Stress induced spontaneous recurrence of methamphetamine psychosis: the relation between stressful experiences and sensitivity to stress

Drug and Alcohol Dependence 58 (2000) 67 – 75 www.elsevier.com/locate/drugalcdep

Stress induced spontaneous recurrence of methamphetamine psychosis: the relation between stressful experiences and sensitivity to stress Kunio Yui a,*, Kimihiko Goto b, Shigenori Ikemoto c, Takeo Ishiguro a a

Department of Psychiatry, Jichi Medical School, Minamikawachi, Tochigi 329 -0498, Japan b Oyama National College of Technology, Nakakiku, Tochigi 233 -0806, Japan c Department of Legal Medicine and Human Genetics, Jichi Medical School, Minamikawachi, Tochigi 329 -0498, Japan Received 19 January 1999; received in revised form 22 March 1999; accepted 1 June 1999

Abstract We examined increased sensitivity to stress in relation to spontaneous recurrences of methamphetamine (MAP) psychosis (i.e., flashbacks). Plasma monoamine metabolite levels were assayed in: 26 flashbackers, of whom 11 were on neuroleptics before and during the study, and the other 15 received neuroleptics in the course of the study; 18 non-flashbackers with a history of MAP psychosis; eight subjects with persistent MAP psychosis; and 23 MAP user and 11 non-user controls. The 26 flashbackers had experienced stressful events and/or MAP-induced fear-related psychotic symptoms during previous MAP use. Mild psychosocial stressors then triggered flashbacks. During flashbacks plasma norepinephrine levels increased markedly; among the flashbackers, those with a history of stressful events, whether or not they had experienced fear-related symptoms, showed a further increase in 3-methoxytyramine levels. Stressful experiences, together with MAP use, may therefore induce sensitization to stress associated with noradrenergic hyperactivity, involving increased dopamine release, and so triggering flashbacks. © 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Methamphetamine psychosis; Flashbacks; Stressful experiences; Norepinephrine; 3-methoxytyramine

1. Introduction Spontaneous recurrences of amphetamine- (AMP) or methamphetamine- (MAP) induced paranoid-hallucinatory states (i.e., flashbacks) occasionally occur in response to stress (Utena, 1966; Yui et al., 1996, 1997). We have reported that noradrenergic hyperreactivity to mild stress may be a precipitating factor in the development of flashbacks (Yui et al., 1996, 1997). By further studying subjects with flashbacks, we find using monoamine metabolite analysis the possible involve Institute at which the work was carried out: Department of Legal Medicine and Human Genetics, Jichi Medical School, Minamikawachi, Tochigi 329-0431, and Medical Care Section, Tochigi Prison, Ministry of Justice, Sozya 2484, Tochigi 328-0002, Japan. * Corresponding author. Present address: Takasago 3-16-34-31, Urawa 336-0011, Japan. Tel.: +81-48-8627520; Fax: + 81-488361372. E-mail address: [email protected] (K. Yui)

ment of dopaminergic changes in addition to noradrenergic hyperactivity, in the development of flashbacks. Stress-induced noradrenergic hyperreactivity to mild stress may be a precipitating factor in stress-related psychiatric disorders (Irwin et al., 1986). Stress-induced increase in noradrenergic activity has been implicated in poor coping with mild stress (Petty et al., 1994) and in the recall of traumatic events in post-traumatic stress disorder (PTSD), involving reexperiencing of the trauma with hallucinations (Southwick et al., 1993). AMP induces enduring sensitization to stress via dopaminergic changes, which may predispose subjects to a stress-precipitated psychotic episode as seen in former AMP addicts (Robinson et al., 1986). It is therefore possible that sensitization to stress associated with noradrenergic hyperactivity, to which dopaminergic changes may contribute, could be critical in the development of flashbacks. The aim of this study is to examine the nature, determinants, and significance of

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this stress sensitization in the development of flashbacks. Since plasma levels of catecholamines (such as norepinephrine or epinephrine) are used as an indicator of physiological response to stress (Pe´ronnet et al., 1986), we investigated plasma monoamine metabolite levels in three subgroups of subjects with flashbacks. These subjects were classified according to a history of stressful events or MAP-induced fear-related psychotic symptoms.

2. Methods

2.1. Subject The subjects were 86 physically healthy females, including 44 with a history of MAP psychosis, eight with persistent MAP psychosis, and 34 normal controls (23 MAP users and 11 non-users, none of whom had experienced MAP psychosis or flashbacks). These were recruited from inmates at a women’s prison. Twenty-six of the 44 subjects with a history of MAP psychosis experienced flashbacks during their 15 – 20 months of incarceration (designated as flashbackers); the other 18 did not (non-flashbackers) (Table 1). The 26 flashbackers were selected as having experienced a severe to catastrophic type of psychosocial stressor (DSM-III-R axis IV scores of 4 – 6) or MAP-induced fear-related paranoid-hallucinatory states, or both, during previous MAP use. The 18 non-flashbackers were selected as having broadly similar times of resolution of MAP psychosis to times for the 26 flashbackers (within 730 days of blood sampling; flashbackers: mean= 2389 209.4 S.D. days; non-flashbackers: 249.79 199.1 S.D. days). The eight subjects with persistent MAP psycho-

