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Friday, 24.03.2017

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

Burton Angrist’s comment: Clinical aspects

When I began my residency training, Psychiatry was more or less overwhelmingly dominated by psychoanalytic thought.  I was excited and couldn’t wait to begin healing the sick with my clever psychotherapeutic insights.  The only problem was that the sick were inconsiderate enough not to get better.

I was using medications but my supervisor, recognizing his own limitations in this area, suggested I consult with Don Klein, our hospital’s research psychopharmacologist. Don generously reviewed my patients in detail and made suggestions for many about changes in dose, drug, etc.  They all improved!  (Some a lot, some less, but all were better to some degree).  I was floored and decided to get postdoctoral training in psychopharmacology.

I went to Jerome Jaffe, one of my Pharmacology professors in medical school, for advice and Jerry steered me to Sam Gershon, who had recently started a Psychopharmacology Research Unit at NYU/Bellevue.

I liked Sam immediately.  He was gracious, utterly without pretense, and often hilariously funny.  Over time. this fondness continued to grow but I also recognized some of his other qualities, his remarkable astuteness and clarity of thought and a real wisdom complementing his enormous knowledge base.

I began working on some of the ongoing clinical trials on the unit, learning to do some ratings, and saw some of the patients in Sam’s study of lithium vs. chlorpromazine in acute mania that led to the introduction of lithium in the US.

Soon, however, in order to stimulate my enthusiasm, Sam sat down with me and asked about my own specific interests in Psychiatry and Psychopharmacology.  Rather than naming a specific area, I said that I was interested in fine-grained clinical assessment as a clue to biologic substrates.  For example, we lump together as “paranoid” both patients who are hyper-aroused, fearful and diffusely referential, and those who calmly and with little affect say they simply have “known” for years that the government, mafia or CIA has been spying on them. Surely, there must be a different biologic basis to these clinical presentations. I remember Sam’s response,  “That’s very commendable.  Why don’t you have a look at the similarities and differences between amphetamine psychosis and schizophrenia?  Kety and others have been saying that it’s an excellent pharmacologic model.”

I was skeptical and excited – skeptical that any drug psychosis could model the rich, complex symptoms of schizophrenia but excited because I already had an interest in substance abuse and Bellevue had many patients with extraordinarily heavy and varied substance abuse histories.  (It was the mid-1960’s and I was a bit of a hippie.)  I began reading up on amphetamine psychosis and interviewing patients admitted to Bellevue after using the drug.

The literature review at first seemed surprisingly sparse.  From 1938 when it was first reported (Young & Scoville 1958) to 1958, only about 20 reports described about 30 cases of amphetamine psychosis.  In 1958, however, Connell’s monograph alone concisely and clearly described 42 patients with amphetamine psychosis (Connell 1958).  The first, clinical section of the monograph ended with 17 conclusions, three of which will be repeated here:


1.     Psychosis associated with amphetamine usage is much more common in this country than would be expected from reports in the literature.

2.     The clinical picture is primarily a paranoid psychosis with ideas of reference, delusions of persecution, auditory and visual hallucinations, in a setting of clear consciousness.

3.     The mental picture may be indistinguishable from acute or chronic paranoid schizophrenia.


Finding newly admitted patients and seeing them quickly, before their symptoms cleared might have been enormously difficult in a hospital the size of Bellevue were it not for a research screening program previously set up by Dr. Arnold Friedhoff.  In this program, a research nurse reviewed the prior 24 hours’ admission notes and listed the patient name, ward and chief complaint (or gave a description of the circumstances of admission if no complaint was offered – ie., “Found wandering nude in Central Park,” etc.)  If amphetamine was mentioned or if presenting symptoms were obviously those of an acute paranoid psychosis, I’d go interview the patient on the ward and, sometimes transfer them to Sam’s research ward.

