Sleep Deprivation & Amphetamine Induced Psychosis

Abstract

Objectives

To explore the relationship between sleep deprivation and amphetamine-induced psychosis.

Methods

The patient group included 78 patients with a diagnosis of amphetamine (Captagon)-induced psychosis. The control group included 49 patients with no current or past history of amphetamine (Captagon)-induced psychosis. All study subjects underwent the following: a demographic sheet, a structured clinical interview for SM-IV (SCID 1), a drug use questionnaire, a questionnaire to explore any relationship between sleep deprivation and Captagon-induced psychosis, routine medical investigation, and urine screening for detection of drugs.

Results

The patient group showed significantly higher both regular and maximum daily doses of Captagon. Patients showed more periods of sleep deprivation with the use of Captagon in comparison to controls, especially with the increase of the Captagon dose. Patients believed that the occurrence and termination of sleep deprivation were the cause of the start and end of psychotic experiences (more so than the increase and decrease or stoppage of Captagon doses).

Conclusion

sleep deprivation plays an essential role in the development of psychotic symptoms in patients who are using Captagon.

Introduction

Abuse of amphetamines is widespread in the general population. Amphetamine and methamphetamine use can prolong wakefulness, increase focus and feelings of energy, and decrease fatigue.¹

Captagon is a central nervous system stimulant. The psychoactive substance in Captagon is fenethylline. An oral dose of fenethylline is metabolized to form two drugs; amphetamine (24.5% of the oral dose) and theophylline (13.7% of the oral dose). Both drugs are active stimulants; the stimulant effect of fenethylline seems to result from a combination of the effects of both drugs.^2,3

According to Harro,⁴ amphetamines may cause different psychiatric symptoms; the most troublesome of which are psychosis and aggressive behavior. The association between amphetamine use and acute psychosis has received much attention, but several questions about this complex relationship remain unanswered. It is poorly understood whether such psychosis is due to amphetamine use per se, vulnerabilities in the user, or both these factors.¹

Several factors have been shown to affect the relationship between amphetamine use and psychosis. One of these factors is that amphetamines cause prolonged wakefulness. This lack of sleep may induce psychosis-like symptoms.⁵

One of the aims of this study is to explore the effect of Captagon on the sleep profile of patients especially insomnia. The main aim of the study is to investigate if sleep deprivation has any role in Captagon-induced psychosis or if they are both; sleep deprivation and psychosis; are separate and unrelated effects of using Captagon.

This study builds on a clinical observation that many of the patients using Captagon often mention that they experience psychotic symptoms when they cannot sleep for several days, and that psychosis disappear when they finally manage to sleep. This is obvious when following up patients admitted with the diagnosis of Captagon induced psychosis. Those patients usually improve fast than other patients.

Patients and Methods

Study Design

A cross sectional questionnaire-based study.

Study Subjects

• – Patients were admitted to the Al Amal Hospital, Jedda, Saudi Arabia during the period from January 2020 to December 2020. Patients were divided into two groups. The first group included 78 patients with a diagnosis of amphetamine (Captagon)-induced psychosis and was called the patient group. The second control group included 49 patients with a history of amphetamine (Captagon) use and with no current or past history of developing amphetamine (Captagon)-induced psychosis. The study subjects were assessed after recovery from withdrawal symptoms. The patient group was assessed after recovery from acute psychosis.

The inclusion criteria were patients

• – with no history of primary psychiatric illness such as schizophrenia, delusional disorders, or BAD;

• – with no history of chronic medical disorder;

• – who were only using Captagon;

• – who were aged between 18 and 60;

• – who were males; and

• – Who had consent to share in the study.

The exclusion criteria were patients who

• – had a history of primary psychiatric illness, such as schizophrenia, delusional disorders, or BAD;

• – had a history of chronic medical disorder;

• – used other substances such as cannabis or alcohol; or

• – did not give their consent to take part in the study.

Both patient and control groups were subject to the following tests and questionnaires:

• – a structured clinical interview for DSM-IV (SCID 1).

• – a demographic sheet.

• – a drug use questionnaire.

• – a questionnaire to explore any relationship between sleep deprivation and Captagon-induced psychosis. The questionnaire was developed by the first author. It was an ordinal questionnaire with no total score targeted. The questionnaire was written in Arabic and was sent to five expert judges for evaluation. Modifications were done according to the judges’ instructions. A pilot study with 20 patients showed that the alpha Cronbach factor was 0.7 after excluding three items on the scale. This indicated a good inter-item correlation. The final form of the scale included nine items. The first four questions dealt with the problem of sleep deprivation related to the use of Captagon. The second five questions explored the role of sleep deprivation and/or increased dosage of Captagon in the development of psychosis (delusions and/or hallucinations). Patients were educated regarding the meanings of the terms “hallucinations” and “delusions” during the SCID 1 interview. Patients were also informed that these five questions asked about the delusions and hallucinations that they had experienced before.

  The interviewer read each question to the subject, who responded by choosing one of the following answers: never, occasionally, sometimes, very often, and always. All study subjects answered the first four questions while the last five questions were answered only by subjects in the patient group.