sis, which lasted for at least 6 months prior to blood collection (15.3910.9 months), were included for comparison with the flashbackers (spontaneous versus persistent recurrence) in their plasma monoamine metabolite levels. Twelve of the 26 flashbackers, six of the 18 non-flashbackers, 15 of the 23 user controls, seven of the 11 non-users (Yui et al., 1996, 1997), and six of the eight subjects with persistent MAP psychosis (Yui et al., 1996) had participated in our previous studies. The subject subgroups were age-matched (between the subject subgroups, Z or Zc= 0.06–1.66, P= 0.10–0.96). All subjects were deemed physically healthy based on physical and neurological examinations and biochemical screening. All subjects had been tested for other illicit drugs by the police and results were negative. None of the subjects experienced any other psychiatric disorder in the absence of MAP use. Informed consent was obtained from each individuals before participation in this study, which was approved by the Medical Care and Classification Division of the Ministry of Justice. Clinical diagnosis was confirmed using the DSM-IV criteria for AMP-induced psychotic disorder, based on a structured interview and inmate record review. Subjects were further screened using the DSM-IV checklist for the following exclusion criteria: schizophrenia, brief psychotic disorders, anxiety disorders, or PTSD. Flashbacks due to previous MAP psychosis were defined with reference to the DSM-IV criteria for hallucinogen persisting perception disorder (flashbacks), and a general definition of psychedelic drug flashbacks (Matefy et al., 1978) as a spontaneous recurrence of MAP-induced paranoid-hallucinatory states following a period of normalcy during which the pharmacological effects of MAP were fully worn off.

Table 1 Subject subgroupsa

Flashbackersb Flashbackers with a history of stressful events plus fear-related symptoms Flashbackers with a history of stressful events Flashbackers with a history of fear-related symptoms Medicated flashbackersc Later-medicated flashbackersd Non-flashbackers Subjects with persistent MAP psychosis Control subjects MAP users MAP non-users

n

MAP use

MAP psychosis

Flashbacks

26 11 7 8 11 15 18 8

+ + + + + + + +

+ + + + + + + +

+ + + + + + − −

23 11

+ −

− −

− −

a +, Subjects who had experienced methamphetamine (MAP) psychosis or related flashbacks; −, subjects who had not experienced MAP psychosis or related flashbacks. b The 26 flashbackers were classified into three subgroups: 11 who had experienced stressful events plus MAP-induced fear-related paranoid-hallucinatory states, seven who had experienced stressful events alone, and eight who had experienced fear-related symptoms alone. c The flashbackers who received neuroleptic treatment before and during the study. d The flashbackers who received neuroleptic treatment following blood-collection during flashbacks, and during remission.

K. Yui et al. / Drug and Alcohol Dependence 58 (2000) 67–75

Of the 26 flashbackers, 11 were maintained on haloperidol (1–6 mg/day), chlorpromazine (50 – 75 mg/ day), or thioridazine (30 – 75 mg/day) for at least 4 weeks before and during the study (medicated flashbackers). The other 15 flashbackers were unmedicated for at least 3 months prior to blood collection. However, they received the above neuroleptic treatment following blood collection during flashbacks, because of flashback aggravation (later-medicated flashbackers). Defining clinical characteristics did not differ between the two subgroups. To determine the effects on plasma monoamine metabolite levels of the above neuroleptic treatment, we compared plasma monoamine metabolite levels among the 11 medicated flashbackers, the 15 later-medicated flashbackers, and the 23 user and 11 non-user controls. The eight subjects with persistent MAP psychosis were treated with haloperidol (1–10 mg/day) or chlorpromazine (50 – 125 mg/day) for at least 1 month before blood collection (3.191.5 months). The 18 non-flashbackers were unmedicated for at least 3 months before and during the study since they had no psychiatric symptoms. All subjects were free of other medications.

2.2. Procedures Background information concerning the experiences during previous MAP use were obtained from structured interviews and inmate record reviews. Stress is usually defined as a physical or psychological factor that poses a threat to the well-being of the subjects, producing a defensive response (Landau, 1986). Accordingly, the criteria for stressful events were based on whether the subjects had been overwhelmingly distressed and whether the events met the DSM-III-R criteria for a severe to catastrophic type of psychosocial stressor. The criteria for MAP-induced fear-related paranoid-hallucinatory states (perception of threat) were whether the subjects had been overwhelmingly threatened and whether they had taken refuge near or in their houses out of fear (defensive response). Axis IV of the DSM-III-R was used as an indicator of the severity of psychosocial stressors. To examine the nature and determinants of sensitization to stress associated with noradrenergic hyperactivity and dopaminergic changes, the 26 flashbackers were divided into three subgroups: 11 who had experienced fearrelated symptoms under stressful conditions; seven who had been exposed to stressful events alone; and eight who had experienced fear-related symptoms alone. The factors triggering flashbacks were found from structured interviews and reports made by prison staff. The State–Trait Anxiety Inventory (STAI) (Spielberger, 1983) was used to assess anxiety levels related to

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stress. The scale consists of two separate 20-question scales intended to measure both levels of transitory anxiety at the time of testing (state anxiety), and more stable long-lasting anxiety (trait anxiety). STAI data were available for a random subsample of 13 of the 26 flashbackers, at two times (when the flashbacks occurred and at remission), and at one time for random subsamples consisting of 12 of the 18 non-flashbackers, ten of the 23 user controls, and nine of the 11 non-user controls (upon admission to the prison). Blood pressure and heart rate were measured simultaneously with blood sampling.

