Significations et usages de Ketamine

Ketamine

Systematic (IUPAC) name
(RS)-2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone
Clinical data
AHFS/Drugs.com	Consumer Drug Information
Pregnancy cat.	B
Legal status	Controlled (S8) (AU) Schedule I (CA) CD (UK) Schedule III (US)
Dependence liability	Medium
Routes	IV, IM, Insufflated, oral, topical
Pharmacokinetic data
Metabolism	Hepatic, primarily by CYP3A4[1]
Half-life	2.5–3 hours.
Excretion	renal (>90%)
Identifiers
CAS number	6740-88-1 Y
ATC code	N01AX03 N01AX14
PubChem	CID 3821
DrugBank	DB01221
ChemSpider	3689 Y
UNII	690G0D6V8H Y
KEGG	D08098 Y
ChEBI	CHEBI:6121 Y
ChEMBL	CHEMBL742 Y
Chemical data
Formula	C13H16ClNO
Mol. mass	237.725 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C13H16ClNO/c1-15-13(9-5-4-8-12(13)16)10-6-2-3-7-11(10)14/h2-3,6-7,15H,4-5,8-9H2,1H3 Y Key:YQEZLKZALYSWHR-UHFFFAOYSA-N Y
Physical data
Melt. point	262 °C (504 °F)
Y (what is this?)  (verify)

Ketamine is a drug used mostly for the care of the eyes in humans and veterinary medicine, but is also used for the treatment of bronchospasms. Its hydrochloride salt is sold as Ketanest, Ketaset, and Ketalar. Pharmacologically, ketamine is classified as an NMDA receptor antagonist.^[2] At high, fully anesthetic level doses, ketamine has also been found to bind to opioid μ receptors type 2 in cultured human neuroblastoma cells – however, without agonist activity^[3] – and to sigma receptors in rats.^[4] Also, ketamine interacts with muscarinic receptors, descending monoaminergic pain pathways and voltage-gated calcium channels.^[5] Like other drugs of this class such as tiletamine and phencyclidine (PCP), it induces a state referred to as "dissociative anesthesia"^[6] and is used as a recreational drug.

Ketamine has a wide range of effects in humans, including analgesia, anesthesia, hallucinations, elevated blood pressure, and bronchodilation.^[7] Ketamine is primarily used for the induction and maintenance of general anesthesia, usually in combination with a sedative. Other uses include sedation in intensive care, analgesia (particularly in emergency medicine), and treatment of bronchospasm. It has been shown to be effective in treating depression in patients with bipolar disorder who have not responded to other anti-depressants.^[8] In persons with major depressive disorder, it produces a rapid antidepressant effect, acting within two hours as opposed to the several weeks taken by typical antidepressants to work.^[9] It is also a popular anesthetic in veterinary medicine.

Ketamine is a chiral compound. Most pharmaceutical preparations of ketamine are racemic; however, some brands reportedly have (mostly undocumented) differences in enantiomeric proportions. The more active enantiomer, (S)-ketamine, is also available for medical use under the brand name Ketanest S.^[10]

Ketamine is a core medicine in the World Health Organization's "Essential Drugs List", a list of minimum medical needs for a basic healthcare system.^[11]

  Medicinal use

Indications for use as an anaesthetic:

• Pediatric anesthesia (as the sole anesthetic for minor procedures or as an induction agent followed by muscle relaxant and endotracheal intubation);
• Asthmatics or patients with chronic obstructive airway disease;
• As part of a cream, gel, or liquid for topical application for nerve pain — the most common mixture is 10% ketoprofen, 5% Lidocaine, and 10% ketamine. Other ingredients found useful by pain specialists and their patients as well as the compounding pharmacists who make the topical mixtures include amitriptyline, cyclobenzaprine, clonidine, tramadol, and mepivicaine and other longer-acting local anaesthetics.
• In emergency medicine if entrapped patient is suffering severe trauma;^[12]
• Emergency surgery in field conditions in war zones;
• To supplement spinal / epidural anesthesia / analgesia utilizing low doses;
• To improve bipolar depression. ^[13]

In medical settings, ketamine is usually injected intravenously or intramuscularly.^[14] Since it suppresses breathing much less than most other available anaesthetics,^[15] ketamine is still used in human medicine as an anesthetic; however, due to the hallucinations which may be caused by ketamine, it is not typically used as a primary anesthetic, although it is the anaesthetic of choice when reliable ventilation equipment is not available. Ketamine tends to increase heart rate and blood pressure. Because ketamine tends to increase or maintain cardiac output, it is sometimes used in anesthesia for emergency surgery when the patient's fluid volume status is unknown (e.g., from traffic accidents). Ketamine can be used in podiatry and other minor surgery, and occasionally for the treatment of migraine. There is ongoing research in France, the Netherlands, Russia, Australia and the US into the drug's usefulness in pain therapy, depression suppression, and for the treatment of alcoholism^[16] and heroin addiction.^[17]

In veterinary anesthesia, ketamine is often used for its anesthetic and analgesic effects on cats, dogs, rabbits, rats, and other small animals. Veterinarians often use ketamine with sedative drugs to produce balanced anesthesia and analgesia, and as a constant rate infusion to help prevent pain wind-up. Ketamine is used to manage pain among large animals, though it has less effect on bovines. It is the primary intravenous anesthetic agent used in equine surgery, often in conjunction with detomidine and thiopental, or sometimes guaifenesin.

Ketamine may be used in small doses (0.1–0.5 mg/kg·h) as a local anesthetic, particularly for the treatment of pain associated with movement and neuropathic pain.^[18] It may also be used as an intravenous co-analgesic together with opiates to manage otherwise intractable pain, particularly if this pain is neuropathic (pain due to vascular insufficiency or shingles are good examples). It has the added benefit of counter-acting spinal sensitization or wind-up phenomena experienced with chronic pain. At these doses, the psychotropic side effects are less apparent and well managed with benzodiazepines.^[19] Ketamine is a co-analgesic, and so is most effective when used alongside a low-dose opioid; while it does have analgesic effects by itself, the higher doses required can cause disorienting side effects.^[19] The combination of ketamine with an opioid is, however, particularly useful for pain caused by cancer.^[20]

The effect of ketamine on the respiratory and circulatory systems is different from that of other anesthetics. When used at anesthetic doses, it will usually stimulate rather than depress the circulatory system.^[21] It is sometimes possible to perform ketamine anesthesia without protective measures to the airways. Ketamine is also a potent analgesic and can be used in sub-anesthetic doses to relieve acute pain; however, its psychotropic properties must be taken into account. Patients have reported vivid hallucinations, "going into other worlds" or "seeing God" while anesthetized, and these unwanted psychological side-effects have reduced the use of ketamine in human medicine. They can, however, usually be avoided by concomitant application of a sedative such as a benzodiazepine.^[19]

Low-dose ketamine is recognized for its potential effectiveness in the treatment of complex regional pain syndrome (CRPS), according to a retrospective review published in the October 2004 issue of Pain Medicine.^[22] Although low-dose ketamine therapy is established as a generally safe procedure, reported side effects in some patients have included hallucinations, dizziness, lightheadedness and nausea. Therefore nurses administering ketamine to patients with CRPS should do so only in a setting where a trained physician is available if needed to assess potential adverse effects on patients.^[23]

In some neurological ICUs, ketamine has been used in cases of prolonged seizures. There has been some evidence that the NMDA-blocking effect of the drug protects neurons from glutamatergic damage during prolonged seizures.^[24]

Postoperative pain

The dissociative anesthetic effects of ketamine have also been applied within the realm of postoperative pain management. Low doses of ketamine have been found to significantly reduce morphine consumption as well as reports of nausea following abdominal surgery.^[25]

  Adverse effects

  Short term

The following adverse effects are reported in 40% of patients dosed with continuous subcutaneous infusion (adverse effects are less common upon oral administration):^[26]

delirium dizziness diplopia blurred vision nystagmus altered hearing hypertension tachycardia hypersalivation nausea and vomiting erythema pain at injection site

psychomimetic phenomenon euphoria aphasia blunted affect psychomotor retardation vivid dreams nightmares impaired attention, memory and judgement illusions hallucinations altered body image

Tonic-clonic movements are also reported at higher anesthetic doses in greater than 10% of patients.^[26]

  Long term

Because ketamine is typically administered as a few repeated doses in a clinical setting, long-term effects are primarily reported and investigated in ketamine abusers.^[27]

  Neurological effects

Chronic use of ketamine may lead to cognitive impairments including memory problems.^[28] In 1989, psychiatry professor John Olney reported that ketamine caused irreversible changes in two small areas of the rat brain, which however has significant differences in metabolism from the human brain and therefore may not occur in humans.^[29][30][31]

The first large-scale, longitudinal study of ketamine users found that heavy ketamine users had impaired memory by several measures, including verbal, short-term memory and visual memory. However, occasional (1-2 times per month) ketamine users and former ketamine users were not found to differ from controls in memory, attention and psychological well-being tests. This suggests that occasional use of ketamine does not lead to prolonged harm and that any damage that might occur may be reversible when ketamine use is stopped; however, depression worsened even in the abstinent user group over the period of the study (one year), along with dissociative symptoms still existing among infrequent users.^[32]

Short-term exposure of cultures of GABAergic neurons to ketamine at high concentrations led to a significant loss of differentiated cells in one study, and non-cell-death-inducing concentrations of ketamine (10 μg/mL) may still initiate long-term alterations of dendritic arbor in differentiated neurons. The same study also demonstrated that chronic (>24 h) administration of ketamine at concentrations as low as 0.01 μg/mL can interfere with the maintenance of dendritic arbor architecture. These results raise the possibility that chronic exposure to low, subanesthetic concentrations of ketamine, while not affecting cell survival, could still impair neuronal morphology and thus might lead to dysfunctions of neural networks.^[33][34]

