Metoclopramide

Key Terms: Antiemetic, Dyskinesia.

Definition

Metoclopramide (Reglan, Octamide, Maxeran) is a drug used to prevent the nausea and vomiting caused by cancer chemotherapy, diabetic neuropathy, gastroesophageal reflux, and similar conditions. It has also been approved by the Food and Drug Administration (FDA) to treat the small bowel prior to intubation. Metoclopramide is one of the drugs most frequently used in palliative care for cancer patients.

Purpose

Nausea and vomiting are among the most common side effects of cancer chemotherapy. They are also among the most unpleasant and upsetting side effects for patients. If left untreated, persistent nausea and vomiting can lead to dehydration, dental decay, digestive abnormalities, and nutritional deficiencies. In addition, persistent vomiting may force some patients to stop taking their chemotherapy and risk a recurrence of their cancer. It is therefore very important that these symptoms be adequately treated.

The nausea and vomiting that occurs with chemotherapy is often divided into three types: anticipatory, acute, and delayed. Anticipatory nausea and vomiting usually occurs before or during chemotherapy. These symptoms are thought to be caused by anxiety, and often occur in patients who have been previously treated with very toxic chemotherapy. Acute nausea and vomiting occurs within a few minutes to several hours after drug administration and usually stops within 24 hours. Delayed nausea and vomiting occurs several hours after chemotherapy, and can last several days.

Description

For the majority of patients, nausea and vomiting can be successfully treated with antiemetic medication. Metoclopramide is one of the most widely used and effective antiemetics for treating the delayed nausea and vomiting caused by chemotherapy. It has been used since the 1980s, and works in two ways. It affects a part of the brain known to trigger vomiting, and also affects the speed of intestinal motion. As a result, the stomach empties into the intestines more quickly, and the contents of the intestines move more quickly in the correct direction.

Metoclopramide is most often used in patients taking cisplatin (Platinol) chemotherapy. Cisplatin is used to treat a wide range of cancers including bladder cancer, ovarian cancer and non-small cell lung cancer. Compared with other cancer chemotherapy, cisplatin is often considered to cause the most severe nausea and vomiting. For 60% to 70% of patients taking cisplatin, however, metoclopramide provides adequate control of nausea and vomiting.

Recommended Dosage

Although metoclopramide can be taken either orally or intravenously, cancer patients on chemotherapy usually receive the drug intravenously. Metoclopramide is usually given 30 minutes before chemotherapy, and then two more times after chemotherapy at two hour intervals.

The recommended dose varies from patient to patient, and depends on both the severity of nausea and vomiting, and on the toxicity of the drug. A higher dose will be given to patients with severe symptoms. Higher doses will also be given to patients receiving drugs such as cisplatin that are known to cause severe nausea and vomiting. Some patients receiving cisplatin may be given a combination of three different drugs to help combat their nausea: metoclopramide, dexamethasone (Dexone), and lorazepam (Ativan). The three work on different areas of the body and produce a greater effect together than they do when given separately.

Precautions

Metoclopramide can cause sleepiness and lack of concentration. Patients should avoid tasks that require mental alertness such as driving or operating machinery. Patients should also be aware that metoclopramide may enhance their response to alcohol and drugs that depress the central nervous system. Because metoclopramide can cause depression, patients with a history of serious clinical depression should take this drug only if absolutely necessary.

Metoclopramide can make the symptoms of Parkinson's disease worse, and patients with a history of seizures should not take metoclopramide, because the frequency and severity of the seizures may increase. The drug should also not be used in patients with intestinal problems such as bleeding, tears, or blockages. The safety of metoclopramide for pregnant women or children is unknown. The drug is found in the breast milk of lactating mothers.

Side Effects

The most frequent side effects of metoclopramide are restlessness, drowsiness, and fatigue. These occur in about 10% of patients. Less common side effects include insomnia, headache, and dizziness. These occur in only 5% of patients. Feelings of anxiety or agitation may also occur, especially after a rapid intravenous injection of the drug. Some women may experience menstrual irregularities.

Metaclopramide therapy can cause some patients to make abnormal involuntary movements, a condition known as dyskinesia. These reactions are most common in young adults of 18–30 years of age, and often disappear about a day after the patient stops taking the drug. Among geriatric patients, particularly women, dyskinesia sometimes develops when patients stop taking metoclopramide after long term treatment.

Interactions

Patients who are also taking cabergoline (Dostinex), a drug used to treat hormonal problems and Parkinson's disease, should not take metoclopramide. Because metoclopramide affects the functioning of the intestines, it can interfere with the absorption of certain drugs. The effect of digoxin (Lanoxin), for example, may be reduced, whereas the effects of other drugs like aspirin, cyclosporine (Neoral, Sandimmune, SangCya) and tetracycline (Minocin, Vibramycin) may be enhanced.

Resources

Books

Karch, A. M. Lippincott's Nursing Drug Guide. Springhouse, PA: Lippincott Williams & Wilkins, 2003.

Periodicals

Duby, J. J., R. K. Campbell, S. M. Setter, et al. "Diabetic Neuropathy: An Intensive Review." American Journal of Health-System Pharmacy 61 (January 15, 2004): 160–173.

