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Tuesday, 21.11.2017

Samuel Gershon: Events and Memories. 9. Model psychoses. Amphetamine

Burton Angrist’s comment: 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.e., in the dose range usually associated with psychosis in humans) led to constricted, repetitive stereotyped behavior in which elements of normal behavior such as grooming and eating were completely excluded.  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 1967).

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 1970).

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.

 

1. Studies of Paramethoxy Amphetamine  (PMA) in Humans

 

The first of these studies, however, did not address effects of amphetamine on neurotransmitters.  Rather, it was suggested in discussion at a meeting in which J.R. 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.

This idea was an extension of concepts previously expressed in an influential prior paper, in which it was hypothesized that abnormal methylation might produce psychotoxic metabolites that led to the development of schizophrenia – the “trans-methylation hypothesis” of schizophrenia (Osmond and Smythies 1952).

PMA had mild, brief psychedelic effects and was also found to have strong pressor effects in some subjects (Shulgin and Shulgin 1991).

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. Friedhoff’s lab.  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, Schweitzer, Friedhoff, Gershon 1970).

I was busily patting myself on the back when Dr. Friedhoff interrupted my self-congratulations with the thought, “what if PMA is a very labile, rapidly metabolized molecule?”  We, therefore, administered PMA to normal subjects.  Doses given ranged from 10 mg/subject to 1 mg/kg.  PMA was detected in the urine of all subjects, including those who received the lowest dose (Schweizer, Friedhoff, Angrist, Gershon 1971).  The one high dose subject (myself) had a brief but alarming pressor effect (BP 240/130), from which I learned some lessons about recklessness that have not been forgotten.

 

2.  The Comparative Psychotomimetic Effect of Stereoisomers of Amphetamine

 

Amphetamine was known to increase synaptic levels of both norepinephrine (NE) and dopamine (DA) but the specific relationship to amphetamine-induced behavior remained somewhat uncertain.  In 1970, Snyder et al reported that the d and l isomers of amphetamine had brain area specific magnitudes of effects on (DA) vs. (NE).  For example, d-amphetamine was ten times as potent as the l-isomer in inhibiting the uptake of NE in synaptosomes from cortical areas but only 1 or 2 times as potent as the l-form in inhibiting the uptake of dopamine from striatum.  Behavioral correlates showed a ten to one potency for d- vs. l-amphetamine in causing locomotor stimulation but only a 1 to

2 potency for inducing stereotyped behavior.  These findings, taken together, indicated primarily noradrenergic mediation of increased locomotor behavior and dopaminergic mediation of stereotyped behavior, respectively (Snyder, Taylor, Coyle, Meyerhoff, 1970).

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 510 mg of d- and 640 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.  Some of his productions are noted in part one of this report (see the quotation on the “balance of nature” from the last patient in that report). 

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 (270 mg d-amphetamine, 415 mg of the l-isomer).

The third subject received the same dose of each isomer (475 mg) and developed a paranoid psychosis each time.

The doses of d- and l-amphetamine required to produce these effects were on the order of between 1 and 2/1 (d vs. l), suggesting a role for dopaminergic events in the development of psychosis (Angrist, Shopsin, Gershon 1971).

 

3. 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 400 – 525 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 16.5 hours after the last dose. Cerebrospinal fluid (CSF) was analyzed for 3-methoxy-4-hydroxyphenylglycol (MHPG) and homovanillic acid (HVA).  No changes were seen in either metabolite, and inspection of levels revealed no trend toward consistent change in either (Angrist, Shopsin, Gershon & Wilk, 1972).

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 (Goodwin, Post, Dunner and Gordon, 1973).  We, therefore, studied a fifth subject under 3 conditions:  (1) drug free, (2) after probenecid alone (100mg/kg over 18 hours) and (3) after both amphetamine 250 mg over 21 hours and probenecid 100 mg/kg over the 18 hours before the lumbar puncture was performed. MHPG did not change over the experiment.  However, HVA increased from less than 20 ng/ml drug free, to 120 ng/ml on probenecid alone and to 200 ng/ml after both probenecid and amphetamine 250 mg, suggesting that the amphetamine had indeed increased dopamine turnover (Angrist, Wilk, Gershon, 1974).

 

4.  Antagonism of Amphetamine-Induced Effects by Haloperidol

 

This study was done in 8 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.  The latter group was not psychotic, but did show clear hyperarousal and over-activation.  Each subject was interviewed and his psychiatric pathology rated on the Brief Psychiatric Rating Scale (BPRS).  A single injection of haloperidol 5 mg was then given and psychopathology rated 45 minutes to 1 hour past 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.  Even in this small group, two BPRS items, “suspiciousness” and “excitement”, decreased to a degree that was statistically significant (Angrist, Lee, Gershon 1974).

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.  Thus, the robustness of the clinical effects, particularly after the comparatively low single dose of 5 mg/subject, suggests rather strongly that the effects seen were due to the D2 receptor blockade.

I gratefully acknowledge that the suggestion to do this project was made by Dr. Randrup, when I visited his lab.

 

References:

 

Angrist B, Lee HA, Gershon S.  The antagonism of amphetamine-induced symptomatology by a neuroleptic.  Am J Psychiat 1974; 131:  817 – 9.

 

Angrist B, Schweitze J, Friedhoff AJ, Gershon S. Investigations of p-methoxy-amphetamine excretion in amphetamine- induced psychosis.  Nature 1970; 225: 652-652.

 

Angrist B, Shopsin B, GershonS.  The comparative psychotomimetic effects of stereoisomers of amphetamine.  Nature 1971; 234: 152-155.

 

Angrist B, Shopsin B, Gershon S,  Wilk S.  Metabolites of monoamines in urine and cerebrospinal fluid after large dose amphetamine administration.  Psychopharmacologia 1972; 26: 1-9.

 

Angrist B, Wilk S, Gershon S.  The effect of probenecid and large dose amphetamine administration on cerebrospinal fluid homovanillic acid.  Biol Psychiat 1974; 8: 113-4.

 

Goodwin FK, Post RM, Dunner DL, Gordon EK.  Cerebrospinal fluid amine metabolites in affective illness: the probenecid technique.  Am J  Psychiat 1973; 130: 73-79..

 

Osmond H, Smythies JR. Schizophrenia:  A new approach. J Ment Sci 1952; 98:  309.-15.

 

Randrup A, Munkvad I. Stereotyped activities produced by ampahetamine in several animal species and man. Psychopharmacologia 1967; 11: 300-10.

 

Randrup A, Munkvad I.  Biochemical, anatomical and psychological investigations of stereotped behavior induced by amphetamine.   In Costa E, Garattini S, editors. Amphetamine and Related Compounds.  New York: Raven Press; 1970, pp. 695-712.

 

Shulgin A, Shulgin A, PIHKAL. A Chemical Love Story.  Berkeley:Transform Press; 1991, pp. 707-9.

 

Snyder SH, Taylor KM Coyle JR, Meyerhoff JL.  The role of brain dopamine in behavioral regulation and the actions of psychotropic drugs.  Am J Psychiat 1970; 127: 199 - 207.

 

Schweitzer J, Friedhoff AJ, Angrist B, Gershon S.  Excretion of p-methoxy-amphetamine administered to humans.  Nature 1971; 229: 133-4.

 

Burton Angrist

April 07, 2016