2.3. Checking for secret use of MAP in relation to the occurrence of flashbacks In Japan all offenders are rigorously prohibited from taking MAP or other substances in detention houses or prisons. Incarceration permitted repeated searches. The prison staff thoroughly searched prisoners’ belongings and clothes, every page of their books, and under the mat in their living quarters. Prisoners were prevented from having visitors and receiving sealed correspondence. Thus, neither MAP nor any other substance has been secretly used in detention houses or prisons (Ohashi, 1996). Because all subjects gave legal consent to be searched, they were not frightened by the searches. Urine screening for MAP was carried out by the police. The results were negative. Venous plasma was examined for the presence of MAP in eight randomly selected flashbackers at the time the flashbacks occurred using gas chromatography/mass spectrometry as described previously (Yui et al., 1996). The lowest detectable quantity was 0.5 ng/ml for each product analyzed; all analyses were negative.

2.4. Analysis procedures for plasma monoamine metabolite le6els All subjects received a low-monoamine, alcohol-free and caffeine-restricted diet for at least 3 months before and during the study while confined in detention houses and the prison. Blood was obtained from the 26 flashbackers twice: once during their prominent paranoidhallucinatory flashback states, occurring 2–14 days after the occurrence of flashbacks, and again within 4 weeks of the flashbacks resolving. The other subjects had a single sample assayed when they were transferred to the women’s prison after at least 3 months of confinement in detention houses in similar conditions to the prison. Blood was collected at random by venipuncture between 10:30 and 12:00 h. All prisoners, including our subjects, were restricted in their motor activity. Subjects were supine for 20 min before and during

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Table 2 Stressful experiences during previous MAP use

Stressful events Axis IV scores Fear-related symptomsb Frightening auditory hallucinations Frightening visual hallucinations Delusions of being killed Delusions of being pursued

Flashbackers

Subgroups of the flashbackersa

n= 26 (%)

Events plus symptoms n =11 (%)

Events n = 7 (%)

Symptoms n = 8 (%)

n =18 (%)

18 (69.2)d 3.69 1.8d 19 (73.1)d 13 (50.0)d 6 (23.1)c 5 (19.3)c 11 (42.3)c

11 (100.0)d 4.7 90.7d 11 (100.0)d 7 (63.6)d 3 (27.3)c 3 (27.3)c 6 (54.5)d

7 (100.0)d 4.7 90.5d 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

0 (0.0) 1.3 90.4 8 (100.0)d 6 (75.0)d 3 (37.5)c 2 (25.0)c 5 (62.5)c

1 (5.6) 1.2 9 0.9 1 (5.6) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.6)

Non-flashbackers

a

Events plus symptoms, the 11 flashbackers who had been exposed to stressful events plus fear-related psychotic symptoms; events, the seven flashbackers who had been exposed to stressful events alone; symptoms, the eight flashbackers who had experienced MAP-induced fear-related psychotic symptoms. b Percentages do not total 100 because some subjects had more than one symptom. c PB0.05. d PB0.01 significantly different from the non-flashbackers (the x 2 test).

blood sampling. Plasma, which was obtained within 10 min of collection by centrifuging whole blood, was stored at − 80°C until it was assayed for norepinephrine (NE), normetanephrine (NM), epinephrine (E), dopamine (DA), 3-methoxytyramine (3-MT), and dihydroxyphenylacetic acid (DOPAC), using a previously described high-performance liquid chromatography (HPLC) with an electrochemical detector (Yui et al., 1996). The sensitivity was 0.01 pmol/ml except for NM, at 0.05 pmol/ml. Intra-assay and inter-assay coefficients of variation averaged 11.3 and 12.1%, respectively. Samples were assayed in four instalments within 3 – 5 months of collection. According to Pickar et al. (1986), there were no decrease in plasma HVA levels following storage for 8 months.

2.5. Data analysis The distribution of plasma monoamine metabolite levels was often extremely skewed and far from the normal distribution. These data therefore were square-root transformed to render the distribution normal (Millns et al., 1995). Adequate sample sizes are critical in interpreting the significance of negative clinical studies (Havilcek and Crain, 1988). To avoid misleading results due to small sample size (not exceeding 100) in this study, the t test should be used (Havilcek and Crain, 1988). Therefore, the transformed data were analyzed using a one-way analysis of variance (ANOVA) followed by multiple t statistics, post hoc tests (Fisher’s protected least significant difference). Comparison between the subject subgroups was performed using the Kruskal – Wallis test followed by the Mann – Whitney U test and the g 2 test.

