Central Nervous System Depressants

A depressant, or central depressant, is a drug that lowers neurotransmission levels, which is to depress or reduce arousal or stimulation, in various areas of the brain. Depressants are also colloquially referred to as downers as they lower the level of arousal when taken. Stimulants or "uppers" increase mental or physical function, hence the opposite drug class of depressants is stimulants, not antidepressants.

Depressants are widely used throughout the world as prescription medicines and as illicit substances. Alcohol is a very prominent depressant. Alcohol can be and is more likely to be a large problem among teenagers and young adults. When depressants are used, effects often include ataxia, anxiolysis, pain relief, sedation or somnolence, and 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 also act to produce anesthesia. Cannabis may sometimes be considered a depressant due to one of its components, cannabidiol. The latter is known to treat insomnia, anxiety and muscle spasms similar to other depressive drugs. However, tetrahydrocannabinol, another component, may slow brain function to a small degree while reducing reaction to stimuli, it is generally considered to be a stimulant and main psychoactive agent to sometimes cause anxiety, panic and psychosis instead. Other depressants can include drugs like Xanax (a benzodiazepine) and a number of opioids. Gabapentinoids like gabapentin and baclofen are depressants and have anticonvulsant and anxiolytic effects. Most anticonvulsants like Lamotrigine and Phenytoin are depressants. Carbamates (Felbamate Carisoprodol) are depressants that are similar to barbiturates.

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 these being bromides and channel blockers.

Indications

Depressants are used medicinally to relieve the following symptoms:
* Anxiety disorders such as:
** Generalized anxiety
** Social anxiety
** Panic attacks
* Insomnia
* Obsessive–compulsive disorder
* Seizures
* Convulsions
* Depression
* Pain

Types

Alcohol

An alcoholic beverage is a drink that contains alcohol (also 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.

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" or more correctly 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).

Barbiturates

Barbiturates are effective in relieving the conditions that they are designed to address (insomnia, seizures). They are also commonly used for unapproved purposes, are physically addictive, and have serious potential for overdose. In the late 1950s, when many thought that the social cost of barbiturates was beginning to outweigh the medical benefits, a serious search began for a replacement drug. Most people still using barbiturates today do so in the prevention of seizures or in mild form for relief from the symptoms of migraines.

Benzodiazepines

A benzodiazepine (sometimes colloquially "benzo"; often abbreviated "BZD") 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.

Benzodiazepines enhance the effect of the neurotransmitter gamma-aminobutyric acid (GABA) at the GABA_A receptor, resulting in sedative, hypnotic ( sleep-inducing), anxiolytic (anti-anxiety), anticonvulsant, and muscle relaxant properties; also seen in the applied pharmacology of high doses of many shorter-acting benzodiazepines are amnesic- dissociative actions. These properties make benzodiazepines useful in treating anxiety, insomnia, agitation, seizures, muscle spasms, alcohol withdrawal and as a premedication for medical or dental procedures. Benzodiazepines are categorized as either short-, intermediate-, or long-acting. Short- and intermediate-acting benzodiazepines are preferred for the treatment of insomnia; longer-acting benzodiazepines are recommended for the treatment of anxiety.

In general, benzodiazepines are safe and effective in the short term, although cognitive impairments and paradoxical effects such as aggression or behavioral disinhibition occasionally occur. A minority react reverse and contrary to what would normally be expected. For example, a state of panic may worsen considerably following intake of a benzodiazepine. Long-term use is controversial due to concerns about adverse psychological and physical effects, increased questioning of effectiveness, and, because benzodiazepines are prone to cause tolerance, physical dependence, and, upon cessation of use after long-term use, benzodiazepine withdrawal syndrome. Due to adverse effects associated with the long-term use of benzodiazepines, withdrawal from benzodiazepines, in general, leads to improved physical and mental health. The elderly are at an increased risk of experiencing both short- and long-term adverse effects.

