Major aspects of amphetamine psychosis and its relationship to paranoid schizophrenia

major aspects of amphetamine psychosis and its relationship to paranoid schizophrenia

In this paper, we review certain aspects of this relationship, with also point to amphetamine-induced psychosis as a major risk factor for primary psychosis. Amphetamine Psychosis Schizophrenia Substance-induced Mortality and its association with psychosis and the use of amphetamines will be. which 42 patients with amphetamine psychosis were studied, CONNELL concluded that acute or chronic paranoid schizophrenia.“2 rather strikingly similar to schizophrenia in its presentation but that these two conditions could be .. the drug and examined the dose-response relationships for the induction of psychosis. COMPARISON OF AMPHETAMINE PSYCHOSIS AND SCHIZOPHRENIA. Br J Psychiatry [PubMed]; Kernberg O. Structural derivatives of object relationships. Prolonged cocaine psychosis implies underlying major psychopathology.[J Clin.

Prevalence and clinical presentation Observations strongly suggest a relationship between the intake of amphetamines and the development of acute psychosis.

First, early studies demonstrated that amphetamines could trigger acute psychosis in healthy subjects. In these studies, amphetamine was given in consecutively higher doses until psychosis was precipitated, often after — mg of amphetamine [ 20 - 23 ]. The symptoms subsided within 6 days. The effect was blocked by the use of anti-psychotics [ 24 ].

Not all the subjects in these studies became psychotic, as some had to be removed from the experiment because of health risks caused by elevation of heart rate, blood pressure or body temperature. Secondly, psychosis has been viewed as an adverse event, although rare, in children with ADHD who have been treated with amphetamine [ 25 - 30 ].

The wide variation is probably due to different populations being studied, gender [ 38 ] and the method and duration of amphetamine use [ 39 ]. It may also depend on the instruments used to assess psychosis, e. Lastly, there is a positive correlation between amphetamine availability at a community level and the incidence of psychosis in the same population [ 41 - 44 ]. There is clinical evidence that such binges may end in psychosis.

Types of Drug-induced Psychotic Delusions

Surprisingly, it is poorly understood [ 150 ], whether such psychosis is due to amphetamine use per se amount over time, amount on one occasion or the length of the current bingevulnerabilities in the user or both. It could be that psychosis occurs because of the sleep deprivation that follows amphetamine use, or because of other factors at the end of a binge.

Users will often end their binge by using sedating drugs like alcohol, benzodiazepines, opiates or cannabis. This could be viewed as self-medication [ 51 ] and may be one reason why users often develop problems with several drugs. Only a weak relationship has been reported between psychotic symptoms and the level of amphetamines in the blood of psychotic patients [ 5152 ].

This could be because acute blood levels at the end of a binge are a poor representation of overall amphetamine exposure, but it could also be because individual vulnerability, rather than level of amphetamine exposure, is the critical risk factor for developing acute psychosis. The symptoms of psychosis induced by amphetamines are very similar to those of acute schizophrenia spectrum psychosis and include: Some studies have suggested differences with more pronounced grandiosity and visual hallucinations [ 5254 ].

The thought disorders that occur in schizophrenia characterized by a splitting and loosening of associations, a concreteness of abstract thought, and an impairment in goal-directed thought, may be less prominent in amphetamine induced psychosis [ 55 ]. However, distinguishing the two types of psychosis on the basis of acute symptoms is probably very difficult [ 56 ]. The similarities between the two conditions are, in fact, so pronounced that this has been used as an argument for using amphetamine-induced psychosis as a model for primary psychotic disorders [ 215457 - 59 ].

In contrast to schizophrenic psychosis, acute psychosis induced by amphetamines seems to have a faster recovery [ 60 - 63 ], and appears to resolve with abstinence, although the recovery may be incomplete [ 43 ].

Japanese researchers have argued that psychosis induced by amphetamines could, in fact, be of much longer duration, up to several years [ 64 - 66 ]. Stressful situations seem to trigger such flashbacks in susceptible individuals and several vulnerability factors have been identified, e. It is difficult to distinguish the Japanese chronic amphetamine psychosis from a primary psychosis triggered by the use of amphetamines [ 64 ], although it has been claimed that they constitute separate entities.

Risk factors and acute vs. Sensitization is also seen in human subjects [ 72 ]. There is reason to believe that an earlier psychosis involves a risk of future psychotic episodes due to this sensitization [ 4373 - 75 ], or possibly to the development of dopaminergic super sensitivity [ 7677 ]. Psychosis may be precipitated acutely by amphetamine due to its effects on dopaminergic activity in the CNS [ 46 ].

In the longer term, the neurotoxic effects of the drugs on serotonin and dopamine neurons [ 78 ] and dopamine transporters [ 79 ] may play a role. Amphetamine sensitization seems to cause dysregulation of dopamine by the ventral subiculum [ 80 ]. There is an over-expression of the dopamine receptor, subtype 2 DRD2 [ 81 ] and a higher sensitivity of DRD2 to the effects of amphetamines in vulnerable individuals [ 82 ].