3. Results

3.1. Stressful experiences All subjects, except for the 11 non-user controls, averaged from one to ten intravenous injections of 30–60 mg MAP/day during periods of abuse. The 26 flashbackers showed a reactivated MAP psychosis without reexperiencing stressful events. The total duration of flashbacks, during which the subjects continued to experience paranoid delusions and transient auditory and visual hallucinations, varied from 4 to 282 days (64.89 64.6 days). All 26 flashbackers had been exposed to significantly higher numbers of stressful events (x 2 = 8.00) and MAP-induced fear-related psychotic symptoms (x 2 = 8.49) during previous MAP use than the 18 non-flashbackers (Table 2). These events corresponded to severe type (rejecting parents, divorce or unwanted pregnancy; axis IV scores of 4) or extreme type (physical or sexual abuse by a companion in drug use; axis IV scores of 5) of psychosocial stressors. These events overwhelmingly threatened the subjects. The eight flashbackers who had not experienced stressful events had been exposed to fear-related psychotic symptoms. The number of stressful events (x 2 = 8.78–9.86) and fear-related symptoms (x 2 = 9.10–9.86) in each of the three subgroups of the flashbackers were significantly higher than for the 18 non-flashbackers. The factors triggering flashbacks were found to meet the DSM-III-R criteria for a mild type of psychosocial stressor, involving mainly mild fear of other people, and met the general definition of stress (Table 3). These factors represent non-specific psychosocial stressors that arise in general conflict in the prison.

K. Yui et al. / Drug and Alcohol Dependence 58 (2000) 67–75

The STAI-state scores did not differ significantly among the subject subgroups (during flashbacks: 58.99 9.7; at remission: 55.7912.9; non-flashbackers: 52.39 12.9; user controls: 52.397.4; non-user controls: 53.199.9). STAI-trait scores during flashbacks (61.49 9.1) were significantly higher than in the 12 non-flashbackers (50.398.8) (Z =2.62, P B0.01), the ten user controls (46.398.3) (Z = 3.11, P B 0.01), and the nine non-user controls (47.8913.7) (Z = 2.57, P B0.05). The STAI-trait scores at remission (60.29 13.5) were significantly higher than in the non-flashbackers (Z= 39.5, PB0.05) and in the user-controls (Z = 2.10, PB 0.05). Blood pressure and heart rate did not increase during flashbacks.

3.2. Plasma monoamine metabolite le6els As shown in Table 4, one-way ANOVA showed a significant group difference only in NE levels (F(5,105)=5.22). Plasma NE levels during flashbacks were significantly higher than during remission, and also significantly higher than in the 18 non-flashbackers, and the 23 user and 11 non-user controls. Plasma 3-MT levels during flashbacks were significantly higher than in the user controls. The eight subjects with persistent MAP psychosis had significantly higher NE levels than the user and non-user controls. During flashbacks, both the 11 medicated and the 15 later-medicated flashbackers had significantly higher NE levels than the user and non-user controls. The later-medicated flashbackers had significantly higher 3-MT levels during flashbacks than the medicated flashbackers and the user controls. Plasma E levels did not differ significantly between the subject subgroups (P =0.33 – 0.99). During flashbacks, the 11 flashbackers with a history of stressful events plus fear-related symptoms had significantly higher NE Table 3 Factors that triggered the flashbacksa Factor

Frequency n= 59 (%)b

Mild fear of other people Conflicts and confrontations with inmates Fear of disciplinary punishment Fear of emitting body odor Fear of prison setting, involving fear of the prison staff Fear of other inmates’ words and actions Being afraid of meeting own husband Other factorsc

54 25 3 4 11

(91.5) (42.4) (5.1) (6.8) (18.6)

7 (11.9) 4 (6.8) 7 (11.9)

a Percentages do not total 100 because some subjects had more than one factor. b The 26 flashbackers experienced one to ten flashbacks each, for a total of 59 flashbacks. c Obligation to perform prison labor (n = 5), abdominal pain (n = 1), and general fatigue (n=1).

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levels than during remission, and significantly higher NE levels than in the 18 non-flashbackers, the 23 user controls, and 11 non-user controls. The seven flashbackers with a history of stressful events alone, and also the eight flashbackers with a history of fear-related symptoms alone, had significantly higher NE levels during flashbacks than the user and non-user controls. Plasma 3-MT levels during flashbacks in the two subgroups with a history of stressful events (irrespective of whether they had experienced fear-related symptoms) were significantly higher than in the user controls. 4. Discussion The short-lived paranoid-hallucinatory states, characterized by vivid visual hallucinations and the absence of thought disorder without marked reduction in levels of functioning, in the flashbackers and in the non-flashbackers during previous MAP use, and also in the subjects with persistent MAP psychosis, appear to be distinct from subsequent development of schizophrenia (Bell, 1965). The flashbackers developed transient psychotic aspects of flashbacks, with periods of normalcy following resolution of their previous MAP psychosis and a return to full premorbid functioning in response to mild psychosocial stressors. There was no possibility of secret use of MAP or other substances. Thus, the flashbacks most likely occurred as a spontaneous psychosis due to previous MAP psychosis. Since psychedelic drug flashbacks persist for 1–2 years (Matefy et al., 1978), or even 5 years or more (DSMIV; American Psychiatric Association, 1987, 1994), the total duration of flashbacks appears to be consistent with that of psychedelic drug flashbacks. In view of the relatively prolonged flashback states which represent recrudesce of previous MAP psychosis, the flashbacks are appropriately termed ‘‘recurrence of MAP psychosis’’ (Hausner, 1980). Our flashbackers had been exposed to threatening, stressful events, or MAP-induced fear-related psychotic symptoms, or both, during previous MAP use. They then exhibited flashbacks due to previous MAP psychosis in situations of mild psychosocial stressors, involving mainly a mild fear of other people. On the evidence of animal studies (Irwin et al., 1986; Petty et al., 1994), prior exposure to stressful stimuli produces noradrenergic hyperreactivity to subsequent stress that is mild enough to have no measurable effect on non-exposed animals so that reexposure to similar but less severe stress can readily evoke excessive NE release. AMP induces long-term sensitization to stress via dopaminergic changes (Robinson et al., 1986). Thus, frightening stressful experiences together with MAP use may greatly increase sensitivity to subsequent mild (non-specific) stressors. Mild psychosocial stressors were then able to trigger flashbacks.

