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Haloperidol
Haloperidol is a typical antipsychotic1 of the butyrophenone class used to treat schizophrenia, psychosis, and agitation. It was first synthesized in 1958 by Paul Janssen. It does not reliably block serotonergic psychedelic effects and may worsen psilocybin-related psychosis. It can cause potentially permanent movement disorders2, neuroleptic malignant syndrome3, and QT interval prolongation, particularly with intravenous administration.4 It increases the risk of death in older people with dementia-related psychosis.
Dosage & Duration
Dosage
Doses are population estimates that vary widely between individuals.
Duration
Subjective Effects
Pharmacology
Pharmacodynamics
Haloperidol acts primarily by strongly antagonizing dopamine D2 receptors, with high affinity and slow dissociation. Its antipsychotic action involves D2 blockade in mesolimbic and mesocortical pathways, while D2 antagonism in the chemoreceptor trigger zone contributes to its antiemetic action. It inhibits dopamine signaling and increases dopamine turnover, although its exact mechanism is not fully understood and competitive postsynaptic blockade is proposed.5 It preferentially binds D2 and α1 receptors at lower doses, with reported ED50 values of 0.13 and 0.42 mg/kg, respectively, whereas 5-HT2 binding occurs at higher doses (ED50 2.6 mg/kg). Secondary actions include serotonin receptor antagonism, D3 inverse agonism, and irreversible sigma-1 receptor blockade.
Pharmacokinetics
Haloperidol is well absorbed orally, but metabolism in the liver before it reaches the circulation reduces oral bioavailability to 40-75%.7 Oral exposure varies widely, with a reported AUC of 43.73 μg/L·h (range 14.89-120.96 μg/L·h). Intramuscular absorption is rapid and bioavailability is higher than with oral administration; intravenous bioavailability is 100%. The intramuscular decanoate depot releases the drug slowly and reaches steady-state plasma concentrations after the third or fourth dose.8 Haloperidol is highly lipophilic, with an apparent distribution volume of 9.5-21.7 L/kg and a plasma free fraction of 7.5-11.6%. In a postmortem study, human brain tissue concentrations were 10-30 times higher than optimal serum concentrations used to treat schizophrenia, and the calculated brain tissue elimination half-life was 6.8 days.9 Haloperidol also passes into breast milk.6 Hepatic metabolism is extensive,6 with reduction accounting for approximately 23% of biotransformation,6 and N-dealkylation and pyridinium formation for a reported 20-30%. In studies of CYP-mediated disposition in vitro, CYP3A4 appears to be the major isoform responsible for haloperidol metabolism in humans.10 Reduced metabolites can undergo oxidation back to the parent drug. Haloperidol is also listed as a substrate of CYP1A1, CYP1A2, CYP2C19, CYP2C9, CYP3A5, CYP3A7, UGT1A9, and P-glycoprotein, and as an inhibitor of CYP2D6, CYP3A4 (moderate), and P-glycoprotein. Some human studies associate reduced CYP2D6 activity with lower clearance and higher concentrations, while other laboratory and human studies have not consistently supported this relationship. Intravenous clearance is 0.39-0.708 L/h/kg; reported oral clearance is 141.65 L/h (range 41.34-335.80 L/h), and clearance after extravascular administration is 0.9-1.5 L/h/kg. A population analysis in patients with schizophrenia estimated 44% variability in clearance between individuals. Only about 1% of a dose is excreted unchanged in urine. Following a single radiolabeled oral dose, approximately 30% of the radioactivity was recovered in urine, including 18% as a glucuronide conjugate, which is also the most abundant plasma metabolite during regular treatment.
Interactions
An unlisted combination is an unknown one, not a safe one. Check a dedicated combination chart before mixing.
Tolerance
Harm Potential
Addiction & Dependence
Psychological
Prolonged haloperidol use can lead to psychological dependence.
Physical
Withdrawal symptoms commonly include nausea, vomiting, and reduced appetite; restlessness, sweating, and insomnia may also occur. Vertigo, numbness, and muscle pain are less common, and tardive dyskinesia can rarely emerge after discontinuation.
Toxicity
Haloperidol overdose can be fatal. Prognosis is generally favorable after survival of the initial phase.
LD50 Data
| Species | Route | Value |
|---|---|---|
| rat | oral | 71 mg/kg |
Haloperidol can cause parkinsonism, dystonia, akathisia, and tardive dyskinesia, with akathisia and tardive dyskinesia potentially persisting permanently. Higher doses can cause severe extrapyramidal symptoms and muscle rigidity lasting hours, while severe overdose can cause coma. Evidence also suggests possible neurotoxicity.
Haloperidol has been associated with QT prolongation, torsades de pointes, and sudden death, with greater arrhythmia risk at doses above recommendations and with intravenous administration. Overdose can cause hypotension or hypertension, severe hypotension with shock, and rarely serious ventricular arrhythmia.
Haloperidol can cause respiratory depression, including during severe overdose accompanied by coma.11
Haloperidol overdose can cause dry mouth, constipation, and paralytic ileus.
Haloperidol overdose can cause difficulty urinating.
Haloperidol can cause weight gain; 14% of users gained weight with more than six months of use. Prolactin changes are also described among adverse effects of its antipsychotic class.11
Haloperidol can be associated with potentially fatal neuroleptic malignant syndrome, involving extreme fever, muscle rigidity, altered mental status, and autonomic instability.11 Associated findings can include elevated creatine phosphokinase, rhabdomyolysis with myoglobinuria, and acute renal failure.11
Animal experiments found no teratogenicity from haloperidol but demonstrated embryotoxicity at high doses, while human pregnancy reports describe possible fetal harm. Infants exposed during pregnancy may experience adverse effects.13
Haloperidol increases mortality risk in older people with dementia-related psychosis.
Psychosis Risk
Tentative evidence suggests that stopping antipsychotic treatment can precipitate psychosis; discontinuation may also allow the treated condition to recur.
History & Culture
Discovery and early development
Haloperidol was discovered in 1958 by Paul Janssen's team at Janssen Pharmaceutica in Belgium. It emerged from research into centrally acting analgesics derived from pethidine, also known as meperidine, and methadone. After synthesizing phenoperidine, the researchers investigated related compounds…
Legality
By Country
United StatesPrescription only
AustraliaPrescription only
CanadaPrescription only
GermanyPrescription only
SwitzerlandPrescription only
United KingdomPrescription onlyReferences
Citations
Further Reading
Article Status
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