In addition to the increased risk of psychosis following the use of amphetamines in people who have experienced amphetamine-induced psychosis previously, patients with schizophrenia [ 83 ] and schizotypal personality traits [ 7484 ] may more readily become psychotic after the use of amphetamines. Other risk factors for psychosis may include amphetamine use disorders abuse and dependencethe presence of other psychiatric disorders primarily attenuated psychosis syndrome, personality disorders and affective disordersearly cognitive dysfunction such as those found in the prodromal states of schizophreniafamily history of mental disorder and the use of other drugs like opiates, benzodiazepines, cannabis and alcohol [ 3767747585 - 87 ].

Several susceptibility genes have been found in common for amphetamine-induced psychosis and schizophrenia [ 3258 ]. These genes increase the risk both for becoming psychotic and for a poorer clinical course of the disease. Studies in Japan also indicate that primary and drug induced psychosis may be genetically linked. Relatives of methamphetamine-users with a lifetime history of amphetamine psychosis are 5 times more likely to have schizophrenia than methamphetamine-users without a history of psychosis [ 85 ].

Patients with schizophrenia and those with psychosis induced by amphetamines both show significantly increased peripheral plasma levels of norepinephrine compared to methamphetamine users who do not have psychosis, and to non-using conrols [ 6588 ].

This seemingly common vulnerability is important considering the difficulties in distinguishing between the two conditions in the long term. The precipitation of psychosis by amphetamines in healthy subjects can be blocked by anti-psychotics [ 2489 ]. Similarly, psychotic symptoms caused by amphetamines can, like acute schizophrenic psychosis, be treated with anti-psychotics [ 90 ]. A Cochrane review from [ 91 ] identified only one randomized controlled trial of treatment for psychosis induced by amphetamines which met the criteria for included studies.

It showed that both olanzapine and haloperidol in clinically relevant doses were effective in treating psychotic symptoms [ 92 ]. One problem with using anti-psychotics could be that such drugs have a tendency to block the DRD2, potentially increasing anhedonia that could, in turn, cause a greater vulnerability to relapse into drug abuse.

Some studies indeed point in this direction [ 93 - 95 ]. The use of alternative therapeutic drugs, such as benzodiazepines, will reduce the chance of extra pyramidal adverse effects [ 96 ] and decrease the risk of intoxication [ 97 ]. However, one argument against this strategy is that anti-psychotics seem to protect against the neurotoxic effects of amphetamines [ 9899 ]. In my human form, He might let me act human, for the rest must still wonder at my actions, which make them doubt my having been used to enlighten.

Every thought that stops me from accepting all knowledge, more than man has ever known.

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It is just part of the supreme game to make you wait until it is time for you to receive everlasting good. It is not mine to give. I bring His will, call it prophet.

major aspects of amphetamine psychosis and its relationship to paranoid schizophrenia

The other became emotionally labile, infantile, provocative and hostile. She frequently glanced to the side with alarm, but denied visual hallucinations. Probably, neither could be described as formally psychotic. In subsequent studies Angrist et al. He rejected explanations that his experiences were drug induced with sardonic mock agreement e.

What Does Amphetamine Psychosis Model? This observation is from memory of studies done about 40 years ago. Thought disorder in amphetamine psychosis is also somewhat controversial. It was not noted in the studies of Griffith et al.

major aspects of amphetamine psychosis and its relationship to paranoid schizophrenia

Living in a glass house would shatter your whole being. Like the marijuana laws. It affects young trees. You mess with the balance of nature you lose buffalo, you lose birds. In addition to schizophrenia, another condition that amphetamine psychosis models quite faithfully is psychotic mania.

Post noted that the response to increasing doses of CNS stimulants progresses in a continuum from activation and euphoria through dysphoria to psychosis. A similar longitudinal evolution occurs in an episode of psychotic mania Carlson and Goodwin, Fibiger noted this and proposed that amphetamine psychosis be considered a model of psychotic mania.

So, which is it — schizophrenic or psychotic mania? I think the two often cannot be distinguished in the acute phase at a single point in time. Biological aspects The clinical similarities between amphetamine psychosis, on the one hand, and acute schizophrenia, psychotic mania or other unspecified acute psychotic states, on the other, suggested the possibility of common biologic substrates.

Pioneering work on the mechanism of action of amphetamine and the biologic basis of its effects particularly at high doses was done in the laboratory of the Danish pharmacologist Axel Randrup and co-workers Munkvad, Scheel, Kruger, Schorring and others. These workers found that in animals, high dose stimulant treatment i. The type of behavior varied with species. As doses increased, rats sniffed, licked or chewed the cage. Cats moved eyes or head from side to side. Monkeys repetitively moved the body limbs or hands.