There is controversy concerning the safety of benzodiazepines in pregnancy. While they are not major teratogens, uncertainty remains as to whether they cause cleft palate in a small number of babies and whether neurobehavioural effects occur as a result of prenatal exposure; they are known to cause withdrawal symptoms in the newborn. Benzodiazepines can be taken in overdoses and can cause dangerous deep unconsciousness. However, they are much less toxic than their predecessors, the barbiturates, and death rarely results when a benzodiazepine is the only drug taken; however, when combined with other central nervous system depressants such as alcohol and opiates, the potential for toxicity and fatal overdose increases. Benzodiazepines are commonly misused and taken in combination with other addictive drugs. In addition, all benzodiazepines are listed in Beers List, which is significant in clinical practice.

Cannabis

Cannabis is often considered either in its own unique category or as a mild psychedelic. The chemical compound tetrahydrocannabinol (THC), which is found in cannabis, has many depressant effects such as muscle relaxation, sedation, decreased alertness, and less tiredness. Contrary to the previous statement, activation of the CB1 receptor by cannabinoids causes an inhibition of GABA, the exact opposite of what central nervous system depressants do.

Carbamates

Carbamates are a class of depressants or " tranquilizers" that are synthesized from urea. Carbamates have anxiolytic, muscle relaxant, anticonvulsant, hypnotic, antihypertensive, and analgesic effects. It has other uses like muscle tremors, agitation, and alcohol withdrawal. It's muscle relaxant effects are useful for strains, sprains, and muscle injuries together with rest, physical therapy, and other measures. The effects, synthesis and mechanism of action of Carbamates are very similar to barbiturates. There are many different types of Carbamates, some only produce anxiolytic effects and hypnotic effects while some only have anticonvulsant effects.

Side effects of Carbamates include drowsiness, dizziness, headache, diarreha, nausea, flatulence, liver failure, poor coordination, nystagmus, abuse, dizziness, weakness, nervousness, euphoria, overstimulation and dependence. Uncommon but potentially severe adverse reactions include hyper sensivity reactions including Stevens Johnson syndrome, embryo-fetal toxicity, stupor, and coma. Carbamates are fatal in overdose, which is why a lot of them have been replaced with benzodiazepines. It is not recommended to use most Carbamates like Carisoprodol for a long time as physical and psychological dependence does occur.

Meprobamate which metabolizes to ''Carisoprodol'' was launched in 1955. It quickly become the first blockbuster 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, from Amepromat through Quivet to Zirpon. Carisoprodol, which is still used today mainly for it's muscle relaxant effects has high abuse potential. It's mechanism of action is very similar to barbiturates, alcohol, methaqualone and benzodiazepines. Carsidoprodol allosterically modulates and directly activates the human α1β2γ2 GABAAR ( GABA_A) in the central nervous system in a barbiturate-like manner. This causes chloride channels to open, allowing chloride to flood into the neuron, slowing down communication betwen neurons; thus slowing down the nervous system. Unlike benzodiazpines which increase the frequency of the chloride channel opening, Carisoprodol increase the duration of channel opening when GABA is bound. GABA is the main inhibitory neurotransmitter in the nervous system, which causes its depressant effects.

Carbamates are fatal in overdose. Symptoms are similar to a barbiturate overdose. Symptoms typically include difficulty thinking, poor coordination, decreased level of consciousness, and a decreased effort to breathe (respiratory depression). An overdose is more likely to be fatal when it is mixed with another depressant that suppresses breathing. Death occurs this is typically due to a lack of breathing.

Physical and psychological dependence does happen with long term use of Carbamates; particularly Carisoprodol. Today Carisoprodol is only used short term for muscle pain, particularly back pain. Discontuation 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 & visual), insomnia, decreased appetite, anxiety, psychomotor agitation, pressured speech, tremor, tachycardia, seizures which could be fatal.