Nauck, F., C. Ostgathe, E. Klaschik, et al. "Drugs in Palliative Care: Results from a Representative Survey in Germany." Palliative Medicine 18 (March 2004): 100–107.

Steely, R. L., D. R. Collins Jr., B. E. Cohen, and K. Bass. "Postoperative Nausea and Vomiting in the Plastic Surgery Patient." Aesthetic Plastic Surgery 28 (January-February 2004): 29–32.

Organizations

American Society of Health-System Pharmacists (ASHP). 7272 Wisconsin Avenue, Bethesda, MD 20814. (301) 657-3000. .

United States Food and Drug Administration (FDA). 5600 Fishers Lane, Rockville, MD 20857-0001. (888) INFO-FDA. .

—Alison McTavish, M.Sc.; Rebecca J. Frey, Ph.D.

Brand names: Octamide®Reglan®

Chemical formula:

Drug Forms:
• Metoclopramide Hydrochloride Solution for injection (below)
• Metoclopramide Hydrochloride Oral tablet
• Metoclopramide Hydrochloride Oral solution
• Metoclopramide oral solution
• Metoclopramide injection
• Metoclopramide Hydrochloride Oral disintegrating tablet

Español:
• Clorhidrato de metoclopramida, Solución para inyección
• Clorhidrato de Metoclopramida, Tableta oral
• Clorhidrato de Metoclopramida, Solución oral
• Solución oral de metoclopramida
• Inyección de metoclopramida
• Clorhidrato de Metoclopramida, Tableta oral que se desintegra por vía oral

Metoclopramide Hydrochloride Solution for injection

What is this medicine?

METOCLOPRAMIDE (met oh kloe PRA mide) is used to treat people with slow emptying of the stomach and intestinal tract. It may be used to prevent nausea and vomiting caused by cancer treatment or surgery. This medicine may also be used before certain stomach exams or procedures.
 
This medicine may be used for other purposes; ask your health care provider or pharmacist if you have questions.

What should I tell my health care provider before I take this medicine?

They need to know if you have any of these conditions:
•breast cancer
•depression
•diabetes
•heart failure
•high blood pressure
•kidney disease
•liver disease
•Parkinson's disease or a movement disorder
•pheochromocytoma
•seizures
•stomach obstruction, bleeding, or perforation
•an unusual or allergic reaction to metoclopramide, procainamide, sulfites, other medicines, foods, dyes, or preservatives
•pregnant or trying to get pregnant
•breast-feeding

How should I use this medicine?

This medicine is for injection into a muscle or for infusion into a vein. It is given by a health care professional in a hospital or clinic setting.
 
A special MedGuide will be given to you by the pharmacist with each prescription and refill. Be sure to read this information carefully each time.
 
Talk to your pediatrician regarding the use of this medicine in children. Special care may be needed.
 
Overdosage: If you think you have taken too much of this medicine contact a poison control center or emergency room at once.
NOTE: This medicine is only for you. Do not share this medicine with others.

What may interact with this medicine?

•acetaminophen
•cyclosporine
•digoxin
•medicines for blood pressure
•medicines for depression, especially an Monoamine Oxidase Inhibitor (MAOI)
•medicines for diabetes, including insulin
•medicines for hay fever and other allergies
•medicines for Parkinson's disease, like levodopa
•medicines for sleep or for pain
•tetracycline
 
This list may not describe all possible interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.

What should I watch for while using this medicine?

It may take a few weeks for your stomach condition to get better. However, do not take this medicine for longer than 12 weeks. The longer you take this medicine, and the more you take it, the greater your chances are of developing serious side effects. If you are an elderly patient, a female patient, or you have diabetes, you may be at an increased risk for side effects from this medicine. Contact your doctor immediately if you start having movements you cannot control such as lip smacking, rapid movements of the tongue, involuntary or uncontrollable movements of the eyes, head, arms and legs, or muscle twitches and spasms.
 
Patients and their families should watch out for worsening depression or thoughts of suicide. Also watch out for any sudden or severe changes in feelings such as feeling anxious, agitated, panicky, irritable, hostile, aggressive, impulsive, severely restless, overly excited and hyperactive, or not being able to sleep. If this happens, especially at the beginning of treatment or after a change in dose, call your doctor.
 
Do not treat yourself for high fever. Ask your doctor or health care professional for advice.
 
You may get drowsy or dizzy. Do not drive, use machinery, or do anything that needs mental alertness until you know how this drug affects you. Do not stand or sit up quickly, especially if you are an older patient. This reduces the risk of dizzy or fainting spells. Alcohol can make you more drowsy and dizzy. Avoid alcoholic drinks.

What side effects may I notice from receiving this medicine?

Side effects that you should report to your doctor or health care professional as soon as possible:
•allergic reactions like skin rash, itching or hives, swelling of the face, lips, or tongue
•abnormal production of milk in females
•breast enlargement in both males and females
•change in the way you walk
•difficulty moving, speaking or swallowing
•drooling, lip smacking, or rapid movements of the tongue
•excessive sweating
•fever
•involuntary or uncontrollable movements of the eyes, head, arms and legs
•irregular heartbeat or palpitations
•muscle twitches and spasms
•unusually weak or tired
 
Side effects that usually do not require medical attention (report to your doctor or health care professional if they continue or are bothersome):
•change in sex drive or performance
•depressed mood
•diarrhea
•difficulty sleeping
•headache
•menstrual changes
•restless or nervous
 
This list may not describe all possible side effects. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Where should I keep my medicine?