In this way, I was able to identify and interview 60 patients with amphetamine- related admissions to Bellevue in a little over a year.  Connell’s first conclusion “psychosis associated with amphetamine usage is much more common ---- than would be expected from reports in the literature” was certainly correct.

Of these 60 patients, over half (32) had paranoid or paranoid-hallucinatory symptoms. (Auditory and visual hallucinations were most commonly seen but less frequently olfactory and tactile hallucinations were encountered.  Thus, Connell’s conclusion that “the mental picture may be indistinguishable from acute or chronic paranoid schizophrenia” also was supported). Other presentations also were seen and included:  emotional lability, tearfulness or anger, suicide attempts (cutting), potentially suicidal behavior (a patient jumped from a third story and sustained a leg fracture to escape persecutors). Unprovoked assaultiveness or bizarre behavior (a patient who took down a chain link fence and “played drums” on garbage cans) were also encountered (Angrist & Gershon 1969).

If the patients seen on other wards acknowledged amphetamine use and were willing, they were transferred to the research ward where symptoms were rated daily and urine was collected.  In this way we intended:  1. to confirm the presence of amphetamine; 2. to determine the duration required for psychotic symptoms to clear; and 3. To examine any relationships between symptoms and urine amphetamine levels.  These levels were determined in Dr. Friedhoff’s laboratory by Dr. Jack Schweitzer.

However, the design of our studies also raised some important and troublesome problems.  We didn’t know our patients’ pre-drug status and schizophrenic patients also sometimes took amphetamine.  Thus, if a patient showed thought disorder, bizarre delusions or psychotic symptoms that did not resolve rapidly (as most did) did that imply pre-existing schizophrenia or rather did it mean that amphetamine could cause such effects in normals? What was due to the drug and what was due to substrate?  I obsessed about the questions over and over and finally came to Sam with the problem. He smiled at me and said, “Doctor! You’re trying to decide whether the chicken or the egg came first.”  That of course was the answer.  The question was logically insolvable.

For a partial, perhaps imperfect solution, I fell back on Kraepelin’s concept that recovery, in schizophrenia in not a full restitutio ad integram.  When no longer psychotic, schizophrenic patients still show some residual symptoms such as blunted affect, diffuseness in line of thought and association, and perhaps, some mild delusional ideation.  I decided to have patients seen by three senior psychiatrists (Drs. Gershon, Friedhoff and our research ward senior clinician Dr. Leon Hekimian), not when acutely ill but when apparently fully recovered, prior to discharge.  Patients were then assigned to two groups, one who showed complete clearing and another with residual schizophrenic psychopathology (C & RSP). The study then showed that 1.  amphetamine was present in all patients’ urine; 2. psychotic symptoms cleared rapidly and this clearing paralleled the curve of declining amphetamine levels; 3. Not all patients reported hallucinations initially, but in those who did, hallucinations were invariably the first symptoms to clear; and 4. there were only trivial and clinically insignificant differences in the rate of clearing between patients who cleared completely and those who, when no longer psychotic, showed residual schizophrenic psychopathology (Angrist, Schweitzer, Friedhoff, Gershon, Hekimian, Floyd 1969).

As this study was nearing completion, Griffith and coworkers reported a new approach to the study of amphetamine psychosis -- the prospective experimental induction of the condition by administration of the drug to screened non-schizophrenic volunteer-abusers.  This stronger design enabled the researchers to observe the development of the psychosis uncontaminated by the possible use of other drugs or by pre-existing Axis I disorders.

Dextroamphetamine 5 to 10 mg per hour was administered orally.  Blood pressure, pulse rate and temperature were checked before each dose.  EKGs were done at baseline and if any change in cardiac rhythm was noted. This was done around the clock for as long as subjects tolerated it.  Four subjects participated (Griffith, Oates, Cavanaugh 1968).

As noted in more detail in a subsequent report (Griffith, Cavananaugh, Held, Oates 1972), all four subjects became paranoid.  Some felt they were being secretly photographed or described on TV.  One felt that the entire study was a subterfuge.  Another felt an assassin had been hired to kill him.  Yet another became aware of a “giant oscillator” hidden in the ceiling that both controlled his thoughts and the behavior of others.