There is a long list of medicines that could counteract these potential toxic effects^{[dubious – discuss]}, including clonidine, anticholinergics, benzodiazepines, barbiturates and risperidone, which are also highly addictive.^[30][31][35]

  Urinary tract effects

According to a recent systematic review, 110 documented reports of irritative urinary tract symptoms from ketamine dependence exist.^[36] Urinary tract symptoms have been collectively referred as ketamine-induced ulcerative cystitis or ketamine-induced vesicopathy, and they include urge incontinence, decreased bladder compliance, decreased bladder volume, detrusor overactivity, and painful haematuria (blood in urine). Bilateral hydronephrosis and renal papillary necrosis have also been reported in some cases.^[27][36] The pathogenesis of papillary necrosis has been investigated in mice, and it has been suggested that mononuclear inflammatory infiltration in the renal papilla resulting from ketamine dependence is a possible mechanism.^[37]

The time of onset of lower urinary tract symptoms varies depending, in part, on the severity and chronicity of ketamine use; however, it is unclear whether the severity and chronicity of ketamine use corresponds linearly to the presentation of these symptoms. All reported cases where the user consumed greater than 5 grams per day reported symptoms of the lower urinary tract.^[36] Urinary tract symptoms appear to be most common in daily ketamine abusers who have abused the drug for an extended period of time.^[27] These symptoms have presented in only one case of medical use of ketamine. However, following dose reduction, the symptoms remitted.^[27]

Management of these symptoms primarily involves ketamine cessation, for which compliance is low. Other treatments have been used, including antibiotics, NSAIDS, steroids, anticholinergics, and cystodistension.^[36] Both hyaluronic acid instillation and combined pentosan polysulphate and ketamine cessation have been shown to provide relief in some patients, but in the latter case, it is unclear whether relief resulted from ketamine cessation, administration of pentosan polysulphate, or both. Further follow-up is required to fully assess the efficacy of these treatments.^[36]

  Case reports of hepato-toxicity in chronic pain management

In case reports of three patients treated with S(+)ketamine for relief of chronic pain, liver enzyme abnormalities occurred following repeat treatment with ketamine infusions, with the liver enzyme values returning below the upper reference limit of normal range on cessation of the drug. The result suggests that liver enzymes have to be monitored during such treatment.^[38]

  Drug interactions

Ketamine may increase the effects of other sedatives, including but not limited to: benzodiazepines, barbiturates, opiates/opioids, anesthetics, and alcoholic beverages.

  Mechanism of action

Central nervous system

Ketamine is a noncompetitive NMDA receptor (NMDAR) antagonist. More specifically, ketamine binds to the PCP site within the NMDA channel to inhibit calcium influx. The S(+) and R(-) stereoisomers bind with different affinities: K_i = 3200 and 1100 nM, respectively.^[39] NMDAR antagonism effects analgesia by preventing central sensitization in dorsal horn neurons; in other words, ketamine's actions interfere with pain transmission in the spinal cord.^[26] Ketamine also inhibits nitric oxide synthase, inhibiting production of nitric oxide, a neurotransmitter involved in pain perception, and hence further contributing to analgesia.^[40] Ketamine also interacts with sigma and opioid receptors, but with lower affinity and without significantly contributing to analgesia.^[41]

Ketamine also interacts with a host of other receptors to effect analgesia. It blocks voltage-sensitive calcium channels and depresses sodium channels, attenuating hyperalgesia; it alters cholinergic neurotransmission, which is implicated in pain mechanisms; and it acts as a noradrenergic and serotonergic uptake inhibitor, which are involved in descending antinociceptive pathways.^[26][42]

Peripheral systems

Ketamine affects catecholaminergic transmission as noted above, producing measurable changes in peripheral organ systems, including the cardiovascular, gastrointestinal, and respiratory systems:^[40]

• Cardiovascular: Ketamine inhibits reuptake of catecholamines, stimulating the sympathetic nervous system, resulting in cardiovascular symptoms.
• Gastrointestinal: Inhibition of neuronal uptake and increased serotonergic activity are thought to underly nausea and vomiting.
• Respiratory: Induced catecholamine release and stimulation of β₂ adrenergic receptors effects bronchodilation.

  Pharmacokinetics

Ketamine is absorbable via intravenous, intramuscular, oral, and topical routes due to both its water and lipid solubility.^[43] When administered orally, Ketamine undergoes first-pass metabolism, where it is biotransformed in the liver by CYP3A4 (major), CYP2B6 (minor), and CYP2C9 (minor) iso-enzymes into norketamine (through N-demethylation) and finally dehydronorketamine.^[44] Intermediate in the biotransformation of norketamine into dehydronorketamine is the hydroxylation of norketamine into 5-hydroxynorketamine by CYP2B6 and CYP2A6. Dehydronorketamine, followed by norketamine, is the most prevalent metabolite detected in urine.^[45] As the major metabolite of ketamine, norketamine is one-third to one-fifth as potent anesthetically, and plasma levels of this metabolite are three times higher than ketamine following oral administration.^[43][46] Bioavailability through the oral route reaches 17-20%; bioavailability through other routes are as follows: 93% intramuscularly, 25-50% intranasally, 30% sublingually, and 30% rectally.^[26][44] Peak plasma concentrations are reached within 1 minute intravenously, 5–15 minutes intramuscularly, and 30 minutes orally.^[46] Ketamine's duration of action in a clinical setting is 30 minutes to 2 hours intramuscularly and 4–6 hours orally.^[26]

Plasma concentrations of ketamine are increased by diazepam and other CYP3A4 inhibitors.^[26]

  Synthesis

Ketamine is synthesized from 2-chlorobenzonitrile, which reacts with cyclopentylmagnesium bromide to give 1-(2-chlorobenzoyl)cyclopentane.^[47][48] The next step is bromination using bromine to the corresponding bromoketone, which upon reaction with an aqueous solution of methylamine forms the methylimino derivative. During this reaction a simultaneous hydrolysis of the tertiary bromine atom occurs. On further heating the reaction product in decalin, a ring expansion rearrangement occurs, causing formation of ketamine.

  History

Medical use

Ketamine was developed in 1962 as a derivative of phencyclidine (PCP), which was synthesized in 1956, a feat made possible by the discovery of the organic Grignard reaction by Parke-Davis scientist Harold Maddox.^[49] Initially known as CI-581, ketamine was first synthesized by Parke-Davis scientist Calvin Stevens. Pharmacological investigations in human subjects began in 1964.^[49] These investigations demonstrated that ketamine's shorter duration of action and lesser psychomimetic profile made it favorable over PCP as a "dissociative" anesthetic.^[50] Following FDA approval in 1970, ketamine anesthesia was first given to American soldiers during the Vietnam War.

Nonmedical use

Nonmedical use of ketamine was documented in the early 1970s in underground literature (see The Fabulous Furry Freak Brothers). It was used in psychiatric and other academic research through the 1970s, culminating in 1978 with the publishing of psychonaut John Lilly's The Scientist and Marcia Moore and Howard Alltounian's Journeys into the Bright World, which documented the unusual phenomenology of ketamine intoxication.^[51] The incidence of nonmedical ketamine use increased through the end of the century, especially in the context of raves and other parties.^{[52][53][54][55][56]} However, its emergence as a club drug differs from other club drugs (e.g. MDMA) due to its anesthetic properties (e.g., slurred speech, immobilization) at higher doses;^[56] in addition, reports of ketamine being sold as "ecstasy" are common.^[57] The use of ketamine as part of a "post-clubbing experience" has also been documented.^[58] Ketamine's rise in the dance culture was most rapid in Hong Kong by the end of the 1990s.^[56]

  Society and culture

  Legal status

The increase in illicit use prompted ketamine's placement in Schedule III of the United States Controlled Substance Act in August 1999.^[59] In the United Kingdom, it became labeled a Class C drug on 1 January 2006.^[45][60] In Canada ketamine is classified as a Schedule I narcotic, as of August 2005.^[61] In Hong Kong, as of the year 2000, ketamine is regulated under Schedule 1 of Hong Kong Chapter 134 Dangerous Drugs Ordinance. It can only be used legally by health professionals, for university research purposes, or with a physician's prescription.^[62] By 2002, ketamine was classified as schedule III in Taiwan; given the recent rise in prevalence in East Asia, however, rescheduling into schedule I or II is being considered.^[45]

  International brand names

Brand names for ketamine vary internationally:^[63]

Anesject (ID) Brevinaze (ZA) Calypsol (AE, BB, BG, BH, BM, BS, BZ, CY, CZ, EG, GY, HU, IL, IQ, IR, JM, JO, KW, LB, LY, OM, PK, PL, PR, QA, RU, SA, SR, SY, TH, TT, YE) Ivanes (ID) Kanox (MY) Keiran (VE) Ketacor (PH) Ketalar (AE, AR, AT, AU, BB, BE, BH, BM, BR, BS, BZ, CH, CY, DK, EG, ES, FI, FR, GB, GR, GY, HK, HN, ID, IE, IL, IN, IQ, IR, IT, JM, JO, KW, LB, LU, LY, MY, NL, NO, OM, PE, PT, QA, SA, SE, SR, SY, TR, TT, TW, UY, YE, ZA) Ketalin (MX)

Ketamax (PH) Ketamin-S (+) (PY) Ketanest (NL, HR, PL, DE) Ketashort (CO) Ketava (MY) Ketazol (PH) Ketmin (IN) Ketalor (ES) Narkamon (DE, PL Alan Shearer's Breakfast Salt (NWCSTL) paard (BE) Soon-Soon (TW) Tekam (AE, BH, CY, EG, IL, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE) Velonarcon (PL)

  Recreational use

Ketamine sold illicitly comes either from diverted legitimate supplies and semi-legitimate suppliers, or from theft of legitimate suppliers. It produces effects similar to phencyclidine (PCP) and dextromethorphan (DXM).

