Consequences of 1,4-Butanediol Misuse: A Review

Abstract

Gamma-hydroxybutyrate (GHB), along with its precursors, 1,4-butanediol (1,4-BD) and gamma-butyrolactone (GBL), are potent central depressant agents widely illicitly used for their euphoric and relaxant effects. The article presents a review of the literature on the 1,4-BD misuse, the clinical picture of intoxication, development of addiction and delirium. The available evidence shows that 1,4-BD is a substance with its own psychoactive effects, a high addiction potential and potentially severe withdrawal symptoms.

Gamma-hydroxybutyrate (GHB), along with its precursors, 1,4-butanediol (1,4-BD), gamma-butyrolactone (GBL) and gamma-valerolactone (GVL), are potent central depressant agents, legally and illicitly used for very heterogeneous purposes, internationally.¹ GHB, GBL, and 1,4-BD are widely illicitly used for their euphoric and relaxant effects. 1,4-BD was discovered in 1890,² and first investigations with GBL stated in 1947.³ Both substances have since then been extensively used by the chemical industry as precursors for the synthesis of plastics and industrial solvents. They are found in floor-cleaning products, nail polish (previously nail polish removers), and superglue removers.

Users ingest 1,4-BD (pure, diluted with water, or mixed with alcohol) or convert it into GHB prior to ingestion. Instructions for this conversion process can be found on the Internet, where 1,4-BD may also be purchased for illicit use.⁴ GHB and 1,4-BD are well absorbed orally and peak plasma concentrations are reached after 25–60 minutes.⁵ Pharmacological studies revealed that following the oral administration of 25 mg/kg of 1,4-BD in healthy adult volunteers, the mean 1,4-BD C_max was reached at 24 ± 12 minutes, with measurable plasma GHB concentrations within 5 minutes post-ingestion and the mean C_max at 39.4 ± 11.2 minutes.⁶ 1,4-BD is metabolized in the liver through a two-step conversion, via hepatic alcohol dehydrogenase to gammahydroxybutyraldehyde followed by metabolism into GHB via hepatic acetaldehyde dehydrogenase.⁷ Animal studies have shown that both ethanol and fomepizole competitively block the metabolism of 1,4-BD to GHB.⁸ Following the oral administration of 1,4-BD 25 mg/kg, the mean elimination half-life was reported to be 39.3 ± 11 minutes in healthy adult volunteers.⁹

As self-reported GBL and 1,4-BD use are less common than GHB use, the prevalence of GBL and 1,4-BD abuse may be underestimated.¹⁰ Meanwhile, current evidence shows that GHB and its precursors, including 1,4-BD, are highly addictive, both in humans and animals, probably through a GABA_B receptor-related mechanism.¹¹ The severity of withdrawal symptoms can be considered a medical emergency due to a risk of intoxication death. The development of an addiction to 1,4-BD generally follows three phases.

The first (initial) phase of addiction develops within 2 to 4 weeks since the onset of use and lasts for approximately 2–3 weeks. The recreational use of 1,4-BD typically begins with a single oral administration of 1 mL of a 13% solution. Due to the fact that 1,4-BD is rapidly absorbed in the gastrointestinal tract, its psychoactive effect is experienced in 7–10 minutes when taken in the fasted state and in 15–30 minutes in fed conditions. The effect of a low 1,4-BD dose initially results in sedation, mild drowsiness, relaxation, and a moderate elevation of mood; if there was anxiety, it subsides.¹² As a person repeats 1,4-BD use, after about 10–15 times its effect increases and changes. Users experience improvement in mood that can reach euphoria and a pleasant feeling of warmth spreading throughout the body; their motor activity accelerates whereas motor coordination is moderately impaired. Thought acceleration and a short sexually stimulating effect are also typical at this stage. At the peak of intoxication, short periods of drowsiness, muscle relaxation, immobility, short-term sleep similar to oblivion, and moderate general weakness are experienced. Due to the fact that 1,4-BD has a short half-life, the substance effects last for about 30 minutes and then weaken within 30 minutes to one hour.¹³

Repeated substance use reduces both the intensity and duration of its effects, leading to a subjective experience of desire to use a drug. The increase in daily dose and tolerance occurs by increasing the frequency of drug administration rather than the single dosage of the substance. After about 2 to 4 weeks, the frequency of use increases to 3–5 times per day, and the daily dose reaches 5–10 mL. Increased sexual desire at the beginning of 1,4-BD use is promptly replaced by sexual dysfunction.¹⁴ In the sober state, patients experience a moderate increase in anxiety, sleep disturbances, and a growing indifference to work, family, former interests, and hobbies. This may lead to absenteeism and interpersonal problems.