We pursued similar studies with the same safety measures Griffith et al. had devised, but slightly changed the drug and dosing regimen.  Racemic amphetamine tables were used and dosing was made more flexible and potentially somewhat more aggressive (0-50 mg per hour could be given with the dose determined by the blood pressure and pulse rates determined immediately before) .

The first study involved 4 patients (Angrist & Gershon 1970). The first developed a characteristic syndrome that occurred each time he took amphetamine or related drugs (mephentermine inhalers) (Angrist, Schweitzer, Gershon, Friedhoff 1970) and which had led to many prior hospitalizations at Bellevue.  He began to smell a “vile” smell that he thought was caused by the drug being excreted in his perspiration.  He would then feel that he was so offensive to others that they or some “gang” would “clean me up” or kill him. Often voices would reinforce these fears.  In this case (after a cumulative dose of 230 mg), he began to take one of several showers.  Later, lying in bed and still preoccupied with ideas about smelling, he heard other patients (who were on a separate part of the ward at the time) discussing him, “He’s stupid.  Why is he doing it?  He’s not doing anything.  He’s just staying up.”  He saw someone working in a laboratory across the street and felt he had been “planted” to observe him.

The second subject in this series began to feel that he had received special enlightenment from God and became “a prophet.”  He began writing his “revelations” frantically, then stopped and stood preaching them loudly to the world at large:


“My consciousness in the form of what you know as human. My feeling which I receive from Him.  I bring the answer to the unknown and yet.  In my human form, He might let me act human, for the rest must still wonder at my actions, which make them doubt my havingbeen used to enlighten.   Every thought that stops me from accepting all knowledge, more than man has ever known.  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 am His.  I bring His will, call it prophet.”


Of the other two subjects, one became withdrawn and irritable and described a momentary episode of “terror” (feeling someone was behind him).  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, Shopsin, Gershon, Wilk 1972), florid psychotic states conforming precisely to prior descriptions of amphetamine psychosis were seen.

One subject, after 465 mg racemic amphetamine over 23 hours saw “colored haloes” around lights, then “heard” a gang coming on the ward to kill him.  His suspicions included the experimenter, who he assumed “set up the trap” and he lunged, but was able to stop himself.  He rejected explanations that his experiences were drug induced with sardonic mock agreement (e.g., “Oh? Hah! So that’s the way it’s going to be?”). At other times, he became tearful and begged the experimenter to explain “what was really going on.”  He had visual hallucinations of gangsters and doors opening and closing in the shadows and visual illusions (e.g., paper on a bulletin board “turned into” a gangster in a white raincoat).  He jumped at the slightest sound, assuming it was the gang coming to “get” him.


What Does Amphetamine Psychosis Model?


Connell’s fourth conclusion was “the mental picture may be indistinguishable from acute or chronic paranoid schizophrenia.”  Some controversy exists, particularly with respect to affect and thought disorder in amphetamine psychosis.

In his review of Connell’s monograph, Slater (1969) commented that the two disorders may differ with respect to “the brisk emotional reactions usually in the direction of anxiety”.  In contrast, Griffith and co-workers (1972) noted that “subjects who were previously quite verbal and relatively trusting became quite taciturn and reserved and negativistic, and described their affect as “cold” and “detached.”  Bell did a study in which methamphetamine was given intravenously in doses individualized to raise blood pressure 50% and observed psychoses while subjects were still acutely elated. (Bell 1973).  He commented that “the relatively slow oral administration of the drug in their (Griffith and co-workers) study probably “confused the issue” (Bell 1973).