Unlike the other well-known dissociatives PCP and DXM, ketamine is very short-acting, its hallucinatory effects lasting sixty minutes when insufflated or injected and up to two hours when ingested, the total experience lasting no more than a couple of hours.^[64] At subanesthetic doses, ketamine produces a dissociative state, characterised by a sense of detachment from one's physical body and the external world which is known as depersonalization and derealization.^[65] At sufficiently high doses, users may experience what is called the "K-hole", a state of dissociation whose effects are thought to mimic the phenomenology of schizophrenia.^[66] John C. Lilly,^[67] Marcia Moore^[68] and D. M. Turner^[69] (amongst others) have written extensively about their own entheogenic use of, and psychonautic experiences with, ketamine. (Both Moore^[70] and Turner^[71] died prematurely in a way that has been linked to their ketamine use.)

  Research

Antidepressant use

When treating patients suffering from complex regional pain syndrome (CRPS) with a low-dose (subanesthetic) ketamine infusion, it was observed that some patients made a significant recovery from associated depression. This recovery was not formally documented, as the primary concern was pain management. It was not possible to quantify to what degree depression recovery was secondary to the patient's recovery from CRPS.

One trial administered a short-term ketamine regimen to patients with severe depression, with the dose carefully monitored to prevent hallucinogenic side effects. The patients' normal medications were continued as it was feared that stopping them might result in severe depressive episodes. Before and following each treatment with ketamine, at patient clinic visits, the Beck Depression Inventory (BDI) and the Hamilton Rating Scale for Depression (HAMD-17) were obtained. Two of the patients demonstrated significant, long-term improvement.^[72] Another small study found that ketamine significantly improved treatment-resistant major depression within hours of injection.^[73] The improvement lasted up to one week after the single dose.^[74] These patients were previously treatment resistant, having tried an average of six other treatments that failed. NIMH director Dr. Thomas Insel remarked:

"To my knowledge, this is the first report of any medication or other treatment that results in such a pronounced, rapid, prolonged response with a single dose. These were very treatment-resistant patients."

The researchers apparently attribute the effect to ketamine being an NMDA receptor antagonist.^[75] Those findings of Zarate et al. corroborate earlier findings by Berman et al..^[76] However Zarate et al. do raise some concerns about their results due to a possible lack of blinding, because of the inebriating effects of low dose ketamine infusion, and it is recommended that future studies include an active placebo.

These findings are corroborated by Liebrenz et al., who successfully, according to an attending doctor, treated a patient with a treatment-resistant major depression and a co-occurring alcohol and benzodiazepine dependence by giving an intravenous infusion of 0.5 mg/kg ketamine over a period of 50 minutes and Goforth et al. who helped a patient with severe, recurrent major depressive disorder that demonstrated marked improvement within 8 hours of receiving a preoperative dose of ketamine and one treatment of electroconvulsive therapy with bitemporal electrode placement.^[77][78]

However, a new study in mice by Zarate et al. shows that blocking the NMDA receptor is an intermediate step. According to this study, blocking NMDA increases the activity of another receptor, AMPA, and this boost in AMPA activity is crucial for ketamine’s rapid antidepressant actions. NMDA and AMPA are receptors for the neurotransmitter glutamate. The glutamate system has been implicated in depression recently. This is a departure from previous thinking, which had focused on serotonin and norepinephrine. The glutamate system may represent a new avenue for treatment and research.^[79]

Krystal et al. retrospectively compared the seizure duration, ictal EEG, and cognitive side effects of ketamine and methohexital anesthesia with ECT in 36 patients.^[80] Ketamine was well tolerated and prolonged seizure duration overall, but particularly in those who had a seizure duration shorter than 25 seconds with methohexital at the maximum available stimulus intensity. Ketamine also increased midictal EEG slow-wave amplitude. Thus, a switch to ketamine may be useful when it is difficult to elicit a robust seizure. Faster post-treatment reorientation with ketamine may suggest a lower level of associated cognitive side effects.

Kudoh et al. investigated whether ketamine is suitable for depressed patients who had undergone orthopedic surgery.^[81] Depressed mood, suicidal tendencies, somatic anxiety, and hypochondriasis significantly decreased in the active group as compared with the control. The group receiving ketamine also had significantly lower postoperative pain.

Acute administration of ketamine at the higher dose, but not imipramine, increased BDNF protein levels in the rat hippocampus. The increase of hippocampal BDNF protein levels induced by ketamine might be necessary to produce a rapid onset of antidepressant action in rats.^[82]

Treatment of addiction

The Russian doctor Evgeny Krupitsky (Clinical Director of Research for the Saint Petersburg Regional Center for Research in Addiction and Psychopharmacology) has claimed to have encouraging results by using ketamine as part of a treatment for alcohol addiction which combines psychedelic and aversive techniques.^[83][84] This method involved psychotherapy, controlled ketamine use and group therapy, and resulted in 60 of the 86 alcoholic males selected for the study remaining fully abstinent through one year of treatment. For heroin addiction, the same researcher reached the conclusion that one ketamine-assisted psychotherapy session was significantly more effective than active placebo in promoting abstinence from heroin during one year without any adverse reactions. In a recently published study, 59 detoxified inpatients with heroin dependence received a ketamine-assisted psychotherapy (KPT) session prior to their discharge from an addiction treatment hospital, and were then randomized into two treatment groups.

Participants in the first group received two addiction counseling sessions followed by two KPT sessions (with a single im injection of 2 mg/kg ketamine), with sessions scheduled on a monthly interval (multiple KPT group). Participants in the second group received two addiction counseling sessions on a monthly interval, but no additional ketamine therapy sessions (single KPT group). At one-year follow-up, survival analysis demonstrated a significantly higher rate of abstinence in the multiple KPT group. Thirteen out of 26 subjects (50%) in the multiple KPT group remained abstinent, compared to 6 out of 27 subjects (22.2%) in the single KPT group (p < 0.05). No differences between groups were found in depression, anxiety, craving for heroin, or their understanding of the meaning of their lives. It was concluded that three sessions of ketamine-assisted psychotherapy are more effective than a single session for the treatment of heroin addiction.^[85][86]

Krupitsky and Kolp summarized their work to date in 2007.^[87]

Jovaisa et al. from Lithuania demonstrated attenuation of opiate withdrawal symptoms with ketamine. A total of 58 opiate-dependent patients were enrolled in a randomized, placebo-controlled, double-blind study. Patients underwent rapid opiate antagonist induction under general anesthesia. Prior to opiate antagonist induction patients were given either placebo (normal saline) or subanesthetic ketamine infusion of 0.5 mg/kg·h. Ketamine group presented better control of withdrawal symptoms, which lasted beyond ketamine infusion itself. Significant differences between ketamine and Control groups were noted in anesthetic and early postanesthetic phases. There were no differences in effects on outcome after 4 months.^[17]

Complex regional pain syndrome

Ketamine is being used as an experimental and controversial treatment for Complex Regional Pain Syndrome (CRPS) also known as Reflex Sympathetic Dystrophy (RSD). CRPS/RSD is a severe chronic pain condition characterized by sensory, autonomic, motor and dystrophic signs and symptoms. The pain in CRPS is continuous, it worsens over time, and it is usually disproportionate to the severity and duration of the inciting event. The hypothesis is that ketamine manipulates NMDA receptors which might reboot aberrant brain activity. There are two treatment modalities, the first consist of a low dose ketamine infusion of between 25–90 mg per day, over five days either in hospital or as an outpatient. This is called the awake technique. Open label, prospective, pain journal evaluation of a 10-day infusion of intravenous ketamine (awake technique) in the CRPS patient concluded that "A four-hour ketamine infusion escalated from 40–80 mg over a 10-day period can result in a significant reduction of pain with increased mobility and a tendency to decreased autonomic dysregulation".^[88]

Case notes of 33 patients whose CRPS pain was treated by the inpatient administration of a continuous subanesthetic intravenous infusion of ketamine were reviewed at Mackay Base Hospital, Queensland, Australia. A total of 33 patients with diagnoses of CRPS who had undergone ketamine treatment at least once were identified. Due to relapse, 12 of 33 patients received a second course of therapy, and two of 33 patients received a third. There was complete pain relief in 25 (76%), partial relief in six (18%), and no relief in two (6%) patients.

The degree of relief obtained following repeat therapy (N=12) appeared even better, as all 12 patients who received second courses of treatment experienced complete relief of their CRPS pain. The duration of relief was also impressive, as was the difference between the duration of relief obtained after the first and after the second courses of therapy. In this respect, following the first course of therapy, 54% of 33 individuals remained pain free for 3 months or more and 31% remained pain free for 6 months or more. After the second infusion, 58% of 12 patients experienced relief for a year or more, while almost 33% remained pain free for over 3 years. The most frequent side effect observed in patients receiving this treatment was a feeling of inebriation. Hallucinations occurred in six patients. Less frequent side effects also included complaints of light-headedness, dizziness, and nausea. In four patients, an alteration in hepatic enzyme profile was noted; the infusion was terminated and the abnormality resolved thereafter. No long-term side-effects were noted.^[88] This procedure has only recently been allowed in the United States for the treatment of CRPS.

