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= Psychotomimetic = From Wikipedia, the free encyclopedia

A psychotomimetic (or psychotogenic) is a psychoactive drug that is induces symptoms of psychosis. Psychotomimetics often result in symptoms that are similar to those found in schizophrenia and schizophrenics may see their symptoms worsen after taking these drugs Psychotomimesis is the onset of psychotic symptoms following the administration of such a drug.

Stimulants
Stimulants do not typically act as psychotomimetics at normal therapeutic doses, but stimulant psychosis may occur as a result of acute overdose or chronic use of certain stimulants such as methylphenidate, amphetamines and cocaine. Psychosis has also been linked to chronic use of caffeine in schizophrenic individuals. These drugs (with the exception of caffeine) act to increase dopamine concentrations in the brain, typically through dopamine reuptake inhibition.

Opioids
Some drugs of the opioid class have psychotomimetic effects such as hallucinations, dissociation and dysphoria. Particularly, mixed kappa opioid receptor agonist/mu opioid receptor antagonist opioid analgesics can cause dose-related psychotomimesis. This adverse effect, incidence 1–2%, limits their use. Pentazocine, butorphanol and Salvinorin A fall under this opioid class. (The majority of this section is in the original article)

Dissociatives
Dissociatives such as ketamine, PCP, dextromethorphan and nitrous oxide can induce dissociation in subjects, which can result in psychotomimetic symptoms such as detachment from reality, hallucinations and a trance-like state. These drugs are NMDA receptor antagonists and as such differ from kappa opioid receptor agonists in their mechanism of action.

Serotenergic Hallucinogens
While "hallucinogen" is a broad category for any number of substances which may induce hallucinations (such as dissociatives), Serotenergic Hallucinogens in particular are members of the tryptamine, phenethylamine and ergoline families of chemical compounds which show affinity for various 5-HT receptors which may induce hallucination, altered states of consciousness,delirium and loss of contact with reality. These compounds include LSD, mescaline, psilocybin and DMT. These compound's effects are heavily dependent on the user's personality, the expectations of the user and the setting of the use. Researchers Barr et al. commented in a 1972 article: ‘‘...the phenomena induced by LSD (and probably by any similar drug) cannot be predicted or understood in purely pharmacological terms; the personality of the drug taker plays an enormous and critical role in determining how much effect there will be and of what particular type."

Anticholinergics
Anticholinergic drugs are capable of inducing delirium and hallucinations in individuals at high doses and are commonly referred to as "deliriants" These compounds include diphenhydramine, dimenhydrinate, atropine and scopolamine. The majority of these compounds are muscarinic antagonists.

Cannabis
There is evidence that cannabinoids are psychotomimetic, especially delta-9-tetrahydrocannabinol (THC). D'Souza et al. (2004) found that intravenous THC produced effects that resemble schizophrenia in both the positive symptoms (illusions, paranoia and disorganized thinking) and negative symptoms (apathy, anhedonia, alogia, asociality, avolition).Some types of cannabis may be more psychotomimetic than others, probably due to the action of cannabidiol (CBD), which inhibits P450 3A11's metabolic conversion of THC to 11-hydroxy-THC, which is four times more psychoactive. (This section and citations for it are in the original article)

Dopamine Hypothesis of Schizophrenia
Psychotomimetics have been administered to human and animal subjects to model psychosis and to develop antipsychotic treatments based on receptor antagonism. Amphetamines and other psychostimulants (PS) increase synaptic monoamine levels, and were shown to induce psychotic symptoms in 40% of patients with schizophrenia in doses that do not generate this effect in neurologically normal individuals. Other studies had shown that reserpine blocks the reuptake of dopamine and other monoamines and are effective antipsychotics .This finding, among others, provided evidence for an initial dopamine hypothesis of schizophrenia, which linked hyperdopaminergia with schizophrenia. Further studies using PET and SPECT imaging has lead to a refinement of this hypothesis, in which hyperstimulation of D2 receptors and hypostimulation of D1 receptors is linked to the symptoms of schizophrenia.

As discussed above, cannabis has been linked to an increased risk of schizophrenia, and cannibinoid agonists have been shown to increase striatal dopamine release in animals. Dopamine metabolite levels are also shown to be elevated in patients who have experienced an episode of psychosis due to cannabis use. Studies involving ketamine and other NMDA blockers have also been found to increase dopamine release in neurologically normal people to those levels found in schizophrenic patients, indicating that indirect activation of the dopamine system may occur in drugs that do not directly target the dopamine system.

Serotonin and Glutamate Hypotheses of Schizophrenia
Other research using psychotomimetics has challenged a dopamine-centric mechanism of schizophrenia. A criticism of the dopamine hypothesis is that atypical antipsychotics have a lower affinity for dopamine receptors than other neurotransmitters and are more effective in controlling the negative symptoms of schizophrenia. The glutamate hypothesis of schizophrenia originated from findings that NMDA blockers such as PCP and ketamine can induce both positive and negative symptoms of schizophrenia. Research showing that schizophrenic patients have abnormally low levels of glutamate receptors postmortem, and that animal studies show activation of glutamatergic pathways in response to PCP, have lent credence to the hypothesis that hypofunction of NMDA receptors is responsible for the development of the disease. This hypothesis is not necessarily in conflict with the dopamine hypothesis, however, as changes in glutamine receptor function will likely alter dopamine release.

Hypotheses that 5-HT receptors were involved in schizophrenia were originally made after psychotomimetic effects were observed in subjects who had taken LSD and other agonists of 5-HT receptors However this hypothesis was hampered by several factors: namely that LSD produces visual hallucinations rather than auditory, which are common in schizophrenic patients, and that schizophrenic patients present with paranoid delusions, conceptual disorganization and several cognitive impairments whereas LSD does not induce these effects. Interest in 5-HT's role in schizophrenia was limited for a 25 year period until the discovery of 5-HT receptor subtypes and the discovery of antipsychotic medications which had high affinity for 5-HT2A receptors. Further research into the role of 5-HT has shown compelling evidence that it is implicated in the pathogenesis and treatment of schizophrenia.