Carbamates we're popular in the 1950's along with barbiturates. Although they have been slowly phased out; mainly due to the overdose and dependence risks, new derivates still exist. Felbamate is an anticonvulsant that was approved in 1993 that is commonly used today. It is a GABA_A positive allosteric modulator and blocks the NR2B subunit of the NMDA receptor. Some 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, that is over the counter in some countries.. It is a carbamate with muscle relaxant effects. Tetrabamate; a is a controversial drug which is a combination of febarbamate, difebarbamate, and phenobarbital which is marketed in Europe was largely but not completely discontinued. April 4, 1997 after over 30 years of use due to reports of hepatitis and acute liver failure. The decision to restrict the use of the drug had been long-awaited. Carisoprodol; known as, "Soma" is still commonly used today for it's muscle relaxant effects. It is also very commonly abused around the world. It is a Schedule IV substance in the United States. Famous martial artist and actor Bruce Lee died due to an allergic reaction to meprobamate.

Approved
* Carisoprodol/ Meprobamate/Tybamate (Soma/Miltown, Solacen) (muscle relaxant, anxiolytic, tranquilizer)
* Difebarbamate (Atrium, Sevrium) (tranquilizer)
* Emylcamate (Striatran) (anxiolytic and muscle relaxant)
* Ethinamate (Valamin, Valmid) (sedative-hypnotic)
* Febarbamate/Febarbamate, Phenobamate (Solium, Tymium) (anxiolytic and tranquilizer)
* Felbamate (Felbatol) (anticonvulsant)
* Hexapropymate (Merinax) (hypnotic-sedative)
* Mebutamate (Capla, Dormate) (anxiolytic, sedative, antihypertensive)
* Phenprobamate (Gamaquil, Isotonil) (muscle relaxant, sedative, anxiolytic, anticonvulsant, anesthesia)
* Procymate (Equipax) (sedative, anxiolytic)
* Styramate (Sinaxamol) (muscle relaxant, anticonvulsant)
* Tetrabamate (febarbamate, difebarbamate, phenobarbital) (Atrium, G Tril, Sevrium) (anxiety, alcohol withdrawal, muscle tremors, agitation, depression)

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

Not approved

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

Gabapentinoids

Gabapentinoids are a unique and relatively novel class of depressants that selectively Binding site, bind to the auxiliary CACNA2D1, α₂δ subunit (CACNA2D1) and (CACNA2D2), site of certain Voltage-dependent calcium channels, VDCCs, and thereby act as Channel blocker, inhibitors of CACNA2D1, α₂δ subunit-containing Voltage-gated calcium channels. α₂δ is nicknamed the "Gabapentin receptor". At physiologic or resting membrane potential, VDCCs are normally Resting potential, closed. They are activated (opened) at Depolarization, depolarized membrane potentials and this is the source of the "Voltage-gated ion channel, voltage-gated" epithet. Gabapentinoids bind to the CACNA2D1, α1 and CACNA2D2, α2 sites of the α₂δ subunit family. Gabapentin is the Prototype, prototypical gabapentinoid. The α₂δ is found on L-type calcium channels, N-type calcium channels, P-type calcium channel, P/Q-type calcium channels, and R-type calcium channels throughout the central and peripheral nervous systems. α₂δ is located on Chemical synapse, presynaptic neurons and affects calcium channel trafficking and kinetics, initiates extracellular Signal transduction, signaling cascades, gene expression and promotes Excitatory postsynaptic potential, excitatory synaptogenesis through thrombospondin 1 . Gabapentinoids are not direct channel blockers, instead they disrupt the regulatory function of α₂δ and its interactions with other proteins. Most of the effects of gabapentinoids are mediated by the Voltage-gated calcium channel, high voltage activated N and P/Q-type calcium channels. P/Q-type calcium channels are mainly found in the cerebellum (Purkinje neurons) which made be responsible for the Ataxia, ataxic adverse effect of gabapentinoids, while N-type calcium channels are located throughout the central and peripheral nervous systems. N-type calcium 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 channels complex. They act on the α₂δ site to lower the release of many Excitatory postsynaptic potential, excitatory and pro-Nociception, nociceptive neurochemicals including Glutamic acid, glutamate, substance P, calcitonin gene-related peptide (CGRP) and more.