The second treatment modality consists of putting the patient into a medically-induced coma and given an extremely high dosage of ketamine; typically between 600–900 mg.^[89] This version, currently not allowed in the United States, is most commonly done in Germany but some treatments are now also taking place in Monterrey, Mexico. According to Dr Schwartzman, 14 cases out of 41 patients in the coma induced ketamine experiments were completely cured. "We haven't cured the original injury", he says, "but we have cured the RSD or kept it in remission. The RSD pain is gone." He added that "No one ever cured it before... In 40 years, I have never seen anything like it. These are people who were disabled and in horrible pain. Most were completely incapacitated. They go back to work, back to school, and are doing everything they used to do. Most are on no medications at all. I have taken morphine pumps out of people. You turn off the pain and reset the whole system."^[89]

In Tuebingen, Germany Dr Kiefer treated a patient presented with a rapidly progressing contiguous spread of CRPS from a severe ligamentous wrist injury. Standard pharmacological and interventional therapy successively failed to halt the spread of CRPS from the wrist to the entire right arm. Her pain was unmanageable with all standard therapy. As a last treatment option, the patient was transferred to the intensive care unit and treated on a compassionate care basis with anesthetic doses of ketamine in gradually increasing (3–5 mg/kg·h) doses in conjunction with midazolam over a period of 5 days. On the second day, edema, and discoloration began to resolve and increased spontaneous movement was noted. On day 6, symptoms completely resolved and infusions were tapered. The patient emerged from anesthesia completely free of pain and associated CRPS signs and symptoms. The patient has maintained this complete remission from CRPS for 8 years now. The psychiatric side effects of ketamine were successfully managed with the concomitant use of midazolam and resolved within 1 month of treatment.^[90]

  References

  External links

• The Merck Manual: Ketamine
• Ketamine on RxList
• DEA: Ketamine
• Center for Substance Abuse Research: Ketamine

Recreational drug use Major recreational drugs Opioids Buprenorphine (Subutex · Suboxone) Codeine Dextropropoxyphene (Darvon · Darvocet) Diamorphine (heroin) \ Morphine (Opium) Hydrocodone Hydromorphone (Dilaudid) Methadone Mitragyna speciosa (Kratom) Oxycodone Depressants Barbiturates Benzodiazepines Ethanol (Alcoholic beverages) GHB Kava Nonbenzodiazepines Stimulants Amphetamine Arecoline (Areca) Betel Caffeine (Coffee Tea) Cathinone (Khat) Cocaine (Coca) Ephedrine (Ephedra) Mephedrone Methamphetamine Methylphenidate Nicotine (Tobacco) Theobromine (Cocoa) Entactogens MDA MDMA (Ecstasy) Hallucinogens Psychedelics Bufotenin Psychoactive toads Vilca Yopo DMT (Ayahuasca) LSA LSD-25 Mescaline Peruvian Torch Peyote San Pedro Psilocybin \ Psilocin (Psilocybin mushrooms) Dissociatives DXM Inhalants Nitrous oxide alkyl nitrites – poppers, such as amyl nitrite Ketamine MXE Muscimol (Amanita muscaria) PCP Salvinorin A (Salvia divinorum) Deliriants Atropine and Scopolamine Datura Deadly Nightshade Henbane Mandrake Dimenhydrinate Diphenhydramine Cannabinoids JWH-018 THC (Cannabis Hashish Hash oil) Oneirogens Calea zacatechichi Silene capensis Drug culture Cannabis 420 Cannabis cultivation Cannabis smoking Legal history of cannabis in the United States Legality of cannabis Marijuana Policy Project Medical cannabis NORML Religious and spiritual use of cannabis Stoner film Psychedelic Art Drug Experience Literature Music Other Club drug Counterculture of the 1960s Dance party Drug paraphernalia Drug tourism Entheogen Hippie Party and play Poly drug use Rave Self-medication Sex and drugs Problems with drug use Abuse Dependence Prevention Opioid replacement therapy Rehabilitation Responsible use Drug-related crime Fetal alcohol spectrum disorder Illegal drug trade Long-term effects of cannabis Neurotoxicity Overdose Date-rape drug Passive smoking (of tobacco or other substances) Legality of drug use International 1961 Narcotic Drugs 1971 Psychotropic Substances 1988 Drug Trafficking Cannabis reform at the international level State level Drug policy Decriminalization Prohibition Supply reduction Policy reform Demand reduction Drug Policy Alliance Harm reduction Law Enforcement Against Prohibition Liberalization Students for Sensible Drug Policy Transform Drug Policy Foundation Drug policy by country Australia Canada Germany India Netherlands Portugal Sweden Switzerland Soviet Union United States Just Say No Office of National Drug Control Policy School district drug policies California Colorado Maryland Virginia Other Arguments for and against drug prohibition Capital punishment for drug trafficking Designer drug Drug court Drug possession Drug test Hard and soft drugs Illegal drug trade in Colombia Mexican Drug War Narc Opium production in Afghanistan Politics of drug abuse War on Drugs Zero tolerance Lists of countries by... Alcohol consumption Cannabis legality Annual use Lifetime use Cigarette consumption Cocaine use Opiates use

Depressants Antihistamines H1R inverse agonists First-generation Dimenhydrinate Diphenhydramine Doxylamine Hydroxyzine Promethazine ... Others Amitriptyline Doxepin Mianserin Mirtazapine ... Antipsychotics Mixed MOA Typicals Chlorpromazine Haloperidol ... Atypicals Aripiprazole Clozapine Olanzapine Quetiapine Risperidone Ziprasidone ... Channel blockers Carbamazepine Ethosuximide Gabapentin Lamotrigine Oxcarbazepine Phenytoin Pregabalin Topiramate Zonisamide Dissociatives NMDAR antagonists Arylcyclohexylamines 3-MeO-PCP Dieticyclidine Esketamine Eticyclidine Gacyclidine Ketamine PCPr Phencyclidine Rolicyclidine Tenocyclidine Tiletamine Morphinans Dextromethorphan / Methorphan Dextrorphan / Morphanol Others Dexoxadrol Dizocilpine (MK-801) Etoxadrol Nitrous oxide Selfotel Xenon ... GABAergics Barbiturates Amobarbital Pentobarbital Phenobarbital Secobarbital ... Benzodiazepines Alprazolam Chlordiazepoxide Clonazepam Diazepam Lorazepam ... Carbamates Carisoprodol Felbamate Meprobamate ... GABA analogues 1,4-BD Aceburic acid GABA Gabaculine GABOB GBL GHB GHV GVL Isovaleramide Isovaleric acid Phenibut Picamilon Tiagabine Valerenic acid (Valerian) Valeric acid Valnoctamide Valproic acid (Sodium valproate / Valproate semisodium) Valpromide Vigabatrin Neuroactive steroids Alfaxalone Allopregnanolone Ganaxolone Tetrahydrodeoxycorticosterone ... Nonbenzodiazepines Eszopiclone Zaleplon Zolpidem Zopiclone ... Piperidinediones Glutethimide ... Propylphenols Fospropofol Propofol Thymol Quinazolinones Methaqualone ... Others Baclofen Clomethiazole Diethyl ether Ethanol (Alcohol) Etomidate Gaboxadol Kavalactones (Kava Kava) Muscimol Stiripentol Theanine Glycinergics Alanine Cycloserine Dimethylglycine Glycine Hypotaurine Methylglycine / Sarcosine Serine Taurine Trimethylglycine / Betaine Narcotics MOR agonists Opiates Morphine Opium → Codeine Oripavine Thebaine Opioids Alfentanil Buprenorphine Butorphanol Carfentanil Diacetylmorphine (Heroin) Dihydrocodeine Ethylmorphine Etorphine Fentanyl Hydrocodone Hydromorphone Ketobemidone Levacetylmethadol Levorphanol Meperidine / Pethidine Methadone Nalbuphine Oxycodone Oxymorphone Pentazocine Phenazocine Propoxyphene Remifentanil Sufentanil Tapentadol Tramadol Sympatholytics α/β-AR modulators Alpha blockers Doxazosin Phentolamine Prazosin Tamsulosin Urapidil ... Beta blockers Propranolol ... Others Clonidine ... Miscellaneous Chloroform Cyclobenzaprine Trazodone ...