This drug is given in a hospital or clinic and will not be stored at home.

Last updated: 7/1/2002

Important Disclaimer: The drug information provided here is for educational purposes only. It is intended to supplement, not substitute for, the diagnosis, treatment and advice of a medical professional. This drug information does not cover all possible uses, precautions, side effects and interactions. It should not be construed to indicate that this or any drug is safe for you. Consult your medical professional for guidance before using any prescription or over the counter drugs.

A dopamine antagonist that stimulates motility of the upper gastrointestinal tract, relaxes the pyloric sphincter, and promotes gastric emptying. Used as an antiemetic.

Metoclopramide
Systematic (IUPAC) name
4-amino-5-chloro-N-(2-(diethylamino)ethyl)- 2-methoxybenzamide
Identifiers
CAS number	364-62-5
ATC code	A03FA01
PubChem	4168
DrugBank	APRD00665
ChemSpider	4024
Chemical data
Formula	C14H22ClN3O2
Mol. mass	299.80 g/mol
Pharmacokinetic data
Bioavailability	80±15% (oral)
Metabolism	Hepatic
Half life	5–6 hours
Excretion	70–85% renal, 2% faecal
Therapeutic considerations
Pregnancy cat.	A (Au), B (U.S.)
Legal status	S3/S4 (Au), POM (UK), ℞-only (U.S.)
Routes	Oral, IV, IM
Y(what is this?)  (verify)

Metoclopramide (INN) (pronounced /ˌmɛtəˈklɒprəmaɪd/) is an antiemetic and gastroprokinetic agent. Thus it is primarily used to treat nausea and vomiting, and to facilitate gastric emptying in patients with gastroparesis.

It is available under various trade names including Maxolon (Shire/Valeant), Reglan (Schwarz Pharma), Degan (Lek), Maxeran (Sanofi Aventis), Primperan (Sanofi Aventis), and Pylomid (Bosnalijek). It was protected under U.S. patent (3177252) until 6 April 1982.

Contents 1 Mode of action 2 Clinical use 2.1 Antiemetic use 2.2 Prokinetic use 2.3 Other indications 3 Contraindications and precautions 3.1 Use in pregnancy 4 Adverse effects 5 Veterinary use 6 See also 7 References 8 Further reading

Mode of action

Metoclopramide was first described by Dr.Louis Justin-Besançon and C. Laville in 1964.^[1] It appears to bind to dopamine D₂ receptors where it is a receptor antagonist, and is also a mixed 5-HT₃ receptor antagonist/5-HT₄ receptor agonist.

The anti-emetic action of metoclopramide is due to its antagonist activity at D₂ receptors in the chemoreceptor trigger zone (CTZ) in the central nervous system (CNS)—this action prevents nausea and vomiting triggered by most stimuli.^[2] At higher doses, 5-HT₃ antagonist activity may also contribute to the anti-emetic effect.

The prokinetic activity of metoclopramide is mediated by muscarinic activity, D₂ receptor antagonist activity and 5-HT₄ receptor agonist activity.^[3][4] The prokinetic effect itself may also contribute to the anti-emetic effect.

Clinical use

Antiemetic use

Metoclopramide 5mg tablets (Pliva).

Metoclopramide is commonly used to treat nausea and vomiting (emesis) associated with conditions including: emetogenic drugs, uraemia, radiation sickness, malignancy, labor, and infection.^[5][6] It is also used by itself or in combination with paracetamol (acetaminophen) (paracetamol/metoclopramide available in the UK as Paramax, and Australia as Metomax) or aspirin (MigraMax) for the relief of migraine.

It is considered ineffective in postoperative nausea and vomiting (PONV) at standard doses, and ineffective for motion sickness.^[5][6] In nausea and vomiting associated with cancer chemotherapy, it has been superseded by the more effective 5-HT₃ antagonists (e.g. ondansetron).

Prokinetic use

Metoclopramide increases peristalsis of the jejunum and duodenum, increases tone and amplitude of gastric contractions, and relaxes the pyloric sphincter and duodenal bulb. These prokinetic effects make metoclopramide useful in the treatment of gastric stasis (e.g. after gastric surgery or diabetic gastroparesis), as an aid in gastrointestinal radiology by increasing transit in barium studies, and as an aid in difficult small intestinal intubation. It is also used in gastroesophageal reflux disease (GERD/GORD).

Other indications

By inhibiting the action of dopamine (prolactin-inhibiting hormone), metoclopramide has sometimes been used to stimulate lactation. It can also be used in the treatment of migraines in the setting of cutaneous allodynia, where it is more effective than triptans.^[7]

Contraindications and precautions

Metoclopramide is contraindicated in phaeochromocytoma. It should be used with caution in Parkinson's disease since, as a dopamine antagonist, it may worsen symptoms. Long-term use should be avoided in patients with clinical depression as it may worsen mental state.^[6] Also contraindicated with a suspected bowel obstruction.