Some human abusers also reported prolonged cleaning, self-washing, sorting items from a purse or dismantling clocks or other mechanical objects Randrup and Munkvad, The pharmacology of this stereotyped behavior was studied intensively.

The findings converged on the conclusion that this behavior was mediated by dopaminergic hyperactivity in the striatum. For example, the behavior could be induced by microinjections of amphetamine, apomorphine, p-hydroxyamphetamine or dopamine itself into the striatum and was antagonized by striatal microinjection or systemic administration of neuroleptics Randrup and Munkvad, These studies were well known and influential.

Thus we recognized that our own biological studies would probably focus on the effects of amphetamine on catecholamine neurotransmitters, particularly dopamine.

We did four such studies, which are described briefly here. Rather, it was suggested in discussion at a meeting in which J. Smythies proposed that amphetamine psychosis might not be related to effects of amphetamine per se, but rather was due to the formation of paramethoxy amphetamine PMA from the amphetamine previously taken.

PMA had mild, brief psychedelic effects and was also found to have strong pressor effects in some subjects Shulgin and Shulgin, I was skeptical about Smythies proposal, since the clinical effects of amphetamine were rather different from those of psychedelic agents.

More pertinent for scientific purposes, however, was the fact that we had saved the urine of our subjects in our studies of experimentally induced amphetamine psychosis. I reported Smythies proposal to Drs. Gershson, Friedhoff and Jack Schweitzer, the analytical chemist in Dr.

They felt sure they could identify PMA if it was present in urine and were eager to run the analyses. This was done and no PMA was found in the urine of any subject Angrist et al. I was busily patting myself on the back when Dr. PMA was detected in the urine of all subjects, including those who received the lowest dose Schweizer et al. The Comparative Psychotomimetic Effect of Stereoisomers of Amphetamine Amphetamine was known to increase synaptic levels of both norepinephrine NE and dopamine DAbut the specific relationship to amphetamine-induced behavior remained somewhat uncertain.

major aspects of amphetamine psychosis and its relationship to paranoid schizophrenia

InSnyder et al. For example, d-amphetamine was 10 times as potent as the l-isomer in inhibiting the uptake of NE in synaptosomes from cortical areas, but only one or two times as potent as the l-form in inhibiting the uptake of dopamine from striatum. Behavioral correlates showed a 10 to 1 potency for d- vs. These findings, taken together, indicated primarily noradrenergic mediation of increased locomotor behavior and dopaminergic mediation of stereotyped behavior, respectively Snyder et al.

We then did a study in which three subjects took cumulative high doses of d- and l-amphetamine on separate occasions. Each had his own characteristic response to both isomers! The first subject received cumulative doses of mg of d- and mg l-amphetamine.

During both studies, he became progressively more irrelevant and diffuse in his thinking and developed mild ideas of reference to the effect that the TV was directed particularly to him, as well as dose-related flattening of affect.

Subject 2 developed the same type of thinking disorder characterized by irrelevance, tangentiality and diffuseness of thought, as well as progressive flattening of affect and olfactory hallucinations on both isomers mg d-amphetamine, mg of the l-isomer. The third subject received the same dose of each isomer mg and developed a paranoid psychosis each time.

Catecholamine Metabolites in Cerebrospinal Fluid After Amphetamine Administration In these studies, four subjects were observed on the research unit drug free prior to lumbar puncture. They then received cumulative doses of — mg racemic amphetamine prior to a second lumbar puncture. One of the four subjects developed a paranoid psychosis that precluded his cooperation with the second LP until No changes were seen in either metabolite, and inspection of levels revealed no trend toward consistent change in either Angrist et al.

However, it was likely that absolute levels of neurotransmitter metabolites did not reflect turnover. Inferences about turnover, however, could be made if egress of transmitter metabolites from CSF was blocked with probenecid Goodwinet al. We, therefore, studied a fifth subject under three conditions: MHPG did not change over the experiment. Antagonism of Amphetamine-Induced Effects by Haloperidol This study was done in eight subjects, who either entered the hospital with acute psychotic symptoms after taking amphetamine or were administered moderate doses of the drug on the research ward.

INHN: Burton Angrist: Studies of Amphetamine Psychosis (Collated by Olaf Fjetland)

The latter group was not psychotic, but did show clear hyperarousal and over-activation. A single injection of haloperidol 5 mg was then given and psychopathology rated 45 minutes to one hour post injection. The antagonism of amphetamine effects was clinically quite striking.

Hyperarousal and activation cleared nearly completely, any psychotic symptoms cleared completely, or nearly so, in almost every case. The effects of haloperidol may not be entirely selective for the D2 receptor, but the affinity at that site is substantially greater than for other biological targets. I gratefully acknowledge that the suggestion to do this project was made by Dr. Randrup, when I visited his lab. Angrist BM, Gershon S.

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