The second (advanced) phase of addiction develops within 1–2 months from the initial use and lasts up to 3–5 months. The frequency of drug use increases to multiple times per day. During the short periods of sobriety, the patients’ mental state worsens: anxiety of greater or lesser intensity is almost constantly noted; the mood is typically depressed, with irritability and anger. Headaches and sleep disorders are also frequent.¹ Patients often suffer from persistent and unwanted compulsive memories of 1,4-BD effects, which are colorful and intense. It becomes impossible to distract oneself from the desire to use the substance and impossible to resist it. During such periods of craving, the person leaves all other things behind and actively and uncompromisingly seeks opportunities to acquire the drug and consume it. Patients may even commit illegal actions to immediately obtain 1,4-BD. Once a person starts using the substance, he loses the ability to control his behavior and regulate the amount of consumed drug. Craving is accompanied by a loss of situational and quantitative control. When the intensity of intoxication subsides, the person feels an irresistible urge to repeat the 1,4-BD intake until consciousness is impaired or until the purchased substance runs out.

Events that occur while intoxicated are completely forgotten. Memory loss may cover a period lasting from a few hours to 2 consecutive days, while the person continues to perform certain actions, move around, and talk. Memories are not restored during periods of sobriety, and patients are poorly oriented in a new environment (e.g., in a hospital ward). At this stage, 1,4-BD consumption typically reduces appetite, patients are exhausted physically and become apathetic and lethargic. Typical complications include toxic hepatitis, nephritis and myocarditis, persistent increase in intracranial pressure.² The frequency of drug use can reach 20–40 times per day, and the daily dose may increase up to 100–150 ml. At this stage of the addiction, the substance is taken more in order to normalize physical and mental well-being, rather than to achieve an unattainable euphoria.

When 1,4-BD is discontinued and its effect ends in about 1–2 hours, users may experience sweating, instability of blood pressure, tremor in the body, temperature rise to 38–39°C, nausea, vomiting, and loss of appetite. Mental disturbances include anxiety, agitation, severe headache, irritability, and insomnia; the ability to comprehend situations is impaired. In such patients, craving becomes irresistible; aggressive behavior is also possible. Furthermore, 1,4-BD withdrawal may be complicated by seizures and rhabdomyolysis.¹⁵ The withdrawal symptoms are not relieved by alcohol, and only the use of 1,4-BD can improve the general condition of the patient. In such cases, treatment is necessary due to the high probability of death caused by cerebral edema and acute renal failure.

The third (final) phase of addiction develops within 3–5 months from the onset of use; its duration is determined by the probability of complications incompatible with life. The irresistible craving becomes permanent and substance consumption therefore occurs constantly, resulting in disorders of consciousness (often in a coma). As the intoxication intensity decreases, the symptoms of anxiety, physical discomfort, tremor of the limbs and head, headache, and insomnia rapidly increase. There is a wide range of somatic disorders due to toxic damage to the cells of the central and peripheral nervous system, heart, lungs, kidneys, liver, and muscles, as well as hyperthermia and cerebral edema. Mental activity also decreases, patients do not understand the essence of what is happening, do not remember events, struggle to understand other people and medical staff, do not know the day of the week, date, current month and year, and become unable to assimilate new knowledge and to learn.¹⁴ These are signs of dementia. In this phase of the disease, patients are unable to work or study, they lead an antisocial lifestyle.

Both in the 1,4-BD intoxication and within the withdrawal, acute psychotic disorders with clinical picture of delirium are very likely to develop.¹⁶ According to the observations of addiction psychiatrists of the Omsk region, up to 70% of psychoses associated with 1,4-BD use are withdrawal psychoses, and 30% are intoxication psychoses.¹⁷ Psychoses manifesting during intoxication may persist and intensify in withdrawal. According to the clinical picture, psychoses are predominantly delirious and less often hallucinatory.¹⁸ Physiological causes of psychotic disorders due to 1,4-butanediol use are hyperstimulation of GABAergic receptors; hyperpolarization of nerve cell membranes; increase in the level of dopamine in the central nervous system; pronounced disorders of electrolyte and vitamin (especially B group) metabolism; damage to brain tissue as a result of inhibition (blockade) of nerve cell metabolism; high vascular permeability for toxic substances; and toxic damage to the liver and kidneys.¹⁹ These biochemical shifts result in hyperexcitation of the central nervous system, which turns into disorganization of its activity and deep depression, in some cases irreversible.

There are three stages of delirium due to 1,4-BD use:

• 1) An initial stage (rapid change of opposite affects, restlessness, and inattentiveness, disorientation to place and time with orientation to self, isolated illusions and episodes of auditory hallucinations; distractibility of attention);

• 2) An advanced stage (increasing agitation in the evening; insomnia; vivid persistent hallucinations—visual, auditory, tactile; hyper-distractibility of attention);

• 3) A terminal stage (confusion; increased psychomotor agitation; coordination disorders, combined hallucinations: visual, auditory, olfactory, thermal, tactile, and general somatic; lack of ability to concentrate attention).¹⁸

Asthenia, a decrease in mental abilities and functional decline are common disorders following delirium. Death occurs as a consequence of the toxic effects of 1,4-BD due to cerebral edema and/or kidney failure.

Conclusion

The available evidence shows that 1,4-BD is a substance with its own psychoactive effects, a high addiction potential and potentially severe withdrawal symptoms. For experts in the field of addiction, it is important to keep track of these quickly changing customs in drug use nowadays, as well as to realize the urgency of withdrawal and psychotic symptoms associated with 1,4-BD addiction.