Gabapentinoids are absorbed from the intestines mainly by the Large neutral amino acid-transporter 1, 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 acid, Branched-chained amino acids Leucine, L-leucine, and Isoleucine, L-isoleucine, both of which also bind to the α₂δ site. Branched-chain amino acid, Branched-chained amino acids like l-leucine, l-isoleucine, and Valine, l-valine have many functions in the central nervous system. They modify Large neutral amino acids transporter small subunit 1, large neutral amino acid (LNAA) transport at the blood–brain barrier, and reduce the synthesis neurotransmitter of neurotransmitters derived from Aromatic amino acid, aromatic-amino acids notably serotonin from tryptophan, and catecholamines from tyrosine and phenylalanine. This may be relevant to the pharmacology of gabapentinoids.

Gabapentin was designed by researchers at Parke-Davis to be an Structural analog, analogue of the neurotransmitter GABA that could more easily cross the blood–brain barrier and was first described in 1975 by Satzinger and Hartenstein. Gabapentin was first approved for epilepsy, mainly as an add-on treatment to Focal seizure, partial seizures. Gabapentinoids are GABA analogues, but they do not bind to the GABA receptors, do not convert into or another GABA receptor agonist ''in vivo'', and do not directly modulate GABA neurotransmitter transport, transport or metabolism. Phenibut and baclofen, two structurally related compounds are exceptions as they mainly act on the GABA B receptor. Also, gabapentin, but not pregabalin, has been found to activate K_vvoltage-gated potassium channels (KCNQ channels, KCNQ). Despite this, gabapentinoids mimic GABAergic, GABA activity by Inhibitory postsynaptic potential, inhibiting neurotransmission. 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 used for hypertension weakly block CACNA2D1, α₂δ.

Gabapentinoids have anxiolytic, anticonvulsant, Allodynia, antiallodynic, and Nociception, antinociceptive properties. Pregabalin and gabapentin are used in epilepsy, mainly Focal seizure, partial seizures (focal). Gabapentinoids are not effective for Generalized epilepsy, generalized seizures. They are also used for postherpetic neuralgia, neuropathic pain associated with diabetic neuropathy, fibromyalgia, generalized anxiety disorder, and restless legs syndrome. Pregabalin and gabapentin have many Off-label use, off-label uses including insomnia, Alcohol withdrawal syndrome, Alcohol and opioid withdrawal, smoking cessation, social anxiety disorder, bipolar disorder, attention deficit hyperactivity disorder, chronic pain, hot flashes, Tinnitus, tinnutus, migraines and more. Baclofen is primarily used for the treatment of Spasticity, spastic movement disorders, especially in instances of spinal cord injury, cerebral palsy, and multiple sclerosis. Phenibut is used in Russia, Ukraine, Belarus and Latvia to treat anxiety and to improve sleep, as in the treatment of insomnia. It is also used for various other indications, including the treatment of asthenia, Depression (mood), depression, alcoholism, alcohol withdrawal syndrome, post-traumatic stress disorder, stuttering, tics, vestibular disorders, Ménière's disease, dizziness, for the prevention of motion sickness, and for the prevention of anxiety before or after surgical procedures or painful diagnostic tests. Phenibut, like other GABAB receptor, GABA B agonists, is also sometimes used by body builders to increase Growth hormone, human growth hormone.

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

In some cases, gabapentinoids are abused and provide similar effects to alcohol, benzodiazepines and Gamma-Hydroxybutyric acid, gamma-hydroxybutyric acid (GHB). The Food and Drug Administration, FDA placed a Boxed warning, black box warning on Neurontin (gabapentin), and Lyrica (pregabalin), for serious Shortness of breath, breathing problems. Mixing gabapentinoids with opioids, benzodiazepines, barbiturates, Gamma-Hydroxybutyric acid, GHB, alcohol, or any other depressant is potentially Drug overdose, deadly.

Common side effects of gabapentinoids include drowsiness, dizziness, weakness, Polyphagia, increased appetite, urinary retention, shortness of breath, involuntary eye movements ( nystagmus), Amnesia, memory issues, Myoclonus, uncontrollable jerking motions, auditory hallucinations, erectile dysfunction, and Myoclonus, myoclonic seizures.