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Table 4 Plasma levels of norepinephrine (NE), normetanephrine (NM), epinephrine (E), 3-methoxytyramine (3-MT), dihydroxyphenylacetic acid (DOPAC), and dopamine (DA)a Age (years)

NE

NM

E

3-MT

DOPAC

DA

Flashbackers during flashbacks Flashbackers with a history of stressful events plus fear-related psychotic symptoms Flashbackers with a history of stressful events Flashbackers with a history of fear-related psychotic symptoms Medicated flashbackers Later-medicated flashbackers

27.5 95.2 28.3 9 7.4 27.9 9 1.7 26.0 95.0 26.3 92.0 28.5 9 6.6

0.589 0.55b,d,e,g,i 0.66 9 0.46c,e,g,i 0.57 90.86g,h 0.479 0.38f,h 0.74 90.70g,i 0.46 90.41g,h

0.4191.04 0.34 9 0.90 0.6491.56 0.319 0.82 0.0990.26 0.6491.31

0.389 0.52 0.3690.60 0.30 9 0.53 0.459 0.49 0.32 9 0.45 0.44 9 0.61

1.36 92.05f 1.939 2.21g 1.80 9 2.53f 0.269 0.74 0.6790.11 1.829 2.42g,j

0.1990.46 0.279 0.62 0.229 0.44 0.0790.10 0.09 9 0.20 0.27 9 0.58

0.08 9 0.15 0.15 90.19 0.0190.01 0.06 9 0.10 0.17 90.20 0.03 90.08

Flashbackers during remission Flashbackers with a history of stressful events plus fear-related psychotic symptoms Flashbackers with a history of stressful events Flashbackers with a history of fear-related psychotic symptoms Medicated flashbackers Later-medicated flashbackers

27.7 95.5 28.5 96.7 28.1 91.6 26.5 95.0 26.3 92.0 28.7 97.0

0.31 90.32 0.299 0.23 0.4190.44 0.24 90.35 0.319 0.31 0.30 90.34

0.099 0.20 0.06 90.13 0.119 0.26 0.13 90.24 0.06 90.13 0.119 0.23

0.359 0.48 0.47 9 0.65 0.219 0.30 0.34 9 0.41 0.3490.35 0.369 0.56

0.6191.23 0.72 91.61 0.699 0.98 0.4090.91 0.79 9 1.59 0.49 9 0.93

0.229 0.55 0.209 0.61 0.169 0.28 0.31 9 0.69 0.069 0.16 0.3490.70

0.18 9 0.28 0.129 0.18 0.41 9 0.45 0.09 90.15 0.13 9 0.19 0.21 9 0.34

Non-flashbackers Subjects with persistent MAP psychosis User controls Non-user controls

28.3 9 8.5 25.4 9 2.6 28.7 95.0 34.7 9 11.7

0.34 90.34 0.60 9 0.45g,i 0.12 90.22 0.10 90.13

0.519 1.73 0.0290.03 0.0190.01 0.029 0.01

0.509 1.00 0.499 0.86 0.6391.60 0.34 90.42

1.1292.13 0.45 90.93 0.289 0.74 0.85 9 1.24

0.319 0.66 0.039 0.09 0.059 0.11 0.119 0.19

0.10 9 0.17 0.15 90.23 0.09 90.17 0.189 0.27

The square-root transformation was applied to all monoaminergic values. Values are means 9 S.D. All monoamine metabolite levels are expressed as pmol/ml. PB0.01 among the subject subgroups (one-way ANOVA). c PB0.05. d PB0.01 compared with the flashbackers during remission. e PB0.05 compared with the non-flashbackers. f PB0.05. g PB0.01 compared with the user controls. h PB0.05. i PB0.01 compared with the non-user controls. j PB0.05 compared with the medicated flashbackers (post hoc tests). a