Hallucinogens Psychedelics 5-HT2AR agonists Lysergamides: AL-LAD ALD-52 BU-LAD CYP-LAD DAM-57 Diallyllysergamide Ergometrine ETH-LAD LAE-32 LSA LSD LSH LPD-824 LSM-775 Lysergic acid 2-butyl amide Lysergic acid 2,4-dimethylazetidide Lysergic acid 3-pentyl amide Methylergometrine Methylisopropyllysergamide Methysergide MLD-41 PARGY-LAD PRO-LAD Phenethylamines: Aleph 2C-B 2C-B-Dragonfly 2C-B-FLY 2C-C-FLY 2C-D-FLY 2C-E-FLY 2C-I-FLY 2CBFly-NBOMe 2C-T-7-FLY 2C-C 2C-C-NBOMe 2C-CN-NBOMe 2C-D 2CD-5EtO 2C-D-NBOMe 2C-E 2C-EF 2C-E-NBOMe 2C-F 2C-F-NBOMe 2C-G 2C-G-NBOMe 2C-H-NBOMe 2C-I 2C-N 2C-N-NBOMe 2C-O 2C-O-4 2C-P 2C-T 2C-T-2 2C-T-4 2C-T-4-NBOMe 2C-T-7 2C-T-7-NBOH 2C-T-8 2C-T-9 2C-T-13 2C-T-15 2C-T-17 2C-T-21 2C-TFM 2C-TFM-NBOMe 2C-YN 2CBCB-NBOMe 25B-NBOMe 25I-NBMD 25I-NBOH 25I-NBOMe 3C-AL 3C-E 3C-P 5-APB 5-APDB 6-APB 6-APDB Br-DFLY DESOXY DMMDA DMMDA-2 DOB DOB-FLY DOM-FLY DOC DOEF DOET DOF DOI DOM DON DOPR DOTFM Escaline Ganesha HOT-2 HOT-7 HOT-17 IAP Isoproscaline Jimscaline Lophophine MDA MDEA MDMA MMA MMDA MMDA-2 MMDA-3a MMDMA Macromerine Mescaline Methallylescaline NBOMe-mescaline Proscaline TCB-2 TFMFly TMA Piperazines: pFPP TMFPP Tryptamines: 1-Methyl-5-methoxy-diisopropyltryptamine 2,N,N-TMT 4,N,N-TMT 4-HO-5-MeO-DMT 4-Acetoxy-DET 4-Acetoxy-DIPT 4-Acetoxy-DMT 4-Acetoxy-DPT 4-Acetoxy-MiPT 4-HO-DPT 4-HO-MET 4-Propionyloxy-DMT 4-HO-MPMI 5-Me-MIPT 5-N,N-TMT 5-AcO-DMT 5-MeO-2,N,N-TMT 5-MeO-4,N,N-TMT 5-MeO-α,N,N-TMT 5-MeO-α-ET 5-MeO-α-MT 5-MeO-DALT 5-MeO-DET 5-MeO-DIPT 5-MeO-DMT 5-MeO-DPT 5-MeO-EiPT 5-MeO-MET 5-MeO-MIPT 5-MeO-MPMI 7,N,N-TMT α,N,N-TMT α-ET α-MT AL-37350A Baeocystin Bufotenin DALT DBT DCPT DET DIPT DMT DPT EiPT Ethocin Ethocybin Iprocin MET Miprocin MIPT Norbaeocystin PiPT Psilocin Psilocybin Others: AL-38022A Elemicin Ibogaine Myristicin Noribogaine Voacangine Dissociatives NMDAR antagonists Adamantanes: Amantadine Memantine Rimantadine Arylcyclohexylamines: 3-MeO-PCP 4-MeO-PCP Dieticyclidine Esketamine Eticyclidine Gacyclidine Ketamine Methoxetamine Methoxyketamine Neramexane Phencyclidine PCPr Rolicyclidine Tenocyclidine Tiletamine Morphinans: Dextrallorphan Dextromethorphan Dextrorphan Racemethorphan Racemorphan Others: 2-MDP 8A-PDHQ Aptiganel Dexoxadrol Dizocilpine Etoxadrol Ibogaine Midafotel NEFA Nitrous oxide Noribogaine Perzinfotel Remacemide Selfotel Xenon Deliriants mAChR antagonists 3-Quinuclidinyl benzilate Atropine BRN-1484501 Benactyzine Benzatropine Benzydamine Biperiden Brompheniramine CAR-226,086 CAR-301,060 CAR-302,196 CAR-302,282 CAR-302,368 CAR-302,537 CAR-302,668 Chlorpheniramine Chloropyramine Clemastine CS-27349 Cyclizine Cyproheptadine Dicyclomine Dimenhydrinate Diphenhydramine Ditran Doxylamine EA-3167 EA-3443 EA-3580 EA-3834 Flavoxate Hydroxyzine Hyoscyamine Meclizine N-Ethyl-3-piperidyl benzilate N-Methyl-3-piperidyl benzilate Pyrilamine Orphenadrine Oxybutynin Pheniramine Phenyltoloxamine Procyclidine Promethazine Scopolamine Tolterodine Trihexyphenidyl Tripelennamine Triprolidine WIN-2299 Miscellaneous Cannabinoids CB1R agonists Cannabinol CP-47,497 CP-55,244 CP-55,940 DMHP HU-210 JWH-018 JWH-030 JWH-073 JWH-081 JWH-200 JWH-250 Nabilone Nabitan Nantradol Parahexyl THC (Dronabinol) WIN-55,212-2 D2R agonists Apomorphine Bromocriptine Cabergoline Lisuride Memantine Pergolide Piribedil Pramipexole Ropinirole Rotigotine * Also indirect D2 agonists such as dopamine reuptake inhibitors (cocaine, methylphenidate), releasing agents (amphetamine, methamphetamine), and precursors (levodopa). GABAAR agonists Eszopiclone Gaboxadol Ibotenic acid Muscimol Zolpidem Zopiclone Inhalants Mixed MOA Aliphatic hydrocarbons Butane Propane Gasoline Kerosene Aromatic hydrocarbons Toluene Ethers Diethyl ether Enflurane Haloalkanes Chloroform Chlorofluorocarbons κOR agonists 2-EMSB 2-MMSB Alazocine Bremazocine Butorphanol Cyclazocine Cyprenorphine Dextrallorphan Dezocine Enadoline Herkinorin HZ-2 Ibogaine Ketazocine LPK-26 Metazocine Nalbuphine Nalorphine Noribogaine Pentazocine Phenazocine Salvinorin A Spiradoline Tifluadom U-50,488 U-69,593 σR agonists Dextrallorphan Dextromethorphan Dextrorphan Noscapine Others Efavirenz Glaucine Isoaminile

Anesthetic: General anesthetics (N01A) Inhalation Ethers Diethyl ether • Methoxypropane • Vinyl ether • halogenated ethers (Desflurane • Enflurane • Isoflurane • Methoxyflurane • Sevoflurane) Haloalkanes Chloroform • Halothane#  • Trichloroethylene Others Cyclopropane • Ethylene • Nitrous oxide#  • Xenon Injection Barbiturates Hexobarbital • Methohexital • Narcobarbital • Thiopental# • Thiotetrabarbital Opioids Alfentanil • Anileridine • Fentanyl • Phenoperidine • Remifentanil • Sufentanil  Neuroactive steroids Alfaxalone • Minaxolone Others Droperidol • Etomidate • Fospropofol • gamma-Hydroxybutyric acid • Ketamine# /Esketamine • Midazolam • Propanidid • Propofol #WHO-EM ‡Withdrawn from market Clinical trials: †Phase III §Never to phase III M: CNS anat(n/s/m/p/4/e/b/d/c/a/f/l/g)/phys/devp noco(m/d/e/h/v/s)/cong/tumr, sysi/epon, injr proc, drug(N1A/2AB/C/3/4/7A/B/C/D)

Analgesics (N02A, N02B) Opioids See also: Opioids template Opium & alkaloids thereof Codeine# Morphine# Opium Laudanum Paregoric Semi-synthetic opium derivatives Acetyldihydrocodeine Benzylmorphine Buprenorphine Desomorphine Dihydrocodeine Dihydromorphine Ethylmorphine Diamorphine Hydrocodone Hydromorphinol Hydromorphone Nicocodeine Nicodicodeine Nicomorphine Oxycodone Oxymorphone Synthetic opioids Alphaprodine Anileridine Butorphanol Dextromoramide Dextropropoxyphene Dezocine Fentanyl Ketobemidone Levorphanol Methadone Meptazinol Nalbuphine Pentazocine Propoxyphene Propiram Pethidine Phenazocine Piminodine Piritramide Tapentadol Tilidine Tramadol Pyrazolones Ampyrone/Aminophenazone Metamizole Phenazone Propyphenazone Cannabinoids Ajulemic acid AM404 Cannabidiol Cannabis Nabilone Nabiximols Tetrahydrocannabinol Anilides Paracetamol (acetaminophen)# Phenacetin Propacetamol Non-steroidal anti-inflammatories See also: NSAIDs template Propionic acid class Fenoprofen Flurbiprofen Ibuprofen# Ketoprofen Naproxen Oxaprozin Oxicam class Meloxicam Piroxicam Acetic acid class Diclofenac Indometacin Ketorolac Nabumetone Sulindac Tolmetin COX-2 inhibitors Celecoxib Rofecoxib Valdecoxib Parecoxib Lumiracoxib Anthranilic acid (fenamate) class Meclofenamate Mefenamic acid Salicylates Aspirin (Acetylsalicylic acid)# Benorylate Diflunisal Ethenzamide Magnesium salicylate Salicin Salicylamide Salsalate Trisalate Wintergreen (Methyl salicylate) Atypical, adjuvant and potentiators, metabolic agents and miscellaneous Amitryptiline Befiradol Bicifadine Carisoprodol Camphor Cimetidine Clonidine Chlorzoxazone Cyclobenzaprine Duloxetine Esreboxetine Flupirtine Gabapentin Glafenine Hydroxyzine Ketamine Menthol Mephenoxalone Methocarbamol Nefopam Orphenadrine Pregabalin Proglumide Scopolamine Tebanicline Trazodone Gabapentin enacarbil Ziconotide #WHO-EM ‡Withdrawn from market Clinical trials: †Phase III §Never to phase III M: CNS anat(n/s/m/p/4/e/b/d/c/a/f/l/g)/phys/devp noco(m/d/e/h/v/s)/cong/tumr, sysi/epon, injr proc, drug(N1A/2AB/C/3/4/7A/B/C/D)