An overdose of gabapentinoids usually consists of Somnolence, severe drowsiness, Ataxia, severe ataxia, blurred vision, Dysarthria, slurred speech, Myoclonus, severe uncontrollable jerking motions, and anxiety. Like most anticonvulsants, pregabalin and gabapentin have an increased risk of Suicidal ideation, suicidal thoughts and behaviors. Gabapentinoids, like all calcium channel blockers are known to cause angioedema. Taking them with an ACE inhibitor can increase the toxic effects of Gabapentinoids. They may also enhance the Edema, fluid-retaining effect of certain Antidiabetic agent, anti-diabetic agents (thiazolidinediones). It is not known if they cause gingival enlargement like other calcium channel blockers. Gabapentinoids are Excretion, excreted by the kidney mostly in their original form. Gabapentinoids can build up in the body when someone has Kidney failure, renal failure. This usually presents itself as myoclonus, and an Altered state of consciousness, altered mental state. It is unclear if it is safe to use Gabapentinoids during pregnancy with some studies showing Drugs in pregnancy, potential harm.

Physical dependence, Physical or Psychological dependence, physiological dependence does occur during long-term use of gabapentinoids. Following abrupt or Cold turkey, rapid discontinuation of pregabalin and gabapentin people report Drug withdrawal, withdrawal symptoms like insomnia, headache, nausea, diarrhea, Influenza-like illness, flu-like symptoms, anxiety, Major depressive disorder, depression, pain, hyperhidrosis, seizures, psychomotor agitation, confusion, disorientation, and Gastrointestinal tract, gastrointestinal complaints. Acute withdrawal from baclofen and phenibut may also cause auditory and visual hallucinations, and acute psychosis. Baclofen withdrawal can be more intense if it is administered intrathecally or for long periods of time. If Baclofen or Phenibut is used for long periods of time it can resemble intense Benzodiazepine withdrawal syndrome, benzodiazepine, Gamma-Hydroxybutyric acid, GHB or alcohol withdrawal. To minimize Drug withdrawal, withdrawal symptoms Baclofen or Phenibut should be tapered down slowly. Cold turkey, Abrupt withdrawal from Phenibut or Baclofen could be possibly be life-threatening, because of it’s mechanism of action. Abrupt withdrawal can cause Generalized tonic–clonic seizure, rebound seizures and Excited delirium, severe agitation.

* Gabapentin (Neurontin)
* Gabapentin enacarbil, Gabapentin Enacarbil (Horizant, Regnite)
* Gabapentin Extended-Release (Gralise)
* Pregabalin (Lyrica)
* Phenibut (Anvifen, Fenibut, Noofen)
* Baclofen (Lioresal)
* Mirogabalin (Tarlige) (Japan Only)
Not approved:

*Imagabalin
* Tolibut
* 4-Fluorophenibut, 4-Flurophenibut
* HSK16149
* Trans-4 and cis-4-[18F] fluorogabapentin (α2δ Positron emission tomography, PET Imaging)
* 4-Methylpregabalin
* PD-217,014
* Atagabalin
* Arbaclofen placarbil, Arbaclofen
* Saclofen
Endogeny (biology), Endogenous (Not Gabapentinoid, Gabapentinoids, endogenous Branched-chain amino acid, BCAA amino acids that bind to CACNA2D1, α₂δ:

* Calcium

* Isoleucine
* Leucine
* Valine
* Aspartic acid, Aspartate

Other CACNA2D1, α2δ ligands:

* Phenylalanine
* NP-118809
* Gababutin
* Ziconotide (Approved for pain)
* Alcohol (drug), Ethanol
* Dextrothyroxine (Agonist of CACNA2D1, α2δ instead of Inhibitor, inhibiting it)
* Ethionine, Ethioninie
* Suloctidil
* Terodiline
* Bepridil

Opioids

Contrary to popular misconception, opioids are not depressants in the classical sense. They do produce central nervous system depression, however, they also excite certain areas of the central nervous system. To remain true to the term 'depressant' – opioids cannot be classified as such. For opioid agonists and opium derivative (chemistry), derivatives, these are classified differently. Analgesic or narcotic correctly identifies these drugs. However, they do have depressant actions nonetheless.
* Morphine
* Heroin
* Codeine
* Hydrocodone
* Oxycodone
* Methadone