b

K. Yui et al. / Drug and Alcohol Dependence 58 (2000) 67–75

Subject subgroups

K. Yui et al. / Drug and Alcohol Dependence 58 (2000) 67–75

The plasma NE levels reported here were within the normal Japanese range (0.04 – 0.4 ng/ml, 0.237–2.37 pmol/ml) (Ozawa, 1991). Normal Japanese limits for plasma 3-MT levels have not been reported. Plasma 3-MT levels in this study were not outside the range of levels found in several healthy Japanese subjects (1.6 or 2.6 pmol/ml) (Wang et al., 1975). The present monoamine metabolite analysis suggest that noradrenergic hyperactivity is related to the occurrence of flashbacks. Consistent with previous reports (Irwin et al., 1986; Petty et al., 1994), after exposure to frightening stressful experiences, subsequent similar but less severe psychosocial stressors may have readily elicited excessive NE release. In this respect, the elevated NE levels in the subjects with persistent MAP psychosis may reflect persistent recurrence of MAP psychosis, possibly through enduring noradrenergic hyperactivity in response to mild (ordinary) psychosocial stressors in the prison. High trait anxiety in the flashbackers may reflect noradrenergic hyperreactivity to mild stress (Pe´ronnet et al. 1986). Plasma NE and 3-MT levels in the three flashbacker subgroups may be related to the significantly higher numbers of stressful events or fearrelated symptoms in these subgroups than in the 18 non-flashbackers. Fear-related symptoms met the general definition of stress. It has been reported that highly emotional experiences (viewing an emotionally arousing story) activate the b-adrenergic system in the regulation of memory storage (Cahill et al., 1994). Thus, fear-related symptoms may have a great impact on noradrenergic systems, inducing elevated NE levels in the eight flashbackers having a history of fear-related symptoms alone. An increasing quantity of evidence indicates that brain 3-MT levels are a more sensitive indicator of DA release than HVA or DOPAC (Wood and Altar 1988; Heal et al. 1990). After intravenous administration of [3H] tyrosine, the specific activity of 3-MT was quantifiable in the rat brain using HPLC with electrochemical detection (van Valkenburg et al., 1984), implying that 3-MT can cross the blood – brain barrier. Thus, there is liable to be an important correlation between plasma and brain 3-MT levels. Overall, a smaller increase in 3-MT levels during flashbacks may reflect some degree of increased DA release. Repeated stressful stimuli sensitize 3-MT release to subsequent stress (Charpusta et al., 1997). The two subgroups with a history of threatening, stressful events, whether or not they had experienced fear-related symptoms, showed a small increase in 3-MT levels. Importantly, prior exposure to threatening stressful events may therefore have contributed to sensitization of DA release. Drawing these strands together, frightening experiences, together with MAP use, may induce sensitization of DA release in addition to noradrenergic hyperactivity in response to mild stress. Thus, following exposure to mild psycho-

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social stressors, NE levels and, to a lesser extent, 3-MT levels may readily increase. In this context, the elevated NE levels and slightly increased 3-MT levels are unlikely to have been caused by the flashbacks. These findings extend noradrenergic hyperreactivity to mild stress as a precipitating factor in the development of flashbacks, as described previously (Yui et al., 1996, 1997). Reproducing noradrenergic hyperactivity is able to elicit the memories of threatening experiences following exposure to trauma (Southwick et al., 1993). Robinson et al. (1986) have suggested that AMP-induced sensitization to stress in dopaminergic systems is related to the enduring hypersensitivity to the psychotogenic effects of stress seen in subjects with a history of AMP psychosis. Therefore, noradrenergic hyperactivity involving increased DA release may have elicited memories of MAP psychosis related to frightening, stressful experiences in response to only mild psychosocial stressors, involving mainly mild fear of other people. This then may trigger flashbacks, with markedly increased NE levels and a small increase in 3-MT levels. A number of limitations of this study should be noted. First, plasma monoamine metabolite levels do not accurately reflect central monoamine neurotransmitter function. Plasma levels of NE (Roy et al. 1988) and 3-MT (Kent et al. 1990), respectively, reflect at best only gross changes in whole brain noradrenergic and dopaminergic metabolism. Changes in antecubital venous levels of NE may lead to underestimation of changes in arterial NE and so cause underestimation of the total body rate of release of NE into the bloodstream due to regional pharmacokinetics (within the skeletal muscle) such as the clearance of NE and the rate of spillover of NE (Goldstein et al., 1987). NE clearance involves changes in regional perfusion and uptake mechanisms, and NE spillover is affected by presynaptic modulation of NE release and the reuptake process (Deegan et al., 1991). Brain 3-MT levels may be affected by processes such as diffusion or uptake of 3-MT into intracellular compartments (e.g., glia) (Cumming et al., 1992). Second, the elevated NE levels (Pe´ronnet et al., 1986) and slightly increased 3-MT levels (Charpusta et al., 1997) may reflect heightened autonomic arousal due to stress or anxiety. Plasma E levels which reflect emotional stress (Dimsdale and Moss, 1980), STAI-state scores, heart rate, and blood pressure were not affected by the flashbacks. A stimulus of sufficient intensity, as indicated by heart rate, activates peripheral noradrenergic systems (Abercrombie and Jacobs, 1987). Thus, the elevated NE and slightly increased 3-MT levels are not necessarily due to heightened sympathetic activity. Third, the neuroleptics used may affect plasma NE and 3-MT levels. A previous clinical study has shown that haloperidol (5–10 mg/day or 10–20 mg/day) re-