Antidepressants (N06A)   Specific reuptake inhibitors (RIs), enhancers (REs), and releasing agents (RAs) Selective serotonin reuptake inhibitors (SSRIs) Alaproclate Citalopram Escitalopram Femoxetine Fluoxetine# Fluvoxamine Indalpine Ifoxetine Litoxetine Lubazodone Omiloxetine Panuramine Paroxetine Pirandamine Seproxetine Sertraline# Zimelidine‡ Serotonin–norepinephrine reuptake inhibitors (SNRIs) Clovoxamine Desvenlafaxine Duloxetine Levomilnacipran Eclanamine Milnacipran Sibutramine Venlafaxine Serotonin–norepinephrine–dopamine reuptake inhibitors (SNDRIs) Amitifadine Bicifadine Brasofensine BTS-74,398 Cocaine Diclofensine DOV-21,947 DOV-102,677 DOV-216,303 EXP-561 Fezolamine JNJ-7925476 NS-2359 PRC200-SS Pridefine SEP-225,289 SEP-227,162 Tesofensine Norepinephrine reuptake inhibitors (NRIs) Amedalin Atomoxetine/Tomoxetine Binedaline Ciclazindol Daledalin Edivoxetine Esreboxetine Lortalamine Mazindol Nisoxetine Reboxetine Talopram Talsupram Tandamine Viloxazine Dopamine reuptake inhibitors (DRIs) Medifoxamine Vanoxerine Norepinephrine-dopamine reuptake inhibitors (NDRIs) Amineptine Bupropion/Amfebutamone# Cilobamine Manifaxine Methylphenidate Nomifensine Radafaxine Tametraline Norepinephrine-dopamine releasing agents (NDRAs) Amphetamine Befuraline Lisdexamfetamine Methamphetamine Phenethylamine Piberaline Tranylcypromine Serotonin-norepinephrine-dopamine releasing agents (SNDRAs) 4-Methyl-αMT αET/Etryptamine αMT/Metryptamine Selective serotonin reuptake enhancers (SSREs) Tianeptine Others Indeloxazine Teniloxazine Tramadol Viqualine   Receptor antagonists and/or reuptake inhibitors Serotonin antagonists and reuptake inhibitors (SARIs) Etoperidone Nefazodone Trazodone Noradrenergic and specific serotonergic antidepressants (NaSSAs) Aptazapine Esmirtazapine Mianserin Mirtazapine Setiptiline/Teciptiline Norepinephrine-dopamine disinhibitors (NDDIs) Agomelatine Serotonin modulators and stimulators (SMSs) Vortioxetine Others Tedatioxetine Vilazodone   Heterocyclic antidepressants (bi-, tri-, and tetracyclics) Bicyclics Tiazesim Tofenacin Tricyclics Amezepine Amineptine Amitriptyline# Amitriptylinoxide Azepindole Butriptyline Cianopramine Clomipramine Cotriptyline Cyanodothiepin Demexiptiline Depramine/Balipramine Desipramine Dibenzepin Dimetacrine Dosulepin/Dothiepin Doxepin Enprazepine Fluotracen Hepzidine Homopipramol Imipramine Imipraminoxide Intriptyline Iprindole Ketipramine Litracen Lofepramine Losindole Mariptiline Melitracen Metapramine Mezepine Naranol Nitroxazepine Nortriptyline Noxiptiline Octriptyline Opipramol Pipofezine Propizepine Protriptyline Quinupramine Tampramine Tianeptine Tienopramine Trimipramine Tetracyclics Amoxapine Aptazapine Azipramine Ciclazindol Ciclopramine Esmirtazapine Maprotiline Mazindol Mianserin Mirtazapine Oxaprotiline Setiptiline/Teciptiline   Monoamine oxidase inhibitors (MAOIs) Nonselective Irreversible: Benmoxin Carbenzide Cimemoxin Domoxin Echinopsidine Iproclozide Iproniazid Isocarboxazid Mebanazine Metfendrazine Nialamide Octamoxin Phenelzine Pheniprazine Phenoxypropazine Pivalylbenzhydrazine Safrazine Tranylcypromine Reversible: Caroxazone Paraxazone Quercetin MAOA-Selective Irreversible: Clorgiline Reversible: Amiflamine Bazinaprine Befloxatone Befol Berberine Brofaromine Cimoxatone Esuprone Harmala Alkaloids (Harmine Harmaline Tetrahydroharmine Harman Norharman, etc) Methylene Blue Metralindole Minaprine Moclobemide Pirlindole Sercloremine Tetrindole Toloxatone Tyrima MAOB-Selective Irreversible: Ladostigil Mofegiline Pargyline Rasagiline Selegiline Reversible: Lazabemide Milacemide   Azapirones and other 5-HT1A receptor agonists Alnespirone Aripiprazole Befiradol Buspirone Eptapirone Flesinoxan Flibanserin Gepirone Ipsapirone Oxaflozane Tandospirone Vilazodone Zalospirone #WHO-EM ‡Withdrawn from market Clinical trials: †Phase III §Never to phase III M: PSO/PSI mepr dsrd (o, p, m, p, a, d, s), sysi/epon, spvo proc(eval/thrp), drug(N5A/5B/5C/6A/6B/6D)

Neurotoxins Animal toxins Batrachotoxin Bestoxin Birtoxin Bungarotoxin Charybdotoxin Conotoxin Saxitoxin Tetrodotoxin Bacterial toxins Botulinum toxin Tetanospasmin Bacterial toxins Fungal toxins Bicuculline Plant toxins Penitrem A Picrotoxin Pesticides Rotenone Nerve agents Cyclosarin EA-3148 Novichok agent Sarin Soman Tabun (nerve agent) VE (nerve agent) VG (nerve agent) VM (nerve agent) VR (nerve agent) VX (nerve agent) Neurotransmitters and precursors Dopamine Glutamate L-Tyrosine L-Phenylalanine L-DOPA (Levodopa) L-Glutamine Neurotoxic drugs 1,4-BD 5,7-DHT 6-OHDA αET αMT Amphetamine Dizocilpine (MK-801) DSP-4 Ethanol GBL GHB Ibotenic Acid Ketamine Lisdexamfetamine Methamphetamine MBDB MDA MDEA MDMA (Ecstasy) MPP+ MPTP Norsalsolinol PBA PCA PIA Phencyclidine (PCP)

