Molindone is available in the form of 5, 10, 25, and 50 mg oral tablets.^[1]

Molindone is known to act as a potent antagonist of the dopamine D₂ receptor (IC₅₀Tooltip half-maximal inhibitory concentration = 84–140 nM) and of the serotonin 5-HT_2B receptor (IC₅₀ = 410 nM).^[10][14] It is far less potent as an antagonist of the dopamine D₁, D₃, and D₅ receptors (IC₅₀ = 3,200–8,300 nM) and of the serotonin 5-HT_2A receptor (IC₅₀ = 14,000 nM).^[14] The drug does not significantly bind to or inhibit the α-adrenergic receptors, nor does it affect various other receptors, such as the serotonin 5-HT_1A, 5-HT_2C, 5-HT₆, and 5-HT₇ receptors.^[14][2] Likewise, molindone has essentially no affinity for the muscarinic acetylcholine receptors and has very little affinity for the histamine H₁ receptor or the α₁-adrenergic receptor.^[2] However, it has been found to have intermediate affinity for the α₂-adrenergic receptor.^[2] The metabolites of molindone appear to be largely inactive in vitro.^[14] The preceding findings suggest that molindone is pharmacologically distinct from most atypical antipsychotics, which act as potent antagonists of both the D₂ and 5-HT_2A receptors.^[14]

Additional binding data on molindone are also available and in some cases have found contrasting results relative to the above findings, for instance high affinity for the dopamine D₃ receptor.^[15][16]

Molindone is described as an antipsychotic, sedative, and major tranquilizer.^[7] In animals, it reduces spontaneous locomotor activity, inhibits conditioned avoidance responses, produces catalepsy and hypothermia, and limits aggression in monkeys.^[2][1] Like other antipsychotics, molindone antagonizes the effects of the dopamine releasing agent amphetamine and the dopamine receptor agonist apomorphine.^[2][1] In contrast to many antipsychotics however, molindone shows antidepressant-like effects in animals, for example reversing ptosis induced by the dopamine depleting agent tetrabenazine, potentiating 5-hydroxytryptophan (5-HTP)-induced tremors, and potentiating certain effects of levodopa (L-DOPA).^[2][1] It shows little anticholinergic activity in animals and its lack of histamine H₁ receptor antagonism suggests less potential for sedation and weight gain than certain other antipsychotics.^[2] The drug shows antiemetic effects in animals.^[1]

Molindone has been reported to inhibit monoamine oxidase both in vitro and in vivo.^[2] However, very high concentrations (~100,000 nM) and high doses (10 and 40 mg/kg) are required for monoamine oxidase inhibition.^[2] Its inhibition of monoamine oxidase is irreversible and is selective for monoamine oxidase A (MAO-A).^[2] The drug is much more potent in inhibiting monoamine oxidase in vivo than in vitro, suggesting that an active metabolite may be responsible for its monoamine oxidase inhibition.^[2] The MAO-A inhibition of molindone may be responsible for its antidepressant-like effects in animals.^[2] It is unclear whether the monoamine oxidase inhibition of molindone observed in preclinical research occurs therapeutically in humans or is clinically significant.^[2]

It has no affinity for the muscarinic acetylcholine receptors.

The elimination half-life of molindone is approximately 2 hours.^[2] This half-life is much shorter than that of most other antipsychotics.^[2] Concentrations of molindone are negligible 12 hours following the last dose even it is used at high doses.^[2] Lithium has been found to prolong the half-life of molindone by at least 4-fold.^[2] In spite of the preceding findings, the duration of action of molindone is 24 to 36 hours.^[2][1] It has been suggested that the antipsychotic effects of molindone may be mediated by active metabolites rather than by molindone itself.^[2]

Some structurally related compounds include L-741,626, losindole, and piquindone. Other indole-containing antipsychotics include ciclindole, flucindole, roxindole, sertindole, and tepirindole.

Molindone has been marketed in the United States, Finland, and Hong Kong.^[23] In 2000, it was available only in these three countries.^[23] By 2017, molindone continued to be marketed only in the United States.^[9]

The drug was discontinued by its original supplier, Endo Pharmaceuticals, on January 13, 2010.^[24] After having been produced and subsequently discontinued by Core Pharma in 2015 to 2017, molindone is available again from Epic Pharma effective December 2018.^[25]

Molindone has been studied in the treatment of depression and anxiety.^[2] Some antidepressant and anxiolytic effects have been observed in small and old clinical studies, but findings in terms of effectiveness were mixed.^[2]

Molindone was found to reduce aggressive symptoms, including agitation, hostility, and uncooperativeness, in adults with schizophrenia in the 1970s. Many other antipsychotics have also shown clinical anti-aggressive effects. Subsequently, molindone was found to potentially be effective in the treatment of hospitalized aggressive children with conduct disorder in a clinical trial comparing it with thioridazine in the 1980s.^[10][11][27] This study eventually led to molindone being developed for treatment of impulsive aggression in youth much later on.^[10]

Low-dose extended-release molindone (developmental code name SPN-810) is under development for the treatment of impulsive aggression in children and adolescents with attention deficit hyperactivity disorder (ADHD).^[10] As of May 2024, it is in phase 3 clinical trials for this indication. Negative effectiveness findings in a phase 3 trial have been reported. The exact mechanism of action of molindone for this indication is unknown, but has been proposed to be related to dopamine D₂ and serotonin 5-HT_2B receptor antagonism.^[10][14]