligands:<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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Gamma-hydroxybutyric acidEdit

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} Template:Multiple image Gamma-hydroxybutyric acid, or "GHB", is a GABA analogue that is a naturally occurring neurotransmitter and depressant drug.<ref name="O'connell 2478–2482">Template:Cite journal</ref><ref name="Cash 291–304">Template:Cite journal</ref><ref>Template:Cite book</ref> It is also naturally found in small amounts in some alcoholic beverages alongside ethanol.<ref>Template:Cite journal</ref> GHB is the prototypical substance among a couple of GHB receptor modulators.<ref name="Nicholson 1–22">Template:Cite journal</ref>

GHB has been used as a general anesthetic<ref>Template:Cite journal</ref> and as a treatment for cataplexy,<ref name="Boscolo-Berto 431–443">Template:Cite journal</ref><ref>Template:Cite journal</ref> narcolepsy,<ref name="Boscolo-Berto 431–443"/><ref>Template:Cite journal</ref> and alcoholism.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> The sodium salt of GHB, sodium oxybate, is commonly used today for narcolepsy,<ref name="Alshaikh 1">Template:Cite journal</ref> sudden muscle weakness,<ref>Template:Cite journal</ref> and excessive daytime sleepiness. It is sold under the brand name Xyrem.<ref name="Carter 1–10">Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="Alshaikh 1"/>

GHB mainly affects the GHB receptor,<ref name="Bay 220–228">Template:Cite journal</ref><ref name="Carter 100–114">Template:Cite journal</ref> an excitatory receptor that releases dopamine and glutamate,<ref name="Kamal 2016 65–80">Template:Cite journal</ref> giving GHB stimulant effects, the opposite of a depressant. But in large doses, GHB activates the GABAB receptor, an inhibitory receptor in the central nervous system, which overpowers the excitatory effects, thus causing central nervous system depression.<ref name="Ingels 47–50">Template:Cite journal</ref><ref>Template:Cite journal</ref> Some antipsychotics are agonists of the GHB receptor.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

GHB can usually be found in either sodium, potassium, magnesium, or calcium salts.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Xywav is a medication that is a mixture of all GHB salts<ref>Template:Cite journal</ref> and is used to treat the same conditions as Xyrem. Both Xywav and Xyrem are Schedule III<ref name="Tunnicliff 278–283">Template:Cite journal</ref><ref>Template:Cite journal</ref> and have a black box warning<ref>Template:Cite journal</ref> for central nervous system depressant effects (hypoventilation and bradycardia) and for their very high potential for abuse.<ref>Template:Cite journal</ref><ref name="Nicholson 1–22" /> Overdose on GHB is fatal with or without mixing other CNS depressants.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</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">Template:Cite journal</ref><ref>Template:Cite journal</ref>

GHB is used illegally as an intoxicant, an aphrodisiac,<ref name="O'connell 2478–2482"/><ref>Template:Cite journal</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 euphoric effects. Similarly to phenibut and baclofen, it is used by bodybuilders to increase the human growth hormone due to GABAB activation.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> It has also been reportedly used as a date-rape drug.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> This caused it to be a Schedule I substance in the United States, Canada, and other countries. Xyrem, which is GHB in its sodium form, is Schedule III in the United States, Canada, and other countries.<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.<ref name="Carter 100–114"/><ref name="Bay 220–228"/><ref>Template:Cite journal</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 but also exhibit a range of effects that were found not to be produced by GABAB activity and so were suspected of being produced by a novel and, at the time, unidentified receptor target. At higher doses, seizures are very common.<ref name="Venzi 123–140"/> This is thought to be mediated through an increased Na+/K+ current and the increased release of dopamine and glutamate.<ref name="Kamal 2016 65–80"/> GHB can also cause absence seizures;<ref name="Venzi 123–140"/><ref name="Hu 427–439">Template:Cite journal</ref><ref>Template:Cite journal</ref> the mechanism is currently not known but it is believed to be due to interactions with the GABAB 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>Template:Cite journal</ref>