Piperidinediones

Piperidinediones are a class of depressants that are not used anymore. There are Piperidinediones that are used for other purposes like breast cancer]

https://books.google.ca/books?id=tsjrCAAAQBAJ&pg=PA14&redir_esc=y#v=onepage&q&f=fals

. The Piperidinedione class is very structurally similar to barbiturates. Piperidinediones inclide Glutethimide, Methyprylon, Pyrithyldione, Glutarimide, and Aminoglutethimide. The first 3, (Glutethimide, Methyprylon, Pyrithyldione) are Depressants, central nervous depressants. The Piperidinedione depressants, specifcally Glutethimide is a positive modulator of the GABA_A Chloride channel, anion channel. The drug increases inhibitory GABAergic, GABAergic tone and causes Ligand (biochemistry), neuro-inhibition of the Cerebral cortex, cortical and limbic systems, observed clinically as a Sedative, sedative-hypnotic effec

Glutethimide is also a potent inhibitor of the CYP2D6, 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 needs to get Metabolism, metabolized to morphine in the liver to have its Psychoactive drug, psychoactive and analgesic effects. Mixing codeine with the Piperidinedione Glutethimide allowed more codeine to be converted into morphine in the body; this increasing its effect. This was known as "hits", "cibas and codeine", "Dors and 4s". 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.

Glutethimide Drug withdrawal, 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 recurrence of symptoms about 5 days later, including Hyperactivity, overactivity, Psychomotor agitation, restlessness, tremors, hyperreflexia, Hypotonia, hypotonus, vasomotor instability, Crying, incessant crying, and Irritability, general irritability.

Glutethimide withdrawal featured severe agitation, tremor and seizures which could be fatal.

Overdose causes stupor or coma and Hypoventilation, respiratory depression.

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

Quinazolinone

Quinazolinones are a class of depressants that are rarely used anymore. Quinazolinone have powerful sedative, hypnotic, and anxiolytic effects. Quinazolinones structures are very similar to some antibiotics. Quinazolines main mechanism of action is binding to the GABA_A receptor. It does not bind to the Alcohol (drug), ethanol, barbiturate, neurosteroid, or benzodiazepine site. Instead it binds on a site right betwen the GABRB2 (β2) and (α1) GABRA1 proteins on the GABA_A receptor. The anesthetic etomidate and Anticonvulsant loreclezole may also bind to this site.

Drug overdose, Overdose on Quinazolinone sometimes causes effects that are the opposite of Quinazolinone like sedation. Overdose consists of hyperreflexia, vomiting, kidney failure, delirium, hypertonia, coma, Myoclonus, myoclonic twitches, somnolence, euphoria, muscular hyperactivity, Excited delirium, agitated delirium, tachycardia, and Generalized tonic–clonic seizure, tonic-clonic seizures. In 1982 2,764 people visited US emergency rooms from overdosing on Quinazolinones, specifically Methaqualone. Mixing Quinazolines with another depressant is Drug overdose, possibly fatal. Death from a Quinazolinone overdose is usually caused by death through Cardiac arrest, cardiac or respiratory arrest. Overdose resembles barbiturate/carbamate overdose.

Quinazolinones Drug withdrawal, withdrawal occurs when someone has become dependent on a quinazolinone substance and stops using them. Quinazolinone withdrawal resembles Alcohol (drug), ethanol, barbiturate, Benzodiazepine withdrawal syndrome, benzodiazepine and carbamate withdrawal. It usually consists of Psychomotor agitation, restlessness, nausea and vomiting, decreased appetite, tachycardia, insomnia, tremor, hallucinations, delirium, confusion, Generalized tonic–clonic seizure, seizures; which could cause death, Photosensitive epilepsy, EEG photoparoxysmal response, Myoclonus, myoclonic twitches, fever, muscle spasms, and irritability.