Our own experience may support Bell’s assessment. We clearly have seen dysphoric and blunted affect in some subjects but I don’t recall ever seeing this response until subjects had been taking the drug overnight at least, a time at which there might have been some admixture of fatigue and “crashing” (Warning! 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. (1973) and Bell explicitly noted that this sign was not seen in amphetamine psychosis (Bell 1965).  We’ve seen some examples which, although relatively mild, are, I believe, recognizably schizophreniform.  Two examples are: 

1.     In response to the proverb “people who live in glass houses shouldn’t throw stones” – “If you throw stones you risk your life.  Living in a glass house would shatter your whole being.”

2.     In a patient who had received 430 mg of l-amphetamine in a study and been asked how he felt, “agitated and annoyed”; (Why?)  “It’s a ridiculous thing! Like the marijuana laws.  That’s totally ridiculous!  It’s like a thunderstorm in the forest.  It affects young trees.  There’s a balance of nature.  You mess with the balance of nature you lose buffalo, you lose birds.  For man, you lose philosophies” (Angrist, Sathananthan, Wilk, Gershon 1974).

In addition to schizophrenia another condition that amphetamine psychosis models quite faithfully is psychotic mania. Post (1975) 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, Goodwin 1973).  Fibiger (1991) 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.  The distinction is made longitudinally and based on interphase functioning and deficits when “well.”  In this, amphetamine psychosis with its usual tendency toward a restitutio ad integram, more closely models psychotic mania.



Angrist BM, Gershon S. Amphetamine abuse in New York City 1966-1968. Seminars in Psychiat. 1969; 195-207.

Angrist, BM, Schweitzer J. Friedhoff, AJ, Gershon S, Hekimian, LJ, Floyd A. The clinical symptomatology of amphetamine psychosis and its relationship to amphetamine levels in urine.  Int Pharmacopsychiat 1969; 2: 125-139.

Angrist BM, Gershon S. The phenomenology of experimentally induced amphetamine psychosis – preliminary observations. Biol Psychiat. 1970; 95-107.

Angrist BM, Schweitzer J, Gershon S, Friedhoff AJ. Mephentermine psychosis: misuse of the wyamine inhaler. Am J Psychiatry 1970; 26: 1315-17.

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

Angrist BM, Sathananthan G, Wilk, S, Gershon, S.  Amphetamine psychosis:  behavioral and biochemical aspects.  J Psychiatric Res 1974; 13-23.

Bell DS.  The experimental reproduction of amphetamine psychosis.  Arch Gen Psychiatry 1973; 29: 35-40. 

Bell DS.  A comparison of amphetamine psychosis and schizophrenia.  Br J  Psychiatry 1965; 3: 703-6.

Carlson, GA, Goodwin, FK.  The stage of mania.  Arch. Gen. Psychiatry 1973; 28: 221-28.

Connell, PH.  Amphetamine psychosis.  Maudsley monographs number 5. London/Nrw York/Philadelphia: Oxford University Press; 1958.

Fibiger, HC, The dopamine hypothesis of schizophrenia and mood disorders:  contradictions and speculations.  The mesolimbic dopamine system: From motivation to action. Chichester (England):  John Wiley & Sons: 1991, pp. 615-37.

Griffith JD, Oates JA, Cavanaugh  J.  Paranoid episodes induced by drugs.  J Am Med Assoc 1968; 205: 39.

Griffith JD, Cavanaugh J, Held J, Oates JA.  Dextroamphetamine evaluation of psychotomimetic properties in man.  Arch Gen Psychiatry 1972;  26: 97-100.

Herman M, Nagler SV.  Psychosis due to amphetamine.  J Nerv Ment Dis 1954; 130: 268-72.

Post, RM. Cocaine psychosis a continuum model.  Am J. Psychiatry 1975; 132:  225-31.

Slater, E.  Review of amphetamine psychosis by P.H. Connell.  Br Med J 1959;  1: 489.

Young D, Scoville NB.  Paranoid psychosis in neurology and the possible danger of Benzedrine treatment.  Med Clin N Am 1978; 22:  637-46.


Burt Angrist

December 31, 2016