Pumped Up and Out of Control: A Case Series on Diverse Psychiatric Manifestations of Mephentermine Misuse

Mephentermine is a sympathomimetic N,2-dimethyl-1-phenylpropan-2-amine, structurally related to amphetamine and methamphetamine. ¹ It acts as a selective alpha-1 receptor stimulant, thereby increasing stroke volume, blood pressure, and cardiac output. ² Mephentermine is unavailable in several countries, although its principal metabolite, phentermine, is available for use in the United States as a medication for weight loss. ³ Historically, it has been used as a vasoconstrictor to help stabilize blood pressure during spinal anesthesia for elective cesarean sections and low-volume states like shock.^{4, 5} Its use has declined due to its abuse potential for its brain stimulant effect by enhancing levels of dopamine and noradrenaline in the central nervous system.^{6, 7} The World Anti-Doping Agency (WADA) has prohibited the use of mephentermine and phentermine in competitive sports due to their potential to enhance athletic performance by increasing energy, focus, and alertness. ¹ In India, mephentermine is restricted as a Schedule H drug ⁸ ; however, it is also available as a non-prescription medication, providing a cost-effective choice for amateur athletes for enhancing performance who are not likely to undergo testing in local competitions. Nevertheless, misuse of this medication, such as abrupt dose increase, can cause adverse consequences, including arrhythmia, sudden restlessness, mental confusion, and hallucinations. ⁹ In our search of literature, although some cases of dependence and psychosis have been reported, their full range of mental health effects is not well understood. ¹⁰ In this article, we report three individuals with mephentermine misuse presenting with diverse psychiatric presentations (Table 1). Our findings underscore the need for awareness, strict regulations, and research into the psychiatric risks associated with mephentermine use. The patients and their legal representatives have given their consent for publication of this manuscript.

Table 1.

Clinical Profile, Acute, and Chronic Effects of Mephentermine Misuse.

Feature	Case 1	Case 2	Case 3
Profile	42M, professional bodybuilder	23M, gym instructor	41M, pharmacist,
Duration of use	~2 weeks	~1.5 years	~4 years
Initial dose & route	30 mg IV/day	15 mg IV on alternate days	30 mg IV/day
Peak dose	210 mg/day	300–450 mg/day	150 mg/day
Acute effects	Palpitations, diaphoresis, hypervigilance, euphoria, insomnia, aggression, persecutory delusions, grandiosity	Increased energy, insomnia, transient psychosis post-use, irritability	Alertness, increased stamina, insomnia, tremors
Chronic effects	Not observed	Escalating doses, persistent psychotic symptoms post drug use	Dependence, withdrawal symptoms, compulsive use, and sleep disturbance
Psychiatric diagnosis 11	Mephentermine induced bipolar disorder	Mephentermine induced psychosis	Mephentermine dependence

Case 1

Mr. A is a 42-year-old, married male from a middle socioeconomic status (SES) background, a diploma graduate, and a professional bodybuilder who owns a gymnasium. He participates in various state and zonal level competitions, has a well-adjusted premorbid personality, and has no comorbidities. In 2023, two weeks before a state-level competition, he was prompted by his friends to use intravenous methamphetamine to enhance his training. He was initially injected with 1 mL (30 mg) of intravenous mephentermine by his co-trainer. Following the first injection, he reported having palpitations, diaphoresis, along with a surge of energy, heightened alertness, and boosted self-confidence. He did not experience fatigue, even after extended practice sessions, and noticed a significant improvement in his endurance and workout duration. His consumption rapidly escalated from 30 mg per day to 210 mg per day in 10 days as the competition drew closer. He would procure mephentermine injections from his co-trainers and use them regularly by self-injection and engaged in workout sessions during most of the day with no rest hours, with the last use around 12 hours before admission. The patient was brought by his wife to the Emergency Department with 5 days history of acute onset irritability, aggression, insomnia, overfamiliarity, suspiciousness that nearby gym owners were doing black magic rituals against him that were leading to his previous poor athletic performance and reduced turnover, hearing non-existent voices of monks telling him he had special powers to control everyone, following which he erroneously claimed to have gained special powers such as being able to control the climate, water flow. He was also seen engaged in altercations with whoever confronted him. The general physical examination revealed a pulse rate (PR) of 120 beats per minute (bpm), blood pressure (BP) of 140/110 mmHg, a BMI of 27.3, and injection site marks in the bilateral cubital fossae. On the mental status examination (MSE), the patient was hostile, agitated, and had increased psychomotor activity. His affect was irritable, and he had inflated self-esteem, delusions of grandiosity and persecution, denied perceptual abnormality, and had Grade 1 insight at the time of admission. The patient was not cooperative for the Higher Mental Function Examination. A provisional diagnosis of stimulant harmful use and stimulant-induced bipolar and related disorder was made as per the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). ¹¹ The Naranjo algorithm ADR probability scale was 6, indicating a probable association of mania with mephentermine use. ¹² He was admitted under section 89 of MHCA to the psychiatry ward, and a cardiac consultation was done to evaluate cardiovascular side effects. His blood investigations were unremarkable. Neuroimaging showed no acute lesions. At the time of admission, his Young Mania Rating Scale (YMRS) score was 34, ¹³ the Brief Psychiatric Rating Scale (BPRS) score was 42, ¹⁴ and the Positive and Negative Syndrome Scale (PANSS) score was 68, ¹⁵ DAST-28 score of 13. ¹⁶ Attempts to calm the patient with appropriate behavioral and psychological techniques were ineffective, requiring intramuscular Inj. Haloperidol 5 mg and Inj. Promethazine 50 mg IM for initial stabilization. The patient started on olanzapine, built up to 20 mg, and received supportive medications. Upon stoppage of mephentermine and with antipsychotics, his psychotic symptoms improved after 3 days, and mood symptoms by 7 days. After 1 week of admission, YMRS was reduced to 12 and PANSS to 34. No features of mephentermine withdrawal were seen in the current admission. He was discharged after 2 weeks of observation. The patient was on follow-up for 3 months, maintained well with medications, and was engaged in relapse prevention therapy. Olanzapine was gradually tapered during subsequent follow-up, and no relapse of mood and/or psychotic symptoms was reported.