Cholinergics   Receptor ligands mAChR Agonists: 77-LH-28-1 AC-42 AC-260,584 Aceclidine Acetylcholine AF30 AF150(S) AF267B AFDX-384 Alvameline AQRA-741 Arecoline Bethanechol Butyrylcholine Carbachol CDD-0034 CDD-0078 CDD-0097 CDD-0098 CDD-0102 Cevimeline cis-Dioxolane Ethoxysebacylcholine LY-593,039 L-689,660 LY-2,033,298 McNA343 Methacholine Milameline Muscarine NGX-267 Ocvimeline Oxotremorine PD-151,832 Pilocarpine RS86 Sabcomeline SDZ 210-086 Sebacylcholine Suberylcholine Talsaclidine Tazomeline Thiopilocarpine Vedaclidine VU-0029767 VU-0090157 VU-0152099 VU-0152100 VU-0238429 WAY-132,983 Xanomeline YM-796 Antagonists: 3-Quinuclidinyl Benzilate 4-DAMP Aclidinium Bromide Anisodamine Anisodine Atropine Atropine Methonitrate Benactyzine Benzatropine/Benztropine Benzydamine BIBN 99 Biperiden Bornaprine CAR-226,086 CAR-301,060 CAR-302,196 CAR-302,282 CAR-302,368 CAR-302,537 CAR-302,668 CS-27349 Cyclobenzaprine Cyclopentolate Darifenacin DAU-5884 Dimethindene Dexetimide DIBD Dicyclomine/Dicycloverine Ditran EA-3167 EA-3443 EA-3580 EA-3834 Etanautine Etybenzatropine/Ethylbenztropine Flavoxate Himbacine HL-031,120 Ipratropium bromide J-104,129 Hyoscyamine Mamba Toxin 3 Mamba Toxin 7 Mazaticol Mebeverine Methoctramine Metixene N-Ethyl-3-Piperidyl Benzilate N-Methyl-3-Piperidyl Benzilate Orphenadrine Otenzepad Oxybutynin PBID PD-102,807 PD-0298029 Phenglutarimide Phenyltoloxamine Pirenzepine Piroheptine Procyclidine Profenamine RU-47,213 SCH-57,790 SCH-72,788 SCH-217,443 Scopolamine/Hyoscine Solifenacin Telenzepine Tiotropium bromide Tolterodine Trihexyphenidyl Tripitamine Tropatepine Tropicamide WIN-2299 Xanomeline Zamifenacin; Others: 1st Generation Antihistamines (Brompheniramine chlorphenamine cyproheptadine dimenhydrinate diphenhydramine doxylamine mepyramine/pyrilamine phenindamine pheniramine tripelennamine triprolidine, etc) Tricyclic Antidepressants (Amitriptyline doxepin trimipramine, etc) Tetracyclic Antidepressants (Amoxapine maprotiline, etc) Typical Antipsychotics (Chlorpromazine thioridazine, etc) Atypical Antipsychotics (Clozapine olanzapine quetiapine, etc) nAChR Agonists: 5-HIAA A-84,543 A-366,833 A-582,941 A-867,744 ABT-202 ABT-418 ABT-560 ABT-894 Acetylcholine Altinicline Anabasine Anatoxin-a AR-R17779 Butinoline Butyrylcholine Carbachol Cotinine Cytisine Decamethonium Desformylflustrabromine Dianicline Dimethylphenylpiperazinium Epibatidine Epiboxidine Ethanol Ethoxysebacylcholine EVP-4473 EVP-6124 Galantamine GTS-21 Ispronicline Lobeline MEM-63,908/RG-3487 Nicotine NS-1738 PHA-543,613 PHA-709,829 PNU-120,596 PNU-282,987 Pozanicline Rivanicline Sazetidine A Sebacylcholine SIB-1508Y SIB-1553A SSR-180,711 Suberylcholine TC-1698 TC-1734 TC-1827 TC-2216 TC-5214 TC-5619 TC-6683 Tebanicline Tropisetron UB-165 Varenicline WAY-317,538 XY-4083 Antagonists: 18-Methoxycoronaridine α-Bungarotoxin α-Conotoxin Alcuronium Amantadine Anatruxonium Atracurium Bupropion Chandonium Chlorisondamine Cisatracurium Coclaurine Coronaridine Dacuronium Decamethonium Dextromethorphan Dextropropoxyphene Dextrorphan Diadonium DHβE Dimethyltubocurarine/Metocurine Dipyrandium Dizocilpine/MK-801 Doxacurium Duador Esketamine Fazadinium Gallamine Hexafluronium Hexamethonium/Benzohexonium Ibogaine Isoflurane Ketamine Kynurenic acid Laudexium/Laudolissin Levacetylmethadol Malouetine Mecamylamine Memantine Methadone (Levomethadone) Methorphan/Racemethorphan Methyllycaconitine Metocurine Mivacurium Morphanol/Racemorphan Neramexane Nitrous Oxide Pancuronium Pempidine Pentamine Pentolinium Phencyclidine Pipecuronium Radafaxine Rapacuronium Rocuronium Surugatoxin Suxamethonium/Succinylcholine Thiocolchicoside Toxiferine Trimethaphan Tropeinium Tubocurarine Vecuronium Xenon   Reuptake inhibitors Plasmalemmal CHT Inhibitors Hemicholinium-3/Hemicholine Triethylcholine Vesicular VAChT Inhibitors Vesamicol   Enzyme inhibitors Anabolism ChAT inhibitors 1-(-Benzoylethyl)pyridinium 2-(α-Naphthoyl)ethyltrimethylammonium 3-Chloro-4-stillbazole 4-(1-Naphthylvinyl)pyridine Acetylseco hemicholinium-3 Acryloylcholine AF64A B115 BETA CM-54,903 N,N-Dimethylaminoethylacrylate N,N-Dimethylaminoethylchloroacetate Catabolism AChE inhibitors Reversible: Carbamates: Aldicarb Bendiocarb Bufencarb Carbaryl Carbendazim Carbetamide Carbofuran Chlorbufam Chloropropham Ethienocarb Ethiofencarb Fenobucarb Fenoxycarb Formetanate Furadan Ladostigil Methiocarb Methomyl Miotine Oxamyl Phenmedipham Pinmicarb Pirimicarb Propamocarb Propham Propoxur; Stigmines: Ganstigmine Neostigmine Phenserine Physostigmine Pyridostigmine Rivastigmine; Others: Acotiamide Ambenonium Donepezil Edrophonium Galantamine Huperzine A Minaprine Tacrine Zanapezil Irreversible: Organophosphates: Acephate Azinphos-methyl Bensulide Cadusafos Chlorethoxyfos Chlorfenvinphos Chlorpyrifos Chlorpyrifos-Methyl Coumaphos Cyclosarin Demeton Demeton-S-Methyl Diazinon Dichlorvos Dicrotophos Diisopropyl fluorophosphate Diisopropylphosphate Dimethoate Dioxathion Disulfoton EA-3148 Echothiophate Ethion Ethoprop Fenamiphos Fenitrothion Fenthion Fosthiazate GV Isofluorophate Isoxathion Malaoxon Malathion Methamidophos Methidathion Metrifonate Mevinphos Monocrotophos Naled Novichok agent Omethoate Oxydemeton-Methyl Paraoxon Parathion Parathion-Methyl Phorate Phosalone Phosmet Phostebupirim Phoxim Pirimiphos-Methyl Sarin Soman Tabun Temefos Terbufos Tetrachlorvinphos Tribufos Trichlorfon VE VG VM VR VX; Others: Demecarium Onchidal (Onchidella binneyi) BChE inhibitors Cymserine * Many of the acetylcholinesterase inhibitors listed above act as butyrylcholinesterase inhibitors.   Others Precursors Choline (Lecithin) Citicoline Cyprodenate Dimethylethanolamine Glycerophosphocholine Meclofenoxate/Centrophenoxine Phosphatidylcholine Phosphatidylethanolamine Phosphorylcholine Pirisudanol Cofactors Acetic acid Acetylcarnitine Acetyl-coA Vitamin B5 (Pantethine Pantetheine Panthenol) Others Acetylcholine releasing agents: α-Latrotoxin β-Bungarotoxin; Acetylcholine release inhibitors: Botulinum toxin (Botox); Acetylcholinesterase reactivators: Asoxime Obidoxime Pralidoxime

Dopaminergics   Receptor ligands Agonists Adamantanes: Amantadine Memantine Rimantadine; Aminotetralins: 7-OH-DPAT 8-OH-PBZI Rotigotine UH-232; Benzazepines: 6-Br-APB Fenoldopam SKF-38,393 SKF-77,434 SKF-81,297 SKF-82,958 SKF-83,959; Ergolines: Bromocriptine Cabergoline Dihydroergocryptine Epicriptine Lisuride LSD Pergolide; Dihydrexidine derivatives: 2-OH-NPA A-86,929 Ciladopa Dihydrexidine Dinapsoline Dinoxyline Doxanthrine; Others: A-68,930 A-77636 A-412,997 ABT-670 ABT-724 Aplindore Apomorphine Aripiprazole Bifeprunox BP-897 CY-208,243 Dizocilpine Etilevodopa Flibanserin Ketamine Melevodopa Modafinil Pardoprunox Phencyclidine PD-128,907 PD-168,077 PF-219,061 Piribedil Pramipexole Propylnorapomorphine Pukateine Quinagolide Quinelorane Quinpirole RDS-127 Ro10-5824 Ropinirole Rotigotine Roxindole Salvinorin A SKF-89,145 Sumanirole Terguride Umespirone WAY-100,635 Antagonists Typical antipsychotics: Acepromazine Azaperone Benperidol Bromperidol Clopenthixol Chlorpromazine Chlorprothixene Droperidol Flupentixol Fluphenazine Fluspirilene Haloperidol Loxapine Mesoridazine Methotrimeprazine Nemonapride Penfluridol Perazine Periciazine Perphenazine Pimozide Prochlorperazine Promazine Sulforidazine Sulpiride Sultopride Thioridazine Thiothixene Trifluoperazine Triflupromazine Trifluperidol Zuclopenthixol; Atypical antipsychotics: Amisulpride Asenapine Blonanserin Cariprazine Carpipramine Clocapramine Clorotepine Clozapine Gevotroline Iloperidone Lurasidone Melperone Molindone Mosapramine Olanzapine Paliperidone Perospirone Piquindone Quetiapine Remoxipride Risperidone Sertindole Tiospirone Ziprasidone Zotepine; Antiemetics: AS-8112 Alizapride Bromopride Clebopride Domperidone Metoclopramide Thiethylperazine; Others: Amoxapine Buspirone Butaclamol Ecopipam EEDQ Eticlopride Fananserin L-745,870 Nafadotride Nuciferine PNU-99,194 Raclopride Sarizotan SB-277,011-A SCH-23,390 SKF-83,959 Sonepiprazole Spiperone Spiroxatrine Stepholidine Tetrahydropalmatine Tiapride UH-232 Yohimbine   Reuptake inhibitors Plasmalemmal DAT inhibitors Piperazines: DBL-583 GBR-12,935 Nefazodone Vanoxerine; Piperidines: BTCP Desoxypipradrol Dextromethylphenidate Difemetorex Ethylphenidate Methylnaphthidate Methylphenidate Phencyclidine Pipradrol; Pyrrolidines: Diphenylprolinol MDPV Naphyrone Prolintane Pyrovalerone; Tropanes: Altropane Brasofensine CFT Cocaine Dichloropane Difluoropine FE-β-CPPIT FP-β-CPPIT Ioflupane (123I) Iometopane RTI-112 RTI-113 RTI-121 RTI-126 RTI-150 RTI-177 RTI-229 RTI-336 Tenocyclidine Tesofensine Troparil Tropoxane WF-11 WF-23 WF-31 WF-33; Others: Adrafinil Armodafinil Amfonelic acid Amineptine Benzatropine Bromantane BTQ BTS-74,398 Bupropion Ciclazindol Diclofensine Dimethocaine Diphenylpyraline Dizocilpine DOV-102,677 DOV-21,947 DOV-216,303 Etybenzatropine EXP-561 Fencamine Fencamfamine Fezolamine GYKI-52,895 Indatraline Ketamine Lefetamine Levophacetoperane LR-5182 Manifaxine Mazindol Medifoxamine Mesocarb Modafinil Nefopam Nomifensine NS-2359 O-2172 Pridefrine Propylamphetamine Radafaxine SEP-225,289 SEP-227,162 Sertraline Sibutramine Tametraline Tedatioxetine Tripelennamine Vesicular VMAT inhibitors Deserpidine Ibogaine Reserpine Tetrabenazine   Releasing agents Morpholines: Fenbutrazate Fenmetramide Morazone Phendimetrazine Phenmetrazine Pseudophenmetrazine; Oxazolines: 4-MAR Aminorex Clominorex Cyclazodone Fenozolone Fluminorex Pemoline Thozalinone; Phenethylamines (also amphetamines, cathinones, etc): 2-OH-PEA 4-CAB 4-FA 4-FMA 4-MA 4-MMA Alfetamine Amfecloral Amfepentorex Amfepramone Amphetamine (Dextroamphetamine Levoamphetamine) Amphetaminil β-Me-PEA BDB BOH Benzphetamine Buphedrone Butylone Cathine Cathinone Clobenzorex Clortermine D-Deprenyl DMA DMMA Dimethylamphetamine Dimethylcathinone Ethcathinone Ethylamphetamine EBDB Ethylone Famprofazone Fenethylline Fenproporex Flephedrone Fludorex Furfenorex Hordenine Hydroxyamphetamine Iofetamine Lophophine Mefenorex Mephedrone Methamphetamine (Dextromethamphetamine, Levomethamphetamine) Methcathinone Methedrone MMDA MMDMA MBDB MDA MDEA MDMA MDMPEA MDOH MDPEA Methylone Ortetamine pBA pCA pIA Pholedrine Phenethylamine Pholedrine Phenpromethamine Prenylamine Propylamphetamine Tiflorex Tyramine Xylopropamine Zylofuramine; Piperazines: 2C-B-BZP BZP MBZP MDBZP MeOPP; Others: 2-ADN 2-AI 2-AT 4-BP 5-IAI Clofenciclan Cyclopentamine Cypenamine Cyprodenate Feprosidnine Gilutensin Heptaminol Hexacyclonate IAP Indanorex Isometheptene Methylhexanamine Naphthylisopropylamine Octodrine Phthalimidopropiophenone Propylhexedrine (Levopropylhexedrine) Tuaminoheptane   Allosteric modulators Quinazolinamines: SoRI-9804 SoRI-20040 SoRI-20041   Enzyme inhibitors Anabolism PAH inhibitors 3,4-Dihydroxystyrene TH inhibitors 3-Iodotyrosine Aquayamycin Bulbocapnine Metirosine Oudenone AAAD/DDC inhibitors Benserazide Carbidopa DFMD Genistein Methyldopa Catabolism MAO inhibitors Nonselective: Benmoxin Caroxazone Echinopsidine Furazolidone Hydralazine Indantadol Iproclozide Iproniazid Isocarboxazid Isoniazid Linezolid Mebanazine Metfendrazine Nialamide Octamoxin Paraxazone Phenelzine Pheniprazine Phenoxypropazine Pivalylbenzhydrazine Procarbazine Safrazine Tranylcypromine; MAO-A selective: Amiflamine Bazinaprine Befloxatone Befol Brofaromine Cimoxatone Clorgiline Esuprone Harmala alkaloids Methylene Blue Metralindole Minaprine Moclobemide Pirlindole Sercloremine Tetrindole Toloxatone Tyrima; MAO-B selective: D-Deprenyl L-Deprenyl (Selegiline) Ladostigil Lazabemide Milacemide Pargyline Rasagiline Safinamide COMT inhibitors Entacapone Nitecapone Tolcapone DBH inhibitors Disulfiram Dopastin Fusaric acid Nepicastat Tropolone   Others Precursors L-Phenylalanine → L-Tyrosine → L-DOPA (Levodopa) Cofactors Ferrous iron (Fe2+) Tetrahydrobiopterin Vitamin B3 (Niacin Nicotinamide → NADPH) Vitamin B6 (Pyridoxine Pyridoxamine Pyridoxal → Pyridoxal phosphate) Vitamin B9 (Folic acid → Tetrahydrofolic acid) Vitamin C (Ascorbic acid) Zinc (Zn2+) Others Activity enhancers: BPAP PPAP; Toxins: 6-OHDA List of dopaminergic drugs