Physical dependence develops quickly and is highly addictive. It shares some similarities, when suddenly discontinued, with the withdrawal symptoms of gabapentinoids phenibut and baclofen due to the activation of the GABAB receptor. It features a typical depressant withdrawal syndrome that mimics alcohol withdrawal.<ref name="van Noorden A1286">Template:Cite journal</ref> Symptoms include delirium, tremor, anxiety, tachycardia, insomnia, hypertension, confusion, sweating, severe agitation which may require restraint,<ref name="Dyer Roth Hyma 2001">Template:Cite journal</ref> auditory and visual hallucinations, and possibly death from tonic-clonic seizures.<ref name="Dyer Roth Hyma 2001"/><ref>Template:Cite journal</ref><ref name="van Noorden A1286"/><ref name="Lingford-Hughes 472">Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="van Noorden 394–396">Template:Cite journal</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:Template:Citation needed

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

Prodrugs that metabolize into GHB:Template:Citation needed

  • γ-Hydroxyvaleric acid (GHV)

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

GHB receptor antagonists:Template:Citation needed

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

NonbenzodiazepinesEdit

Template:Multiple image Nonbenzodiazepines, sometimes referred to as Z-drugs, are a class of hypnotic depressants that are mainly used to treat insomnia and sometimes anxiety.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> They are structurally related to benzodiazepines. They positively modulate the benzodiazepine site of the GABAA receptor, the chief inhibitory receptor of the central nervous system, just like benzodiazepines, but at a molecular level, they are structurally unrelated.Template:Citation needed

Nonbenzodiazepines bind to the benzodiazepine at the GABAA receptor site to keep the chloride channel open.<ref>Template:Cite journal</ref> This causes chloride in the intercellular area to flood into the neuron.<ref>Template:Cite journal</ref> Since chloride has a negative charge, it causes the neuron to rest and cease firing. This results in a relaxing and depressant effect on the central nervous system.Template:Citation needed

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.Template:Citation needed

Nonbenzodiazepines should not be discontinued abruptly if taken for more than a few weeks due to the risk of rebound withdrawal effects and acute withdrawal reactions, which may resemble those seen during benzodiazepine withdrawal. Treatment usually entails gradually reducing the dosage over a period of weeks or several months, depending on the individual, dosage, and length of time the drug has been taken. If this approach fails, a crossover to a benzodiazepine equivalent dose of a long-acting benzodiazepine (such as chlordiazepoxide or, more preferably, diazepam) can be tried, followed by a gradual reduction in dosage. In extreme cases and, in particular, where severe addiction and/or abuse are manifested, inpatient detoxification may be required, with flumazenil as a possible detoxification tool.Template:Fact

OpioidsEdit

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Opioids are substances that act on opioid receptors to reduce pain.<ref>Template:Cite book</ref> Medically, they are primarily used for pain relief, including anesthesia. Opioids also cause euphoria and are highly abused.Template:Citation needed

There are three principal classes of opioid receptors: μ, κ, δ (mu, kappa, and delta),<ref>Template:Citation</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) receptors are no longer considered to be opioid receptors because their activation is not reversed by the opioid inverse-agonist naloxone. The nociception opioid peptide receptor (NOP) (ORL1) is an opioid receptor that is involved in pain responses, anxiety, movement, reward, hunger, memory, and much more. It plays a major role in the development of tolerance to μ-opioid receptor agonists.<ref>Template:Cite journal</ref>

When pain occurs, a signal gets sent from the site of possible injury. This signal goes up the spinal cord into the brain, where it is perceived as a negative emotion known as nociception. In the central nervous system, the spine is connected to the brain by a structure called the brain stem.<ref>Template:Cite journal</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.Template:Fact

The μ-opioid receptor is responsible for the analgesic, euphoric, and adverse effects of opioids. The μ-opioid receptor is a G protein-coupled receptor. When the μ-opioid receptor is activated, it causes pain relief, euphoria, constipation, constricted pupils, itching, and nausea.<ref>Template:Citation</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 trouble urinating and swallowing. The μ-opioid receptor can also reduce androgens, thus decreasing libido and sexual function. The receptor is also known to cause "musical anhedonia".<ref>Template:Cite journal</ref>