• – a routine medical investigation (e.g., CBC, renal function tests, liver function tests); and

• – a urine screening for detection of drugs.

Ethics

This study was approved by the Committee for Research Ethics at Jedda Research and Studies Department, Jeddah Health Affairs, Saudi Arabia.

Statistics

Data were analyzed using SPSS 20.⁶ Quantitative data were expressed as mean ± SD, while qualitative data were expressed as frequencies and percentages. The Mann-Whitney test was used to compare whether there is a difference in the dependent variable for two independent groups. A p-value of less than 0.05 was considered significant.

Results

No differences were found between the two groups regarding marital status or age (mean ± SD = 31 ± 6.5 years in the first group versus mean ± SD = 32.1 ± 8.5 years in the second group). The control group included more unemployed subjects (36.7%) in comparison to the patient group (15.45%). No differences were found between the two groups regarding Captagon using age (mean ± SD = 20.7 ± 5.7 years in the patient group versus mean ± SD = 21.9 ± 6.8 years in the control group), or duration of Captagon use (mean±SD = 10.3 ± 6.4 years in the patients group versus mean ± SD = 10.2 ± 7.2 years in the control group). However, there were significant differences regarding regular dosage (mean ± SD = 3.7 ± 1.9 tablets in the patient group versus mean ± SD = 2 ± 0.98 tablets in the control group) and maximum dosage (mean ± SD = 7.1 ± 4.7 tablets in the patient group versus mean ± SD = 4.2 ± 2.4 tablets in the control group).

Controls gave a history of more periods of insomnia before starting using Captagon, while patients showed more periods of sleep deprivation with the use of Captagon in comparison to controls. This was especially notable with the increase of Captagon dosage (Table 1). While all patients complained of sleep difficulty after using Captagon, only 3.8% reported this issue before using Captagon. Sleep difficulty increased as the dose of Captagon increased (Table 2). While 68% of patients connected between the occurrence of psychosis and increased Captagon dose (as very often or always), 86% of them connected this to the inability to sleep. Also, while 69% of patients connected the disappearance of psychosis to the stoppage of using Captagon (as very often or always), 94.6% of them connected this to their ability to sleep (Table 2).

Table 1. Comparison between Patients and Control Groups Regarding Sleep Profile Changes with the Use of Captagon.

		Never		Few times		Sometimes		Often		Always		Z test	Sig.
Have you ever had difficulty sleeping before taking Captagon?	Patients	75	96.2%	1	1.3%	0	0%	2	2.6%	0	0%	−2.116	0.034
	Controls	42	85.7%	1	2%	2	4.1%	4	8.2%	0	0%
Have you ever had difficulty sleeping while taking Captagon?	Patients	0	0%	0	0%	14	17.9%	16	20.5%	48	61.5%	−5.679	0.000
	Controls	9	18.4%	5	10.2%	19	38.8%	5	10.2%	11	22.4%
Do periods of sleeplessness increase with increasing the dose of Captagon?	Patients	1	1.3%	0	0%	4	5.1%	13	16.7%	60	76.9%	−3.99	0.001
	Controls	5	10.2%	0	0%	10	20.4%	12	24.5%	22	44.9%
If you manage to sleep after a period of sleeplessness, will you sleep longer than your usual sleep period?	Patients	3	3.8%	5	6.4%	16	20.5%	20	25.6%	34	43.6%	−4.629	0.000
	Controls	17	34.7%	5	10.2%	13	26.5%	4	8.2%	10	20.4%

Table 2. Response of Patients Group to Scale Items.

	Never NO %	Few times NO %	Sometimes NO %	Often NO %	Always NO %
Have you ever had difficulty sleeping before taking Captagon?	75 (96.2%)	1 (1.3%)	2 (2.6%)	0 (0%)	0 (0%)
Have you ever had difficulty sleeping while taking Captagon?	0 (0%)	0 (0%)	14 (17.9%)	16 (20.5%)	48 (61.5%)
Do periods of sleeplessness increase with increasing the dose of Captagon?	1 (1.3%)	0 (0%)	4 (5.1%)	13 (6.7%)	60 (76.9%)
If you manage to sleep after a period of sleeplessness, will you sleep longer than your usual sleep period?	3 (3.8%)	5 (6.4%)	16 (20.5%)	20 (25.6%)	34 (43.6%)
During periods of taking Captagon, have you ever had delusions or hallucinations?	0 (0%)	13 (16.7%)	20 (25.6%)	30 (38.5%)	15 (19.2%)
Do delusions or hallucinations occur with the increase of the dose of Captagon?	4 (5.1%)	6 (7.7%)	15 (19.2%)	13 (16.7%)	40 (51.3%)
Do delusions or hallucinations occur if you cannot sleep?	2 (2.6%)	4 (5.1%)	5 (6.4%)	15 (19.2%)	52 (66.7%)
Do the delusions or hallucinations diminish or disappear if you stop taking Captagon?	7 (9%)	4 (5.1% )	13 (6.7%)	22 (28.2%)	32 (41%)
Do delusions or hallucinations diminish or disappear if you manage to sleep?	0 (0%)	1 (1.3%)	4 (5.1%)	8 (10.3%)	65 (83.3%)

There was a significant difference between patients and controls regarding the period subjects stayed awake while using Captagon (mean ± SD = 3.77 ± 1.48 days in the patient group versus mean ± SD = 2.91 ± 1.25 days in the control group). The longest reported period of staying awake was seven days. Approximately 61% of patients used a drug to help them sleep while using Captagon (in comparison to only 22% of controls).