Use in pregnancy

Metoclopramide has long been used in all stages of pregnancy with no evidence of harm to the mother or fetus.^[8] A large cohort study of babies born to Israeli women exposed to metoclopramide during pregnancy found no evidence that the drug increases the risk of congenital malformations, low birth weight, preterm birth, or perinatal mortality.^[9]

Metoclopramide crosses into breast milk.^[8]

Adverse effects

Plastic ampoule of metoclopramide

Common adverse drug reactions (ADRs) associated with metoclopramide therapy include: restlessness, drowsiness, dizziness, lassitude, and/or dystonic reactions. Infrequent ADRs include: headache, extrapyramidal effects such as oculogyric crisis, hypertension, hypotension, hyperprolactinaemia leading to galactorrhoea, diarrhoea, constipation, and/or depression. Rare but serious ADRs associated with metoclopramide therapy include: agranulocytosis, supraventricular tachycardia, hyperaldosteronism, neuroleptic malignant syndrome and/or tardive dyskinesia.^[6] Dystonic reactions are usually treated with benztropine or procyclidine.

The risk of extrapyramidal effects is increased in young adults (<20 years) and children, and with high-dose or prolonged therapy.^[5][6] Tardive dyskinesias may be persistent and irreversible in some patients. In 2009, the U.S. Food and Drug Administration required all manufacturers of metoclopramide to issue a black box warning regarding the risk of tardive dyskinesia with chronic or high-dose use of the drug.^[10]

Veterinary use

Metoclopramide is also used in animals. It is commonly used to prevent vomiting in cats and dogs. It is also used as a gut stimulant in rabbits.

See also

• Benzamide, the chemical class to which metoclopramide belongs
  • Bromopride, the bromo- analogue of metoclopramide
  • Cisapride, a benzamide with a different mechanism of action
  • Itopride, a newer benzamide with effects similar to those of metoclopramide

References

1. ^ Justin-Besançon L, Laville C. Action antiémétique du métoclopramide vis-à-vis de l'apomorphine et de l'hydergine [Antiemetic action of metoclopramide with respect to apomorphine and hydergine]. C R Seances Soc Biol Fil 1964;158:723–7. PMID 14186927.
2. ^ Rang HP, Dale MM, Ritter JM, Moore PK. Pharmacology. 5th ed. Edinburgh: Churchill Livingstone; 2003. ISBN 0-443-07145-4
3. ^ Sweetman S, editor. Martindale: The complete drug reference. 34th ed. London: Pharmaceutical Press; 2004. ISBN 0-85369-550-4
4. ^ Tonini M, Candura SM, Messori E, Rizzi CA. Therapeutic potential of drugs with mixed 5-HT₄ agonist/5-HT₃ antagonist action in the control of emesis. Pharmacol Res 1995;31(5):257-60. PMID 7479521
5. ^ ^{a b c} Valeant Pharmaceuticals. Maxolon (Australian Approved Product Information). Auburn (NSW): Valeant Pharmaceuticals Australasia; 2000.
6. ^ ^{a b c d e} Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3
7. ^ Snow V, Weiss K, Wall EM, Mottur-Pilson C. Pharmacologic management of acute attacks of migraine and prevention of migraine headache. Ann Intern Med. 2002;137:840-9. [PMID: 12435222]
8. ^ ^{a b} Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 8th ed. Philadelphia: Lippincott Williams & Wilkins; 2008. ISBN 0-7817-7876-X. Retrieved on June 11, 2009.
9. ^ Matok I, Gorodischer R, Koren G, Sheiner E, Wiznitzer A, Levy A. The safety of metoclopramide use in the first trimester of pregnancy. N Engl J Med 2009;360(24):2528–35.
10. ^ U.S. Food and Drug Administration (February 26, 2009). "FDA requires boxed warning and risk mitigation strategy for metoclopramide-containing drugs". Press release. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm149533.htm. Retrieved 2009-06-11.  Lay summary – WebMD (February 27, 2009).

Further reading

• Brenner GM. Pharmacology. London: W B Saunders; 2000 ISBN 0-7216-7757-6
• Canadian Pharmacists Association. Compendium of Pharmaceuticals and Specialties. 25th ed. Toronto: Webcom; 2000. ISBN 0-919115-76-4
• Practical Gastroenterology May 2004 Recognition of Movement Disorders and Extrapyramidal side effects - would you recognize them if you see them?. Available on practicalgastro.com