Case 2

Patient is a 23-year-old unmarried male, from lower middle SES, diploma graduate, working as a gymnasium instructor, with no past or family history of mental illness, pre-morbidly described to have impulsivity in decision-making, chronic feelings of emptiness and recurrent efforts to avoid emotional discomfort through maladaptive behaviors suggestive of borderline personality traits, was brought to psychiatry outpatient department with a background of alcohol use not in dependence pattern with last drink 1 month before hospital visit and ongoing use of injectable mephentermine intravenously (IV) over the past 1.5 years last use 3 days back with complaints of irritability, aggression, and insomnia. The patient reported that he was introduced to mephentermine by his co-trainers 1 year ago to improve his endurance and physique. The patient initially took 15 mg of mephentermine IV on alternate days with the aid of his friends, following which he felt full of energy and could exercise more effectively. The patient gradually increased the dose to 300 mg/day. He would procure them by himself from a local pharmacy. His parents observed a significant shift in his behavior, including reduced sleep, becoming increasingly irritable, and getting into arguments with family and friends over minor issues. The patient continued to use IV mephentermine at a dose of 300–450 mg/day. Over the past 3 months, the patient complained of hearing non-existent voices of unknown male and female discussing among themself, referential beliefs, and suspiciousness of being harmed, immediately after taking the drug, lasting for a few hours but not during a sober state. He used to act out of his beliefs by confronting nearby people and feels distressed secondary to voices and is irritable. On general physical examination, the patient had a PR of 101 bpm, BP of 130/100 mmHg, and a BMI of 26.2, with multiple puncture marks and skin discoloration over the bilateral cubital fossae. MSE revealed relevant speech, reactive affect, denied any delusions or perceptual abnormalities, concrete abstraction, and Grade 3 insight at the time of admission. Routine blood investigation and urine analysis were within normal range. A diagnosis of substance-induced psychosis, as per DSM-5 TR, was made. ¹¹ Naranjo algorithm ADR probability scale was 6, suggesting a probable association of psychosis with mephentermine use. ¹² At the time of admission, his BPRS was 36, ¹⁴ DAST-28 score was 15, ¹⁶ SADQ score of 2. ¹⁷ Injection mephentermine was stopped, and the patient was started on oral risperidone 2 mg and a multivitamin supplement. The patient was engaged in Motivational Engagement therapy and anger management. After 1 week of admission, the BPRS score reduced to 22. ¹⁴ Upon stoppage of mephentermine and with low-dose antipsychotics, the patient had no recurrence of psychotic symptoms. The patient was followed up for 6 weeks with three outpatient visits at 2-week intervals. Psychotherapy sessions, including Motivational Enhancement Therapy and anger management, were continued during this period. Tablet risperidone was planned for discontinuation in subsequent follow-ups.