Methaqualone, Methaqualone hydrochloride, a Quinazolinone anxiolytic and hypnotic is referred to as "quaaludes" "ludes" and "disco biscuits". Methaqualone was very commonly Substance abuse, 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 carbamate

Methaqualone became highly abused by people and celebrities after it's introduction in 1965. 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. The drug name "Quaalude" (Methaqualone) is a portmanteau, combining the words "quiet interlude". Methaqualone was discontinued in the United States in 1985, mainly due to its Psychological dependence, psychological addictiveness, widespread abuse, and illegal recreational use. Nonbenzodiazepine, Non-benzodiazepines, and benzodiazepines are now uses to treat insomnia instead. Methaqualone is now a schedule I substance. Some quinazolinone analogues are still sold online. They come with risks of seizures.

Large doses of Methaqualone cause euphoria, disinhibition, Human sexuality, increased sexuality, Social behavior, sociability, Muscle contraction, muscle relaxation, Anxiolytic, anxiolysis, and sedation. Today Methaqualone is widely abused in South Africa. Many celebrities have used Quinazolinone; specifically Methaqualone. Bill Cosby admitted to casual sex involving recreational use of Methaqualone (Quaaludes). 18 year old actor Anissa Jones died at 18 from an overdose of cocaine, Phencyclidine, PCP, Methaqualone, and the barbiturate Seconal. Billy Murcia a drummer for the rock band New York Dolls died at 21 when he Drowning, drowned in a bathtub while overdosing on heroin and Methaqualone.

Cloroqualone was a Quinazolinone that binded to the GABA_A and sigma-1 receptor. It had useful cough suppressant effects and weaker sedative effects than Methaqualone. But it was withdrawan due to its potential for abuse and overdose.

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, GABA_a receptor, antagonist activity at all histamine receptors, inhibition of the PTGS1, cyclooxygenase-1 enzyme, and possibly its agonist activity at both the sigma-1 receptor and sigma-2 receptor. Diproqualone is used primarily for the treatment of Inflammation, inflammatory pain associated with osteoarthritis and rheumatoid arthritis, and 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 in addition to 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, and so it is not sold as a pure drug but only as the Camphorsulfonic acid, camphosulfonate salt in combination mixtures with other medicines such as ethenzamide.

Etaqualone is a quinazolinone-class depressant. It has sedative, hypnotic, muscle relaxant and central nervous system depressant properties. It was highly abused, and had high risk for overdose. Users would snort or smoke the free base Etaqualone hydrochloride salt.

Methylmethaqualone is an analogue of Methaqualone with similar hypnotic and sedative effects. Methylmethaqualone differs from methaqualone by 4-methylation on the phenyl ring. It produces convulsions at only slightly above the effective sedative dose. It would appear that this compound was sold on the black market in Germany as a designer drug Analog (chemistry), analogue of methaqualone.

Nitromethaqualone is a quinazolinone depressant with 10x more powerful hypnotic and sedative effects than Methaqualone.

Quinazolinone's:

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

Miscellaneous

* Alpha blocker, Alpha and beta blockers (carvedilol, propranolol, atenolol, etc.)
* Anticholinergics (atropine, hyoscyamine, Hyoscine hydrobromide, scopolamine, etc.)
* Anticonvulsants (topiramate, carbamazepine, lamotrigine, etc.)
* Antihistamines (diphenhydramine, doxylamine, promethazine, etc.)
* Antipsychotics (haloperidol, chlorpromazine, clozapine, etc.)
* Hypnotics (zolpidem, zopiclone, chloral hydrate, eszopiclone, etc.)
* Muscle relaxants (baclofen, phenibut, carisoprodol, cyclobenzaprine, etc.)
* Sedatives (gamma-hydroxybutyrate, etc.)

Methods of intake

Combining multiple depressants can be very dangerous because the central nervous system's depressive properties have been proposed to increase exponentially instead of linearly. 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.

See also

* Central nervous system depression
* Inhalant

References

External links

Painfully Obvious – A Community Resource

Fact sheets and Harm Reduction Strategies About Depressants and Other Recreational Drugs

U.S. Department of Human and Health Services: Drug Categories for Substances of Abuse



* National Institute on Drug Abuse:
NIDA for Teens: Prescription Depressant Medications
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{{Recreational drug use

Psychoactive drugs
Drugs acting on the nervous system
Health effects of alcohol