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Phenethylamines (also Amphetamines, Cathinones, Phentermines, etc): 2-Hydroxyphenethylamine (2-OH-PEA) • 4-Methylamphetamine (4-MA) • 4-Methylmethamphetamine (4-MMA) • α-Ethylphenethylamine (α-Et-PEA) • Alfetamine • Amphetamine (Dextroamphetamine, Levoamphetamine) • Amphetaminil • Amfepentorex • β-Methylphenethylamine (β-Me-PEA) • Benzodioxolylbutanamine (BDB) • Benzodioxolylhydroxybutanamine (BOH) • Benzphetamine • Buphedrone • Butylone • Cathine • Cathinone • Clobenzorex • Clortermine • Diethylcathinone (Diethylpropion, Amfepramone) • Dibutylone • Dimethoxyamphetamine (DMA) • Dimethoxymethamphetamine (DMMA) • Dimethylamphetamine • Dimethylcathinone (Dimethylpropion, Metamfepramone) • Ethcathinone (Ethylpropion) • Ethylamphetamine • Ethylbenzodioxolylbutanamine (EBDB) • Ethylone • Fenethylline • Fenproporex • Flephedrone • Fludorex • Furfenorex • Hordenine • Indanorex • Indanylamphetamine (IAP) • Lophophine (Homomyristicylamine) • Mefenorex • Mephedrone • Methamphetamine (Desoxyephedrine, Methedrine; Dextromethamphetamine, Levomethamphetamine) • Methcathinone (Methylpropion) • Methedrone • Methoxymethylenedioxyamphetamine (MMDA) • Methoxymethylenedioxymethamphetamine (MMDMA) • Methylbenzodioxolylbutanamine (MBDB) • Methylenedioxyamphetamine (MDA; Tenamfetamine) • Methylenedioxyethylamphetamine (MDEA) • Methylenedioxyhydroxyamphetamine (MDOH) • Methylenedioxymethamphetamine (MDMA) • Methylenedioxymethylphenethylamine (MDMPEA; Homarylamine) • Methylenedioxyphenethylamine (MDPEA; Homopiperonylamine) • Methylone • Naphthylamphetamine (NAP) • Ortetamine • Oxaflozane • Parabromoamphetamine (PBA) • Parachloroamphetamine (PCA) • Parafluoroamphetamine (PFA) • Parafluoromethamphetamine (PFMA) • Parahydroxyamphetamine (PHA) • Paraiodoamphetamine (PIA) • Paramethoxyamphetamine (PMA) • Paramethoxyethylamphetamine (PMEA) • Paramethoxymethamphetamine (PMMA) • Paredrine (Norpholedrine, Oxamphetamine) • Phendimetrazine • Phenethylamine (PEA) • Phenmetrazine • Pholedrine • Phenpromethamine • Propylamphetamine • Tiflorex (Flutiorex) • Tyramine (TRA) • Xylopropamine • Zylofuramine; Piperazines: 2,5-Dimethoxy-4-bromobenzylpiperazine (2C-B-BZP) • Benzylpiperazine (BZP) • Methoxyphenylpiperazine (MeOPP; Paraperazine) • Methylbenzylpiperazine (MBZP) • Methylenedioxybenzylpiperazine (MDBZP; Piperonylpiperazine); Others: 2-Aminoindane (2-AI) • 2-Aminotetralin (2-AT) • 4-Benzylpiperidine (4-BP) • Clofenciclan • Cyclopentamine • Cypenamine • Cyprodenate • Feprosidnine • Gilutensin • Heptaminol • Hexacyclonate • Isometheptene • Methylhexanamine • Octodrine • Phthalimidopropiophenone • Propylhexedrine (PHX) • Tuaminoheptane (Tuamine) Enzyme Inhibitors Anabolism PAH Inhibitors 3,4-Dihydroxystyrene TH Inhibitors 3-Iodotyrosine • Aquayamycin • Bulbocapnine • Metirosine • Oudenone AAAD / DDC Inhibitors Benserazide • Carbidopa • Methyldopa Catabolism MAO Inhibitors (MAOIs) Nonselective: Iproclozide • Iproniazid • Isocarboxazid • Nialamide • Phenelzine • Pheniprazine • Tranylcypromine; MAO-A Selective: Befloxatone • Brofaromine • Cimoxatone • Clorgiline • Harmala Alkaloids • Minaprine • Moclobemide • Pirlindole • Toloxatone • Tyrima; MAO-B Selective: Lazabemide • Pargyline • Rasagiline • Selegiline COMT Inhibitors Entacapone • Tolcapone DBH Inhibitors Disulfiram • 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: Benzofuranylpropylaminopentane (BPAP) • Phenylpropylaminopentane (PPAP)