Glutamatergics Ionotropic AMPA Agonists: 5-Fluorowillardiine AMPA Domoic acid Quisqualic acid; Positive allosteric modulators: Aniracetam Cyclothiazide CX-516 CX-546 CX-614 CX-691 CX-717 Diazoxide HCTZ IDRA-21 LY-392,098 LY-404,187 LY-451,395 LY-451,646 LY-503,430 Org 26576 Oxiracetam PEPA Piracetam Pramiracetam S-18986 Sunifiram Unifiram Antagonists: ATPO Barbiturates BGG492 Caroverine CNQX DNQX GYKI-52466 NBQX Perampanel Talampanel Tezampanel Topiramate; Negative allosteric modulators: GYKI-53,655 NMDA Agonists: Glutamate/acite site competitive agonists: Aspartate Glutamate Homoquinolinic acid Ibotenic acid NMDA Quinolinic acid Tetrazolylglycine; Glycine site agonists: ACBD ACPC ACPD Alanine CCG Cycloserine DHPG Fluoroalanine Glycine HA-966 L-687,414 Milacemide Sarcosine Serine Tetrazolylglycine; Polyamine site agonists: Acamprosate Spermidine Spermine Antagonists: Competitive antagonists: AP5 (APV) AP7 CGP-37849 CGP-39551 CGP-39653 CGP-40116 CGS-19755 CPP LY-233,053 LY-235,959 LY-274,614 MDL-100,453 Midafotel (d-CPPene) NPC-12,626 NPC-17,742 PBPD PEAQX Perzinfotel PPDA SDZ-220581 Selfotel; Noncompetitive antagonists: ARR-15,896 Caroverine Dexanabinol FPL-12495 FR-115,427 Hodgkinsine Magnesium MDL-27,266 NPS-1506 Psychotridine Zinc; Uncompetitive pore blockers: 2-MDP 3-MeO-PCP 8A-PDHQ Alaproclate Amantadine Aptiganel ARL-12,495 ARL-15,896-AR ARL-16,247 Budipine Delucemine Dexoxadrol Dextrallorphan Dieticyclidine Dizocilpine Endopsychosin Esketamine Etoxadrol Eticyclidine Gacyclidine Ibogaine Indantadol Ketamine Ketobemidone Loperamide Memantine Meperidine (Pethidine) Methadone (Levomethadone) Methorphan (Dextromethorphan Levomethorphan) Methoxetamine Milnacipran Morphanol (Dextrorphan Levorphanol) NEFA Neramexane Nitrous oxide Noribogaine Orphenadrine PCPr Phencyclamine Phencyclidine Propoxyphene Remacemide Rhynchophylline Riluzole Rimantadine Rolicyclidine Sabeluzole Tenocyclidine Tiletamine Tramadol Xenon; Glycine site antagonists: ACEA-1021 ACEA-1328 ACPC Carisoprodol CGP-39653 CKA DCKA Felbamate Gavestinel GV-196,771 Kynurenic acid L-689,560 L-701,324 Lacosamide Licostinel LU-73,068 MDL-105,519 Meprobamate MRZ 2/576 PNQX ZD-9379; NR2B subunit antagonists: Besonprodil CO-101,244 (PD-174,494) CP-101,606 Eliprodil Haloperidol Ifenprodil Isoxsuprine Nylidrin Ro8-4304 Ro25-6981 Traxoprodil; Polyamine site antagonists: Arcaine Co 101676 Diaminopropane Acamprosate Diethylenetriamine Huperzine A Putrescine Ro 25-6981; Unclassified/unsorted antagonists: Chloroform Diethyl ether Enflurane Ethanol (Alcohol) Halothane Isoflurane Methoxyflurane Toluene Trichloroethane Trichloroethanol Trichloroethylene Xylene Kainate Agonists: 5-Iodowillardiine ATPA Domoic acid Kainic acid LY-339,434 SYM-2081 Antagonists: BGG492 CNQX DNQX LY-382,884 NBQX NS102 Tezampanel Topiramate UBP-302; Negative allosteric modulators: NS-3763 Metabotropic Group I Agonists: Non-selective: ACPD DHPG Quisqualic acid; mGlu1-selective: Ro01-6128 Ro67-4853 Ro67-7476 VU-71; mGlu5-selective: ADX-47273 CDPPB CHPG DFB VU-1545 Antagonists: Non-selective: MCPG NPS-2390; mGlu1-selective: BAY 36-7620 CPCCOEt LY-367,385 LY-456,236; mGlu5-selective: CTEP Dipraglurant DMeOB LY-344,545 SIB-1757 SIB-1893; Negative allosteric modulators: Fenobam MPEP MTEP GRN-529 Group II Agonists: Non-selective: CBiPES DCG-IV Eglumegad LY-379,268 LY-404,039 LY-487,379 MGS-0028; mGlu2-selective: BINA LY-566,332 Antagonists: Non-selective: APICA EGLU HYDIA LY-307,452 LY-341,495 MCPG MGS-0039: mGlu2-selective: PCCG-4; mGlu3-selective: CECXG; Negative allosteric modulators: RO4491533 Group III Agonists: Non-selective: L-AP4; mGlu4-selective: PHCCC VU-001,171 VU-0155,041; mGlu7-selective: AMN082; mGlu8-selective: DCPG Antagonists: Non-selective: CPPG MAP4 MSOP MPPG MTPG UBP-1112; mGlu7-selective: MMPIP Transporter inhibitors EAATs DHKA PDC WAY-213,613 vGluTs 7-CKA Evans blue Others Precursors L-Glutamine Cofactors α-Ketoglutaric acid Iron Sulfur Vitamin B2 (as FAD and FMN) Vitamin B3 (as NADPH) Others L-Theanine