Case 3

Patient is a 41-years-old, married male, belonging to middle SES, pharmacist by profession, engaged in weightlifting as a hobby, pre-morbidly, the patient exhibited traits consistent with borderline personality, including affective instability, unstable interpersonal relationships with intense attachments, and episodes of impulsive decision-making, with no comorbidities, no family or past history of mental illness with a background of alcohol use in dependence pattern. Patient came to the psychiatry OPD with a history of intravenous mephentermine use of 4 years duration. The patient was introduced to the drug by his peers as a performance enhancer. The patient initially injected 1 mL (30 mg/mL) of mephentermine IV with the help of his trainer, following which he reported feeling more active, having increased stamina, and improved endurance. Thereafter, he began using it daily. Patient, however, had complaints of reduced sleep, which made him use Tab Zolpidem 10 mg intermittently. Having felt that he had achieved balance in the sleep cycle using medications, he started to inject himself with an increased amount of 2 mL (60 mg). He observed an increase in stamina and endurance during workouts. The patient, being a pharmacist, used to procure drugs for himself. The patient gradually escalated the quantity to 5 mL/day (150 mg) over the next 7–9 months and started to use the drug even while not working out, stating that it has become part of his routine. About a year later, the patient started showing withdrawal symptoms like drowsiness, increased appetite, cold hands and feet, and fatigue whenever he tried to stop using mephentermine, resulting in multiple failed abstinence attempts. There was a sense of compulsion to take mephentermine, along with difficulty in controlling the level of its use. The patient also reported using the drug before going for night drives and leisure activities since it made him feel energetic and reduced his need for sleep. Last intake of alcohol and mephentermine was 1 day before admission. On general physical examination, the patient had a PR of 105 bpm, BP was 140/90 mm Hg, and BMI was 25.4, with multiple hyperpigmented scars in both cubital fossae suggestive of chronic injection use. MSE was unremarkable except for bilateral fine postural tremors, concrete abstraction, and Grade 3 insight. Routine blood investigations and urine analysis were within normal limits. The electrocardiogram was suggestive of sinus tachycardia. Patient had a DAST-28 score of 19 and an SADQ score of 38, suggesting severe dependence. A diagnosis of mephentermine dependence and alcohol dependence was made as per DSM-5 TR. ¹¹ The patient was managed with tapering doses of tablet lorazepam to reduce withdrawal symptoms, parenteral thiamine, and other supportive medications. The patient showed improvement in symptoms from the second day of admission, with complete resolution over one week. Tablet Naltrexone 50 mg once daily was started as an anti-craving agent. The patient was engaged in Motivational Enhancement Therapy and then discharged. The patient was on follow-up for two months, maintaining abstinence.

Discussion

Stimulants are the preferred performance-enhancing substances for elite athletes in general, and mephentermine seems to be more common among professional athletes in India. ¹⁸ Mephentermine is an indirectly acting sympathomimetic amine that triggers the release of norepinephrine and enhances dopamine release, contributing to its serious clinical consequences, like psychosis and cardiovascular issues such as hypertension, arrhythmias, and an increased risk of sudden death. ¹⁹ Greenberg and Lustig reported the first case of mephentermine abuse with acute psychotic symptoms after using the substance found in nasal inhalers for a short period. One documented case involved a weightlifter abusing mephentermine injections and experiencing psychosis, but showed improvement after receiving antipsychotic treatment and stopping mephentermine use. ⁷ Singh et al. suggest that the drug’s addictive properties may be attributed to its active metabolite, phentermine, which acts similarly to amphetamine. ³ Our case series suggests three patients with no past or family history of psychiatric illness developing varying neuropsychiatric manifestations following mephentermine misuse, with an average dose of 150–450 mg. None of the patients reported using other performance-enhancing substances; each had been introduced to mephentermine specifically for its purported performance-enhancing effects. In two of our cases, stopping the offending drug, along with supportive management, resulted in a complete resolution of symptoms, suggesting a causal role of mephentermine in the symptom manifestation. Viral markers were negative in all three cases. A limitation in our case series was that urine drug screening was not done. Currently, there are no medications approved for the treatment of stimulant dependence and no established guidelines for their management. Some trialed treatments include agonist therapies with bupropion, modafinil, and methylphenidate, and non-agonist strategies like naltrexone and mirtazapine, aimed at reducing cravings, mitigating withdrawal symptoms, supporting abstinence, and, along with psychotherapies, with variable results.^{3, 8}

Conclusions

Although cases of mephentermine abuse and its neuropsychiatric manifestations are rare in medical literature, there are indications that the problem is on the rise. Thus, our case series adds to the literature on the role of mephentermine in its varied psychiatric presentations, especially in individuals with relatively few risk factors. Psychiatric and medical clinics will likely encounter more cases in the future. There is an urgent need for collaboration among medical specialists, policymakers, and law enforcement agencies to frame specific regulations to ensure restrictions on non-prescription access.

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