v • d • e Serotonergics Receptor Ligands 5-HT1 5-HT1A Agonists: Azapirones: Alnespirone • Binospirone • Buspirone • Eptapirone • Gepirone • Ipsapirone • Perospirone • Tandospirone • Tiospirone • Zalospirone; Lysergamides: Dihydroergotamine • Ergotamine • Methysergide • LSD; Phenethylamines: MDA • MDMA; Piperazines: Eltoprazine • Flesinoxan • Flibanserin; Tryptamines: 5-CT • 5-MeO-DMT • 5-MT • DMT • Psilocin • Psilocybin • Rauwolscine • Yohimbine; Atypical Antipsychotics: Aripiprazole • Asenapine • Clozapine • Quetiapine • Ziprasidone; Others: 8-OH-DPAT • Befiradol • F-11440 • Lesopitron • Lu AA21004 • LY-293,284 • LY-301,317 • MKC-242 • Osemozotan • Piclozotan • PRX-00023 • Repinotan • RU-24969 • S-15535 • Sarizotan • SSR-181,507 • Sunepitron • U-92016A • Urapidil • Vilazodone • Xaliproden Antagonists: Beta Blockers: Alprenolol • Cyanopindolol • Iodocyanopindolol • Oxprenolol • Pindobind • Pindolol • Propranolol; Piperazines: Nefazodone • Trazodone • WAY-100,135 • WAY-100,635; Others: AV965 • BMY-7378 • Dotarizine • GR-46611 • Isamoltane • Lecozotan • Methiothepin • MPPF • NAN-190 • Robalzotan • S-15535 • SB-649915 • SDZ 216-525 • Spiperone • Spiramide • Spiroxatrine • UH-301 • WAY-100,135 • WAY-100,635 • Xylamidine 5-HT1B Agonists: Lysergamides: Dihydroergotamine • Ergotamine • Methysergide; Piperazines: Eltoprazine • TFMPP; Triptans: Eletriptan • Sumatriptan • Zolmitriptan; Tryptamines: 5-CT • 5-MT; Others: CP-93,129 • CP-94,253 • CP-135,807 • RU-24969 Antagonists: Lysergamides: Metergoline • Methiothepin; Tryptamines: Yohimbine; Others: AR-A000002 • GR-127,935 • Isamoltane • SB-216,641 • SB-224,289 • SB-236,057 5-HT1D Agonists: Lysergamides: Dihydroergotamine • Methysergide; Triptans: Almotriptan • Eletriptan • Frovatriptan • Naratriptan • Rizatriptan • Sumatriptan • Zolmitriptan; Tryptamines: 5-CT • 5-MT; Others: CP-135,807 • CP-286,601 • GR-46611 • L-694,247 • L-772,405 • PNU-109,291 • PNU-142,633 Antagonists: Lysergamides: Metergoline • Methiothepin; Tryptamines: Rauwolscine • Yohimbine; Others: BRL-15572 • GR-127,935 • Ketanserin • LY-310,762 • LY-367,642 • LY-456,219 • LY-456,220 • Ritanserin • Ziprasidone 5-HT1E Agonists: Lysergamides: Methysergide; Triptans: Eletriptan; Tryptamines: Tryptamine Antagonists: Methiothepin 5-HT1F Agonists: Triptans: Eletriptan • Naratriptan • Sumatriptan; Tryptamines: 5-MT; Others: LY-334,370 Antagonists: Methiothepin 5-HT2 5-HT2A Agonists: Lysergamides: ALD-52 • Ergonovine • Lisuride • LA-SS-Az • LSD • Lysergic acid 2-butyl amide • Methysergide; Phenethylamines: 25I-NBMD • 25I-NBOH • 25I-NBOMe • 2C-B • 2C-B-FLY • 2C-E • 2C-I • 2C-T-2 • 2C-T-7 • 2C-T-21 • 2CBCB-NBOMe • 2CBFly-NBOMe • Bromo-DragonFLY • DOB • DOC • DOI • DOM • MDA • MDMA • Mescaline • Myristicin • TCB-2 • TFMFly; Piperazines: BZP • Quipazine • TFMPP; Tryptamines: 5-CT • 5-MeO-α-ET • 5-MeO-α-MT • 5-MeO-DET • 5-MeO-DiPT • 5-MeO-DMT • 5-MeO-DPT • 5-MT • α-ET • α-Methyl-5-HT • α-MT • Bufotenin • DET • DiPT • DMT • DPT • Psilocin • Psilocybin; Others: AL-34662 • AL-37350A • PNU-22394 Antagonists: Atypical Antipsychotics: Amperozide • Aripiprazole • Clozapine • Iloperidone • Melperone • Olanzapine • Paliperidone • Pimozide • Quetiapine • Risperidone • Sertindole • Ziprasidone • Zotepine; Typical Antipsychotics: Loxapine • Pipamperone; Antidepressants: Amitriptyline • Amoxapine • Etoperidone • Mianserin • Mirtazapine • Nefazodone • Trazodone; Others: 5-I-R91150 • AC-90179 • Altanserin • AMDA • APD-215 • Blonanserin • Cinanserin • Cyproheptadine • Deramciclane • Dotarizine • Eplivanserin • Fananserin • Flibanserin • Ketanserin • KML-010 • Lubazodone • Methiothepin • Nantenine • Pimavanserin • Pizotifen • Ritanserin • Sarpogrelate • Setoperone • Spiperone • Spiramide • SR-46349B • Volinanserin • Xylamidine • Yohimbine 5-HT2B Agonists: Oxazolines: 4-Methylaminorex • Aminorex; Phenethylamines: Chlorphentermine • DOB • DOC • DOI • DOM • Fenfluramine • MDA • MDMA • Norfenfluramine; Tryptamines: 5-CT • 5-MT • α-Methyl-5-HT; Others: BW-723C86 • Cabergoline • mCPP • Pergolide • PNU-22394 • Ro60-0175 Antagonists: Agomelatine • Asenapine • EGIS-7625 • Ketanserin • Lisuride • LY-272,015 • Rauwolscine • Ritanserin • RS-127,445 • Sarpogrelate • SB-200,646 • SB-204,741 • SB-206,553 • SB-215,505 • SB-221,284 • SB-228,357 • SDZ SER-082 • Tegaserod • Yohimbine 5-HT2C Agonists: Phenethylamines: 2C-B • 2C-E • 2C-I • 2C-T-2 • 2C-T-7 • 2C-T-21 • DOB • DOC • DOI • DOM • MDA • MDMA • Mescaline • Myristicin; Piperazines: Aripiprazole • mCPP • TFMPP; Tryptamines: 5-CT • 5-MeO-α-ET • 5-MeO-α-MT • 5-MeO-DET • 5-MeO-DiPT • 5-MeO-DMT • 5-MeO-DPT • 5-MT • α-ET • α-Methyl-5-HT • α-MT • Bufotenin • DET • DiPT • DMT • DPT • Psilocin • Psilocybin; Others: A-372,159 • AL-38022A • CP-809,101 • Lorcaserin • MK-212 • PNU-22394 • Ro60-0175 • Vabicaserin • WAY-629 • WAY-161,503 • YM-348 Antagonists: Atypical Antipsychotics: Clozapine • Iloperidone • Melperone • Olanzapine • Paliperidone • Pimozide • Quetiapine • Risperidone • Sertindole • Ziprasidone • Zotepine; Typical Antipsychotics: Loxapine • Pipamperone; Antidepressants: Agomelatine • Amitriptyline • Amoxapine • Etoperidone • Fluoxetine • Mianserin • Mirtazapine • Nefazodone • Trazodone; Others: Cinanserin • Deramciclane • Dimebolin • Dotarizine • Eltoprazine • FR-260,010 • Ketanserin • Pizotifen • Ritanserin • RS-102,221 • SB-200,646 • SB-206,553 • SB-221,284 • SB-228,357 • SB-242,084 • SB-243,213 • SDZ SER-082 • Xylamidine 5-HT3 Agonists: Piperazines: BZP • Quipazine; Tryptamines: 2-Methyl-5-HT • 5-CT; Others: Chlorophenylbiguanide • RS-56812 • SR-57,227 • SR-57,227-A • YM-31636 Antagonists: Antiemetics: AS-8112 • Alosetron • Azasetron • Batanopride • Bemesetron • Cilansetron • Dolasetron • Granisetron • Lerisetron • Ondansetron • Palonosetron • Ramosetron • Renzapride • Tropisetron • Zacopride • Zatosetron; Atypical Antipsychotics: Clozapine • Olanzapine • Quetiapine; Tetracyclic Antidepressants: Amoxapine • Mianserin • Mirtazapine; Others: ICS-205,930 • Lu AA21004 • MDL-72,222 • Memantine • Ricasetron 5-HT4 Agonists: Gastroprokinetic Agents: Cisapride • Metoclopramide • Mosapride • Prucalopride • Renzapride • Tegaserod • Zacopride; Others: 5-MT • BIMU-8 • CJ-033,466 • PRX-03140 • RS-67333 • RS-67506 • TD-5108 Antagonists: GR-113,808 • GR-125,487 • L-Lysine • Piboserod • RS-39604 • RS-67532 • SB-203,186 5-HT5 5-HT5A Agonists: Lysergamides: Ergotamine • LSD; Tryptamines: 5-CT; Others: Valerenic Acid Antagonists: Asenapine • Dimebolin • Methiothepin • Ritanserin • SB-699,551 5-HT5B* Agonists: Lysergamides: Ergotamine • LSD Antagonists: Methiothepin * Note that the 5-HT5B receptor is not functional in humans. 5-HT6 Agonists: Lysergamides: Lisuride • LSD • Metergoline; Tryptamines: 5-CT • 5-MT • E-6801 • E-6837 • EMD-386,088 • EMDT • LY-586,713 • WAY-181,187 • WAY-208,466 Antagonists: Antidepressants: Amitriptyline • Amoxapine • Clomipramine • Doxepin • Mianserin • Nortriptyline; Atypical Antipsychotics: Aripiprazole • Asenapine • Clozapine • Fluperlapine • Iloperidone • Olanzapine • Tiospirone; Typical Antipsychotics: Chlorpromazine • Loxapine; Others: BGC20-760 • BVT-5182 • BVT-74316 • Dimebolin • EGIS-12233 • GW-742,457 • Ketanserin • Methiothepin • MS-245 • PRX-07034 • Ritanserin • Ro 04-6790 • Ro 63-0563 • SB-258,585 • SB-271,046 • SB-357,134 • SB-399,885 5-HT7 Agonists: Lysergamides: LSD; Tryptamines: 5-CT • 5-MT; Others: 8-OH-DPAT • AS-19 • Bifeprunox • LP-12 • LP-44 • Sarizotan Antagonists: Antidepressants: Amitriptyline • Amoxapine • Clomipramine • Imipramine • Maprotiline • Mianserin; Atypical Antipsychotics: Amisulpride • Aripiprazole • Clozapine • Olanzapine • Risperidone • Sertindole • Tiospirone • Ziprasidone • Zotepine; Typical Antipsychotics: Chlorpromazine • Loxapine; Others: EGIS-12233 • LY-215,840 • Mesulergine • Metergoline • Methiothepin • Pimozide • Ritanserin • SB-258,719 • SB-258,741 • SB-269,970 • SB-656,104 • SB-656,104-A • SB-691,673 • SLV-313 • SLV-314 • Spiperone • SSR-181,507 Reuptake Inhibitors Plasmalemmal SERT Inhibitors Selective Serotonin Reuptake Inhibitors (SSRIs): Alaproclate • Citalopram • Dapoxetine • Desmethylcitalopram • Desmethylsertraline • Escitalopram • Femoxetine • Fluoxetine • Fluvoxamine • Indalpine • Litoxetine • Lubazodone • Norfluoxetine • Paroxetine • RTI-353 • Sertraline • Vilazodone • Zimelidine; Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): Bicifadine • Desvenlafaxine • Duloxetine • Milnacipran • Venlafaxine; Serotonin-Norepinephrine-Dopamine Reuptake Inhibitors (SNDRIs): Brasofensine • Diclofensine • DOV-102,677 • DOV-21,947 • DOV-216,303 • NS-2359 • SEP-225,289 • SEP-227,162 • Tesofensine; Tricyclic Antidepressants (TCAs): Amitriptyline • Butriptyline • Cianopramine • Clomipramine • Desipramine • Dosulepin • Doxepin • Imipramine • Lofepramine • Nortriptyline • Protriptyline • Trimipramine; Tetracyclic Antidepressants (TeCAs): Amoxapine; Piperazines: Nefazodone • Trazodone; Antihistamines: Brompheniramine • Chlorpheniramine • Diphenhydramine • Mepyramine (Pyrilamine) • Pheniramine • Tripelennamine; Opioids: Meperidine (Pethidine) • Methadone • Propoxyphene • Tramadol; Others: Cocaine • Cyclobenzaprine (CBZ) • Dextromethorphan (DXM) • Mesembrine • Nefopam • SB-649,915 • Sibutramine • Ziprasidone TRPC6 Activators Adhyperforin • Hyperforin Vesicular VMAT Inhibitors Ibogaine • Reserpine • Tetrabenazine Releasing Agents Aminoindanes: Ethyltrifluoromethylaminoindane (ETAI) • Methylenedioxyaminoindane (MDAI) • Methylenedioxymethylaminoindane (MDMAI) • Methoxymethylaminoindane (MMAI) • Trifluoromethylaminoindane (TAI); Aminotetralins: 8-Hydroxydipropylaminotetralin (8-OH-DPAT); Oxazolines: 4-Methylaminorex (4-MAR, 4-MAX) • Aminorex • Clominorex • Fluminorex; Phenethylamines (also Amphetamines, Cathinones, Phentermines, etc): 4-Methylthioamphetamine (4-MTA) • 5-Aminopropyldihydrobenzofuran (5-APDB; 5-Desoxy-MDA) • Benzodioxolylbutanamine (BDB) • Benzodioxolylhydroxybutanamine (BOH) • Brephedrone • Butylone • Chlorphentermine • Dibutylone • Diethylcathinone (Diethylpropion, Amfepramone) • Dimethoxyamphetamine (DMA) • Dimethoxymethamphetamine (DMMA) • Dimethylcathinone (Dimethylpropion, Metamfepramone) • Ethylbenzodioxolylbutanamine (EBDB) • Ethylone • Fenfluramine (Dexfenfluramine) • Flephedrone • Indanylamphetamine (IAP) • Lophophine (Homomyristicylamine) • Mephedrone • Methedrone • Methoxymethylamphetamine (MMA) • Methoxymethylenedioxyamphetamine (MMDA) • Methoxymethylenedioxymethamphetamine (MMDMA) • Methylbenzodioxolylbutanamine (MBDB) • Methylenedioxyamphetamine (MDA; Tenamfetamine) • Methylenedioxyethylamphetamine (MDEA) • Methylenedioxyhydroxyamphetamine (MDOH) • Methylenedioxymethamphetamine (MDMA) • Methylenedioxymethylphenethylamine (MDMPEA; Homarylamine) • Methylenedioxyphenethylamine (MDPEA; Homopiperonylamine) • Methylone • Naphthylamphetamine (NAP) • Norfenfluramine • Parabromoamphetamine (PBA) • Parachloroamphetamine (PCA) • Parafluoroamphetamine (PFA) • Parafluoromethamphetamine (PFMA) • Parahydroxyamphetamine (PHA) • Paraiodoamphetamine (PIA) • Paramethoxyamphetamine (PMA) • Paramethoxyethylamphetamine (PMEA) • Paramethoxymethamphetamine (PMMA); Piperazines: 2,5-Dimethoxy-4-bromobenzylpiperazine (2C-B-BZP) • Benzylpiperazine (BZP) • Metachlorophenylpiperazine (mCPP) • Methoxyphenylpiperazine (MeOPP; Paraperazine) • Methylbenzylpiperazine (MBZP) • Methylenedioxybenzylpiperazine (MDBZP; Piperonylpiperazine) • Parafluorophenylpiperazine (pFPP; Fluoperazine) • Trifluoromethylphenylpiperazine (TFMPP); Quinolines: PK-7059 • Viqualine; Tryptamines: Alphaethyltryptamine (AET; Etryptamine) • Alphamethyltryptamine (AMT; Metryptamine) Enzyme Inhibitors Anabolism TPH Inhibitors AGN-2979 • Fenclonine AAAD Inhibitors Benserazide • Carbidopa Catabolism MAO Inhibitors Nonselective: Iproclozide • Iproniazid • Isocarboxazid • Nialamide • Phenelzine • Pheniprazine • Tranylcypromine; MAO-A Selective: Befloxatone • Brofaromine • Cimoxatone • Clorgiline • Harmala Alkaloids • Minaprine • Moclobemide • Pirlindole • Toloxatone • Tyrima Others Precursors L-Tryptophan → 5-HTP Cofactors Ferrous Iron (Fe2+) • Magnesium (Mg2+) • 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: Benzofuranylpropylaminopentane (BPAP) • Phenylpropylaminopentane (PPAP); Reuptake Enhancers: Tianeptine

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