Discussion

Although disrupted sleep pattern is a common symptom of chronic stimulant use there is not much data about how precisely amphetamines affect sleep structure. In the current study most of the study subjects experienced insomnia while using Captagon (92.9%), but only Fifty-nine of them (50%) reported that insomnia was always present while using Captagon. Periods of inability to sleep increased notably with the increase of the daily doses of Captagon (Table 1). These periods of inability to sleep were followed by periods of increased sleep time as reported by 84% of the study subjects (Table 1).

According to Bramness et al¹ and Fluyau, Mitra, and Lorthe⁷ amphetamines are often taken several times over the course of many days in binges; these may end in psychosis. Auditory and visual hallucinations and delusions of persecution are the most common presentations. It is still not fully understood whether psychosis is due to amphetamine use, individual vulnerabilities such as genetic variations, or a combination of both these factors. Sleep deprivation associated with amphetamine use (or other factors at the end of a binge) may be risk factors for developing psychosis.^1,8

In the present study, there was a significant difference between patients and controls regarding the length of time that subjects stayed awake while using Captagon (mean ± SD = 3.77 ± 1.48 days in the patient group versus mean ± SD = 2.91 ± 1.25 days in the control group). The longest period without sleep reported by a patient was seven days.

Going without sleep for long periods of time can produce misperceptions, hallucinations and delusions. It can result in a condition resembling acute psychosis after 48–70 hours of sleep deprivation.^9,10,11

In the patient group, 24% reported that they experienced psychotic symptoms after 24 hours of staying awake, 54% after 48 hours of staying awake, and 22% after 72 hours of staying awake, respectively. It seems that psychosis developed more quickly than has been reported by the previous studies. The subjects of these studies were mainly non-clinical individuals who were not using any substances of abuse. Of course, this reflects the effect of Captagon on the central nervous system and dopamine receptors precisely.

Despite that sleep deprivation is a direct result of the stimulant effect of Captagon, patients emphasized its role in causing psychosis to a degree more than that of using Captagone. This may be explained by the belief of 94.6% of patients that the disappearance of psychosis was connected this to their ability to sleep after periods of sleep deprivation (Table 2).

According to Wilkerson et al,¹² continuous use of stimulants like cocaine or methamphetamine, particularly if associated with sleep deprivation, may result in psychotic symptoms.

Approximately 61% of patients used a sedating drug in order to end periods of sleep deprivation (in comparison to only 22% of controls). Patients reported using cannabis, alcohol, antihistamines, benzodiazepines, quetiapine, or even clozapine. This may reflect patients’ understanding of the importance of sleep in preventing psychosis. Many patients reported that they used these drugs when they started to experience psychotic symptoms. According to Bramness et al,¹ users usually end their amphetamine binges by using sedating drugs such as alcohol, cannabis, or benzodiazepines.

According to Rognli and Bramness⁵ and Arunogiri et al¹³ there is some evidence of a dose–response relationship between amphetamine and methamphetamine doses and the probability of experiencing psychotic symptoms. This is also in agreement with our findings that patients group showed higher regular and maximum doses of Captagon than controls.

In the current study, patients experiencing psychotic features attributed the disappearance of psychotic symptoms to their ability to sleep after periods of sleep deprivation even more than stoppage of using Captagon. This coincides with the findings of Waters et al,¹¹ who reported that a period of normal sleep served to resolve psychotic symptoms in cases when psychotic symptoms had developed following sleep deprivation.

According to the previous findings, do we should consider sedating drugs in the management of amphetamine psychosis associated with sleep deprivation?

Currently there is no established guideline for the treatment of amphetamine psychosis. There are reports that recommend using sedating drugs in such patients in emergency settings. According to Fluyau, Mitra, and Lorthe,⁷ a benzodiazepine agonist or a histamine agonist is commonly used for excessive agitation associated with amphetamine psychosis. In McIver¹⁴ study, antipsychotics and/or benzodiazepine medications were used to reduce symptoms of psychosis, to minimize side effects and to contain behavioral agitation in amphetamine psychosis patients in the emergency departments.

Also, benzodiazepines have been considered a good choice to medicate patients who present with stimulant-induced psychosis and who are nonresponsive to de-stimulation and de-escalation.¹⁵

Conclusion

Sleep deprivation plays an important role in the development of psychotic symptoms in patients who are using Captagon. A synergistic relationship between Captagon usage and sleep deprivation may cause the acute psychotic state induced by Captagon.

There is a need to repeat the study on a larger sample of patients. There is also a need to assess the efficacy of sedating drugs like benzodiazepines alone for the management of amphetamine psychosis associated with sleep deprivation and compare their results to those of specific drugs like antipsychotics.

Limitations

This study has some limitations. The sample was non-randomized, and the number of subjects included was relatively small.