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duced plasma NE levels over a 6 week course of treatment (Green et al., 1993). Other clinical studies have reported that treatment with haloperidol (4 mg/ day) for 5 weeks (Breier et al., 1994), or haloperidol (4 – 8 mg/day) or thioridazine (150 – 400 mg/day) for at least 10 days (Tuck, 1973) had no significant effect on peripheral noradrenergic activity. Infusion of chlorpromazine (25 mg) has been shown to decrease plasma NE levels (Risbo et al., 1983). However, another study has noted that administration of chlorpromazine (400 –2000 mg/day) for 8 days raised levels of plasma NE (Castellani et al., 1982). Comparative clinical studies of the effect of neuroleptics on plasma 3-MT levels are scarce. Injection of haloperidol (0.5 mg/kg) or chlorpromazine (20 mg/kg) showed no significant effect on brain 3-MT levels in rats (Westerink and Spaan, 1982). However, it has been reported that brain 3-MT levels increased following injection of haloperidol (0.12 – 1.0 mg/kg), chlorpromazine (2.3 or 14 mg/kg), or thioridazine (5 or 30 mg/kg) (Wood and Altar, 1988). Thus, neuroleptic effects on plasma NE levels and brain 3-MT levels remain controversial. In our study, both medicated and later-medicated flashbackers had significantly higher NE levels during flashbacks than the user and non-user controls. The later-medicated flashbackers had significantly higher 3-MT levels during flashbacks, at which point they had not yet received neuroleptic treatment, than the medicated flashbackers and the user controls. Thus, our neuroleptic treatment may not be significant in raising NE and 3-MT levels. Since our analysis of differences between the subject subgroups took into account the use or absence of neuroleptics, an influence of neuroleptics on plasma NE and 3-MT levels cannot be definitively ruled out. Further studies are necessary to answer this question. Finally, our findings are based on only a retrospective study in females in a prison environment. There are also only small numbers of the subjects in the flashbacker subgroups. Results must therefore be interpreted with caution. In summary, both threatening stressful events and fear-related psychotic symptoms, together with MAP use, may be capable of inducing noradrenergic hyperreactivity to subsequent mild psychosocial stressors. Threatening stressful events may further induce sensitization of DA release, as measured by slightly increased 3-MT levels, in response to mild stressors. Mild psychosocial stressors, involving mainly mild fear of other people, may elicit memories of MAP psychosis related to frightening, stressful experiences through sensitization to stress associated with noradrenergic hyperactivity, involving increased DA release. Thus flashbacks, with increased NE levels and a small increase in 3-MT levels, were triggered. These results suggest that this sensitization to stress may be crucial in the development of spontaneous recurrences of MAP psychosis.

References Abercrombie, E.D., Jacobs, B.L., 1987. Single-unit response of noradrenergic neurons in the locus coeruleus of freely moving cats. 1. Acutely presented stressful and nonstressful stimuli. J. Neurosci. 7, 2837 – 2843. American Psychiatric Association, 1987. Diagnostic and Statistical Manual of Mental Disorders, 3rd ed. revised, American Psychiatric Association, Washington DC. American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. American Psychiatric Association, Washington DC. Bell, D.S., 1965. Comparison of amphetamine psychosis and schizophrenia. Br. J. Psychiatry 111, 701 – 707. Breier, A., Buchanan, R.W., Waltrip II, R.W., Listwak, S., Holmes, C., Goldstein, D.S., 1994. The effect of clozapine on plasma norepinephrine: relationship to clinical efficacy. Neuropsychopharmacology 10, 1 – 7. Cahill, L., Prins, B., Weber, M., McGaugh, J.L., 1994. b-adrenergic activation and memory for emotional events. Nature 371, 702– 704. Castellani, S., Ziegler, M.G., van Kammen, D.P., Alexander, P.E., Siris, S.G., Lake, C.R., 1982. Plasma norepinephrine and dopamine-b-hydroxylase activity in schizophrenia. Arch. Gen. Psychiatry 39, 1145 – 1149. Charpusta, S.J., Wyatt, R.J., Masserano, J.M., 1997. Effects of single and repeated footshock on dopamine release and metabolism in the brains of fisher rats. J. Neurochem. 68, 2024 – 2031. Cumming, P., Brown, E., Damsma, G., Fibiger, H., 1992. Formation and clearance of interstitial metabolites of dopamine and serotonin in the rat striatum: an in vivo microdialysis study. J. Neurochem. 59, 1905 – 1914. Deegan, R., He, H.G., Wood, A.J.J., Wood, M., 1991. Effects of anesthesia on norepinephrine kinetics. Anesthesiology 75, 481– 488. Dimsdale, J.E., Moss, J., 1980. Plasma catecholamines in stress and exercise. JAMA 243, 340 – 342. Goldstein, D.S., Eisenhofer, G., Sax, F.L., Keiser, H.R., Kopin, I.R., 1987. Plasma norepinephrine pharmacokinetics during mental challenge. Psychosom. Med. 49, 591 – 605. Green, A.I., Alam, M.Y., Boshes, R.A., Waternaux, C., Pappalardo, K.M., Fitzgibbon, M.E., Tsuang, M.T., Schildkraut, J.J., 1993. Haloperidol response and plasma catecholamines and their metabolites. Schizophr. Res. 10, 33 – 37. Hausner, R.S., 1980. Amantadine-associated recurrence of psychosis. Am. J. Psychiatry 137, 240 – 242. Havilcek, L.L., Crain, R.D., 1988. Practical Statistics for Physical Sciences. American Chemical Society, Washington DC. Heal, D.J., Frankland, A.T.J., Buckett, W.R., 1990. A new and highly sensitive method for measuring 3-methoxytyramine using HPLC with electrochemical detention studies with drugs which alter dopamine metabolism in the brain. Neuropharmacology 29, 1141 – 1150. Irwin, J., Ahiluwalia, P., Anisman, H., 1986. Sensitization of norepinephrine activity following acute and chronic footshock. Brain Res. 379, 98 – 103. Kent, A.P., Stern, G.M., Webster, R.A., 1990. The effect of benserazide on the peripheral and central distribution and metabolism of lovodopa after acute and chronic administration in the rat. Br. J. Pharmacol. 100, 743 – 748. Landau, S.I., 1986. International Dictionary of Medicine and Biology, vol. III. A Wiley Medical Publication, New York, Chichester, Brisbane, Toronto, Singapore. Matefy, R.E., Hayes, C., Hirsh, J., 1978. Psychedelic drug flashbacks: subjective reports and biographical data. Addictive Behav. 3, 165 – 178.

