Pharmacodynamics +<unk>  Site Ki (nM) Action Species Ref ' 44–59 Antagonist Human >10,000 Human >10,000 Human >10,000 Human >10,000 Human σ1 >10,000 Agonist Guinea pig σ2 136 Agonist Rat D2 >10,000 Human D2High 2.7–4.3'144 (EC50) Agonist Rat/human'Human 5-HT2A >10,000 Human 5-HT2AHigh ≥5,000 Agonist? Rat 2,234 Inhibitor Human >10,000 Inhibitor Human >10,000 Inhibitor Human 2 154 ' Human 3H uptake 1,424 (IC50) Inhibitor Rat 3H binding 16,628 (IC50) Inhibitor Rat 3H uptake 347 (IC50) Inhibitor Rat 3H binding 1,547 (IC50) Inhibitor Rat Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.<unk>  is well known for its primary action on the NMDA receptor, an ionotropic glutamate receptor, in rats and in rat brain homogenate. As such,<unk>  is an NMDA receptor antagonist. The role of NMDAR antagonism in the effect of<unk> , ketamine, and related dissociative agents was first published in the early 1980s by David Lodge and colleagues. Other NMDA receptor antagonists include ketamine, tiletamine, dextromethorphan, nitrous oxide, and dizocilpine (MK-801). Research also indicates that<unk>  inhibits nicotinic acetylcholine receptors (nAChRs) among other mechanisms. Analogues of<unk>  exhibit varying potency at nACh receptors and NMDA receptors. Findings demonstrate that presynaptic nAChRs and NMDA receptor interactions influence postsynaptic maturation of glutamatergic synapses and consequently impact synaptic development and plasticity in the brain. These effects can lead to inhibition of excitatory glutamate activity in certain brain regions such as the hippocampus and cerebellum thus potentially leading to memory loss as one of the effects of prolonged use. Acute effects on the cerebellum manifest as changes in blood pressure, breathing rate, pulse rate, and loss of muscular coordination during intoxication.<unk> , like ketamine, also acts as a potent dopamine D2High receptor partial agonist in rat brain homogenate and has affinity for the human cloned D2High receptor. This activity may be associated with some of the other more psychotic features of<unk>  intoxication, which is evidenced by the successful use of D2 receptor antagonists (such as haloperidol) in the treatment of<unk>  psychosis. In addition to its well explored interactions with NMDA receptors,<unk>  has also been shown to inhibit dopamine reuptake, and thereby leads to increased extracellular levels of dopamine and hence increased dopaminergic neurotransmission. However,<unk>  has little affinity for the human monoamine transporters, including the dopamine transporter (DAT). Instead, its inhibition of monoamine reuptake may be mediated by interactions with allosteric sites on the monoamine transporters.<unk>  is notably a high-affinity ligand of the<unk>  site 2 (Ki = 154 nM), a not-well-characterized site associated with monoamine reuptake inhibition. Studies on rats indicate that<unk>  interacts indirectly with opioid receptors (endorphin and enkephalin) to produce analgesia. A binding study assessed<unk>  at 56 sites including neurotransmitter receptors and transporters and found that<unk>  had Ki values of >10,000 nM at all sites except the dizocilpine (MK-801) site of the NMDA receptor (Ki = 59 nM), the σ2 receptor (PC12) (Ki = 136 nM), and the serotonin transporter (Ki = 2,234 nM). The study notably found Ki values of >10,000 nM for the D2 receptor, the opioid receptors, the σ1 receptor, and the dopamine and norepinephrine transporters. These results suggest that<unk>  is a highly selective ligand of the NMDAR and σ2 receptor. However,<unk>  may also interact with allosteric sites on the monoamine transporters to produce inhibition of monoamine reuptake. Mechanism of action<unk>  is an NMDA receptor antagonist that blocks the activity of the NMDA receptor to cause anaesthesia and analgesia without causing cardiorespiratory depression. NMDA is an excitatory receptor in the brain, when activated normally the receptor acts as an ion channel and there is an influx of positive ions through the channel to cause nerve cell depolarisation.<unk>  enters the ion channel and binds, reversibly and non-competitively, inside the channel pore to block the entry of positive ions to the cell, thereby inhibiting cell depolarisation. Neurotoxicity Some studies found that, like other NMDA receptor antagonists,<unk>  can cause a kind of brain damage called Olney's lesions in rats. Studies conducted on rats showed that high doses of the NMDA receptor antagonist dizocilpine caused reversible vacuoles to form in certain regions of the rats' brains. All studies of Olney's lesions have only been performed on non-human animals and may not apply to humans. One unpublished study by Frank Sharp reportedly showed no damage by the NDMA antagonist ketamine, a structurally similar drug, far beyond recreational doses, but due to the study never having been published, its validity is controversial.<unk>  has also been shown to cause schizophrenia-like changes in N-acetylaspartate and N-acetylaspartylglutamate levels in the rat brain, which are detectable both in living rats and upon necropsy examination of brain tissue. It also induces symptoms in humans that mimic schizophrenia.<unk>  not only produced symptoms similar to schizophrenia, it also yielded electroencephalogram changes in the thalamocortical pathway (increased delta decreased alpha) and in the hippocampus (increase theta bursts) that were similar to those in schizophrenia.<unk> -induced augmentation of dopamine release may link the NMDA and dopamine hypotheses of schizophrenia. Pharmacokinetics<unk>  is metabolized into PCHP, PPC and PCAA. The drug is metabolized 90% by oxidative hydroxylation in the liver during the first pass. Metabolites are glucuronidated and excreted in the urine. Nine percent of ingested<unk>  is excreted in its unchanged form. When smoked, some of the compound is broken down by heat into 1-phenylcyclohexene (PC) and piperidine. Conversion of<unk>  into PC and piperidine by heat. The time taken before the effects of<unk>  manifest is dependent on the route of administration. The onset of action for inhalation occurs in 2–5 minutes, whereas the effects may take 15 to 60 minutes when ingested orally.
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