The μ-opioid receptor has many endogenous ligands, including endorphin.<ref>Template:Citation</ref>

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The κ-opioid receptor (KOR) is a G protein-coupled receptor located in the central nervous system. KOR is also a G protein-coupled receptor.<ref>Template:Cite journal</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. Dysregulation of this receptor system has been implicated in alcohol and drug addiction.<ref>Template:Cite journal</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 hallucinations. Antagonizing the κ-opioid receptor may be able to treat depression, anxiety, stress, addiction, and alcoholism.<ref>Template:Cite journal</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 agonists can produce respiratory depression at very high doses; at lower doses, they have the opposite effect. High doses of a δ-opioid agonist can cause seizures, although not all delta agonists produce this effect.<ref>Template:Cite journal</ref> Activation of the δ-opioid receptor is usually stimulating instead of sedating like most opioids.Template:Citation needed

The nociception opioid peptide receptor (NOP) is involved in the regulation of numerous brain activities, particularly instinctive emotional behaviors and pain.<ref>Template:EntrezGene 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>Template:Cite journal</ref>

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An opioid overdose can be fatal.<ref>Template:Cite journal</ref> A person overdosing on opioids presents with respiratory depression, a potentially lethal condition that can cause hypoxia from slow and shallow breathing.<ref>Template:Cite journal</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 pupils, and respiratory depression. Other symptoms include seizures and muscle spasms. Opioids activate μ-opioid receptors in specific regions of the central nervous system associated with respiratory regulation. They activate μ-opioid receptors in the medulla and pons. They are located in the brain stem, which connects to the spine. This area has a high density of μ-opioid receptors as they block pain going up from the spine into the brain. These areas are the oldest and most primitive parts of the brain. They control automatic functions such as breathing and digestion. Opioids stop this process and cause respiratory depression and constipation. The brain stem no longer detects carbon dioxide in the blood, so it does not initiate the inhalation reflex, usually resulting in hypoxia. Some overdose victims, however, die from cardiovascular failure or asphyxiation from choking on their vomit.Template:Fact

Naloxone is a μ-opioid receptor antagonist,<ref name="Theriot 2022">Template:Citation</ref> meaning instead of 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 overdose.<ref>Template:Cite journal</ref> A person dependent on opioids may go into precipitated withdrawal when naloxone is used.<ref name="Sun 544">Template:Cite journal</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>Introduction: The Pharmacology of Buprenorphine, Precipitated Withdrawal & Management of Adverse EffectsTemplate:Full</ref> This can cause withdrawal symptoms like cold sweats and diarrhea.

Opioids activate μ-opioid receptors in the rostromedial tegmental nucleus (RMTg). The rostromedial tegmental nucleus is a GABAergic nucleus that functions as a "master brake" for the midbrain dopamine system.<ref name="Bourdy 681–690">Template:Cite journal</ref><ref name="Barrot 14094–14101">Template:Cite journal</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>Template:Citation</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 positive reinforcing effects in the brain, instructing it to do it again. The RMTg is also responsible for the development of tolerance and addiction. Psychostimulants also excite this pathway.<ref name="Bourdy 681–690" /><ref name="Barrot 14094–14101" />

Fentanyl is very commonly cut into other substances sold on the street.<ref>Template:Citation</ref> Fentanyl is used to increase the potency of substances, thus making the user spend more money on the laced substance.<ref>Template:Cite journal</ref><ref>Template:Cite journal</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.Template:Citation needed

Natural opiates (derived from papaver somniferum and opium):Template:Citation needed

Semi-synthetic morphinan opioids (derived from thebaine):Template:Citation needed

Fully synthetic opioids:

Others:Template:Citation needed

PiperidinedionesEdit

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File:Glutethimide.svg
The structure of glutethimide is very similar to that of barbiturates.

