Dizocilpine (MK-801)
Dizocilpine (MK-801) is a potent, selective, high-affinity non-competitive NMDA receptor antagonist used extensively as a laboratory tool to model NMDA hypofunction and glutamatergic mechanisms. It was investigated as a neuroprotectant and anticonvulsant but abandoned for human therapy due to neurotoxicity; it is not a clinical or recreational drug.
01 Overview
MK-801 is one of the most widely used NMDA antagonists in neuroscience research, valued for its high affinity and selectivity. It reliably produces the behavioural and molecular signatures of NMDA blockade in animals and is a standard pharmacological probe.
In rodents it causes reversible vacuolisation of cingulate/retrosplenial cortex neurons (Olney's lesions) at higher doses, which contributed to the decision not to develop it clinically. Human exposure is essentially confined to accidental or illicit use; there is no established human dose and its safety in people is not characterised.
02 Mechanism
High-affinity, use-dependent open-channel blocker of the NMDA receptor with a slow off-rate, producing profound and prolonged NMDA antagonism.
03 Dosing
| Tier | Dose | Route | Notes |
|---|---|---|---|
| No established human dose | 0 mg | Oral | Laboratory reagent; no validated human dosing exists. |
04 Effects
| Effect | Magnitude | Evidence | |
|---|---|---|---|
| NMDA antagonism (research)Potent blockade used to model schizophrenia-like states and glutamate function in animals. | n/a | Preclinical | |
| Anticonvulsant/neuroprotection (preclinical)Protects against excitotoxic damage in animal ischaemia models; never validated clinically. | n/a | Preclinical |
05 Side effects
| Effect | Severity | Frequency | Evidence | Countermeasures |
|---|---|---|---|---|
| Neurotoxic vacuolisation (Olney's lesions)Reversible then potentially irreversible neuronal injury in specific cortical regions at higher doses in rodents. | Severe | Dose-related (animal) | Preclinical | |
| Psychosis-like stateProduces marked behavioural disturbance and cognitive impairment, the basis of its use as an NMDA-hypofunction model. | Severe | Unknown | Preclinical |