K. Yui et al. / Drug and Alcohol Dependence 58 (2000) 67–75 Millns, H., Woodward, M., Bolton-Smith, C., 1995. Is it necessary to transform nutrient variables prior to statistical analyses? Am. J. Epidemiol. 141, 251 –262. Ohashi, H, 1996. Prison health issues: agenda item 2, the 15th Asian and Pacific Conference of Correctional Administrators (in Japanese). Jpn J. Correct. 107, 36–46. Ozawa, A., 1991. Normal and abnormal values: catecholamines (in Japanese). Sogorinsho (Gen. Pract. Med.) 40, 1332–1338. Pe´ronnet, F., Blier, P., Brisson, G., Diamond, P., Ledoux, M., Volle, M., 1986. Plasma catecholamines at rest and exercise in subjects with high- and low-trait anxiety. Psychosom. Med. 48, 52 – 58. Petty, F., Chae, Y-I., Kramer, C., Jordan, S., Wilson, L., 1994. Learned helplessness sensitizes hippocampal norepinephrine to mild restress. Biol. Psychiatry 35, 903–908. Pickar, D., Labarca, R., Doran, A.R., Wolkowitz, O.M., Roy, A., Breier, A., Linnoila, M., Paul, S.M., 1986. Longitudinal measurement of plasma homovanillic acid levels in schizophrenic patients. Arch. Gen. Psychiatry 43, 669–676. Risbo, A., Jessen, K., Hagelsten, J.O., 1983. Catecholamine response to the clinical use of alpha adrenergic receptor blocking agents. Acta Anaesthesiol. Scand. 27, 72–74. Robinson, T.E., Becker, J.B., Young, E.A., Akil, H., Castaneda, E., 1986. The effects of footshock stress on regional brain dopamine metabolism and pituitary b-endorphin release in rats previously sensitized to amphetamine. Neuropharmacology 26, 679–691. Roy, A., Pickar, D., Jong, J.D., Karoum, F., Linnoila, M., 1988. Norepinephrine and its metabolites in cerebrospinal fluid, plasma, and urine. Arch. Gen. Psychiatry 45, 849–857. Southwick, S.M., Krystal, J.H., Morgan, C.A., Johnson, D., Nagy, L.M., Nicolaou, A., Heninger, G.R., Charney, D.S., 1993. Abnormal noradrenergic function in post-traumatic stress disorder. Arch. Gen. Psychiatry 50, 266–274.

.

75

Spielberger, C.D., 1983. Manual for the State – Trait Anxiety Inventory. Consulting Psychologist Press, Palo Alto, California. Tuck, J.R., 1973. Effects of chlorpromazine, thioridazine and haloperidol on adrenergic transmitter mechanisms in man. Eur. J. Clin. Pharmacol. 6, 81 – 87. Utena, H., 1966. Behavioral aberrations in methamphetamine-intoxicated animals and chemical correlations in the brain. Prog. Brain Res. 21B, 192 – 207. van Valkenburg, C., van der Krogt, J., Moleman, P., van Berkum, H., Tjaden, U., de Jong, J., 1984. A procedure to measure the specific activities of dopamine and its metabolites in rat striatum, based on HPLC, electrochemical detection and liquid scintillation counting. J. Neurosci. Meth. 11, 29 – 38. Wang, M.T., Yoshioka, M., Imai, K., Tamura, Z., 1975. Gas-liquid chromatographic and mass fragmentographic determination of 3-O-methylated catecholamines in human plasma. Clin. Chim. Acta 63, 21 – 27. Westerink, B.H.C, Spaan, S.J., 1982. On the significance of endogenous 3-methoxytyramine for the effects of centrally acting drugs on dopamine release in the rat brain. J. Neurochem. 38, 680–686. Wood, P.L., Altar, C.A., 1988. Dopamine release in vivo from nigrostriatal, mesolimbic, and mesocortical neurons utility of 3methoxytyramine measurements. Pharmacol. Rev. 40, 163–187. Yui, K., Goto, K., Ikemoto, S., Ishiguro, T., 1996. Plasma monoamine metabolites and spontaneous recurrence of methamphetamine-induced paranoid-hallucinatory psychosis: relation of noradrenergic activity to the occurrence of flashbacks. Psychiatr. Res. 63, 93 – 107. Yui, K., Goto, K., Ishiguro, T., Ikemoto, S., 1997. Noradrenergic activity and spontaneous recurrence of methamphetamine psychosis. Drug Alcohol Depend. 44, 183 – 187.