Piperidinediones are a class of depressants that are not used anymore. There are piperidinediones that are used for other purposes, like breast cancer.<ref>Template:Cite book</ref><ref>Template:Cite bookTemplate:Pn</ref><ref>Template:Cite book</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 central nervous depressants. The piperidinedione depressants, specifically glutethimide, are positive modulators of the GABAA anion channel. The drug increases inhibitory GABAergic tone and causes neuro-inhibition of the cortical and limbic systems, observed clinically as a sedative-hypnotic effect.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Glutethimide is also a potent inducer of the CYP 2D6 enzyme in the liver. This enzyme is responsible for converting many drugs, from beta blockers to antidepressants to opioids and opiates. Due to its effects on the conversion of opioids, it was highly abused and mixed with opioids like codeine. Codeine must be metabolized to morphine in the liver to have its psychoactive and analgesic effects. Mixing codeine with glutethimide allowed more codeine to be converted into morphine in the body, thus increasing its effect. These were known as "hits", "cibas and codeine", and "dors and 4s".Template:Fact 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.Template:Fact

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 overactivity, restlessness, tremors, hyperreflexia, hypotonia, vasomotor instability, incessant crying, and general irritability.Template:Fact

Glutethimide withdrawal featured severe agitation, tremors, and seizures, which could be fatal.Template:Fact

List of piperidinediones:Template:Citation needed

QuinazolinoneEdit

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Quinazolinones are a class of depressants that are rarely used anymore. Quinazolinones have powerful sedative, hypnotic, and anxiolytic effects. Quinazolinone's structure is very similar to that of some antibiotics. Quinazolinone's main mechanism of action is binding to the GABAA receptor.<ref name="Hammer 401–420">Template:Cite journal</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 GABAA 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, myoclonic twitches, somnolence, euphoria, muscular hyperactivity, agitated delirium, tachycardia, and tonic-clonic seizures. In 1982, 2,764 people visited US emergency rooms after overdosing on quinazolinones, specifically methaqualone.<ref name="web.archive.org">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Mixing quinazolinones with another depressant is possibly fatal. Death from a quinazolinone overdose is usually caused by death through cardiac or respiratory arrest. An overdose resembles a barbiturate or carbamate overdose.Template:Citation needed

Quinazolinone 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 restlessness, 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, and irritability.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Methaqualone hydrochloride and quinazolinone anxiolytics and hypnotics are referred to as "quaaludes", "ludes", and "disco biscuits". Methaqualone was very commonly abused in the western world during the 1960s and 1970s. Methaqualone was mainly prescribed for insomnia, as it was thought to be safer than barbiturates and carbamates.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</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 medications.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite journal</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 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.Template:Fact

Large doses of methaqualone can cause euphoria, disinhibition, increased sexuality and sociability, muscle relaxation, anxiolysis, and sedation. Today, methaqualone is widely abused in South Africa. Many celebrities have used quinazolinone, most notably methaqualone. Bill Cosby admitted to casual sex involving the recreational use of methaqualone.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite news</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 18-year-old actor Anissa Jones died from an overdose of cocaine, PCP, methaqualone, and the barbiturate Seconal. Billy Murcia, a drummer for the rock band New York Dolls, died at 21 when he drowned in a bathtub while overdosing on heroin and methaqualone.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Cloroqualone was a quinazolinone that bound to the GABAA and sigma-1 receptors. It had useful cough suppressant effects and weaker sedative effects than methaqualone, but was ultimately withdrawn due to its potential for abuse and overdose.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</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 GABAa receptor, antagonist activity at all histamine receptors, inhibition of the 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 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 overdose; it is sold not as a pure drug but as the camphosulfonate salt in combination mixtures with other medicines such as ethenzamide.Template:Fact

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.Template:Citation needed

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 analogue of methaqualone.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Nitromethaqualone is a quinazolinone depressant with ten times more hypnotic and sedative effects than methaqualone.<ref>Template:Cite journal</ref>

Quinazolinones:Template:Citation needed

MiscellaneousEdit

Combining multiple depressantsEdit

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>Template:Cite journal</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.Template:Citation needed

See alsoEdit

ReferencesEdit

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Template:Depressants Template:Major Drug Groups Template:Chemical classes of psychoactive drugs Template:Recreational drug use

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