Inhalants, GHB, and Anabolic–Androgenic Steroids

 

Inhalants

Background

Behavioral and Neural Effects

• Inhalants are abused substances that are often obtained from everyday household items. These substances are volatile liquids or gases at room temperature; are used by sniffing, inhaling, or spraying the substance; and do not belong to another defined class of abused drugs.
• Inhalants comprise five categories of substances: volatile solvents, fuels, halogenated hydrocarbons, anesthetics, and nitrites. They are rapidly absorbed from the lungs and readily enter the brain because of their high lipid solubility. In contrast to most other abused substances, inhalant doses are calculated in parts per million (ppm).
• Inhalants are most commonly used by children and adolescents, and they are often the first substance of abuse tried by a child.
• Low doses of volatile and gaseous inhalants produce effects resembling those seen with alcohol intoxication. Users exposed to greater amounts of these substances show stronger depressant effects, including slurred speech, poor coordination, ataxia, sleepiness, and at very high doses, loss of consciousness and even coma. Sensory distortions, including hallucinations, may also occur.
• Repeated inhalant use can lead to tolerance, dependence, and an abstinence syndrome when drug use is stopped. Withdrawal symptoms include nausea, fatigue, irritability, anxiety, sleep disturbances, and craving.
• Inhalants are reinforcing to humans because of their euphoric effects, and laboratory animal studies have also established the rewarding and reinforcing properties of these substances by means of self-administration, place conditioning, and electrical stimulation of the brain. Studies using toluene as a representative inhalant have found that this compound activates ascending dopaminergic systems, causing increased firing of VTA dopaminergic neurons and enhanced DA release in forebrain projection areas. Activation of the mesolimbic dopaminergic system may play an important role in toluene’s reinforcing and rewarding properties.
• Toluene exerts biphasic effects on locomotor activity in rodents, that is, locomotor activation at low concentrations and locomotor inhibition/sedation at higher concentrations. In drug discrimination studies, toluene and related volatile solvents fully substitute for ethanol and pentobarbital, indicating that these substances produce interoceptive cues like those of other sedative–hypnotic drugs.
• The depressant effects of acute exposure to high concentrations of inhalants such as toluene can generally be attributed to a combination of enhanced activity of inhibitory GABA_A and glycine receptors and inhibited activity of excitatory NMDA and nicotinic receptors. In contrast, prolonged inhalant exposure induces a counterregulatory response characterized by increased GABA_A receptor expression and function and decreased function and expression of NMDA receptors. These changes favor greater brain excitability and may also contribute to locomotor sensitization produced by repeated toluene exposure.
• Inhalants present serious health risks including damage to the liver, kidneys, respiratory tract, and bone marrow. Severe anemia in chronic inhalant users can result from bone marrow toxicity or, in the case of nitrous oxide, as a secondary consequence of vitamin B₁₂ deficiency. Myelin-rich white matter in the brain is particularly vulnerable to toxicity from repeated exposure to inhalants. Loss of myelin and subsequent damage to the previously myelin-sheathed axons is reflected by abnormal MRI scans and can lead to significant cognitive impairment; however, some evidence exists for neurological recovery in most users following long-term abstinence.
• Inhalant use can additionally lead to a rare disorder called sudden sniffing death syndrome, which in some cases results from an inhalant-induced cardiac arrhythmia. Moreover, some offspring exposed to inhalants in utero reportedly suffer from fetal solvent syndrome, which involves craniofacial abnormalities and possibly also cognitive deficits. These effects resemble those seen in individuals diagnosed with fetal alcohol syndrome.

Gamma-Hydroxybutyrate

Background

Behavioral and Neural Effects

Medical and Recreational Uses of GHB

• GHB is an analog of the inhibitory neurotransmitter GABA. It is synthesized in the brain in small amounts and is thought to function as a neurotransmitter/ neuromodulator that may be coreleased with GABA at some synapses.
• GHB was developed pharmacologically as a CNS depressant. It was later marketed in the United States as a bodybuilding supplement and for recreational use.
• Over-the-counter sales of GHB were banned in 1990, and the drug was designated as a Schedule I controlled substance in 2000. Nevertheless, GHB and its precursors GBL and 1,4-BD continue to be available for sale over the internet. GHB is most likely to be consumed by three different subgroups of users: attendees at dances and raves, gay men, and bodybuilders. The compound has also occasionally been used as a date rape drug at clubs.
• GHB is usually taken orally in the form of an aqueous solution. Low doses produce alcohol-like effects including mild euphoria, relaxation, and social disinhibition. These effects, along with enhancement of sexual arousal, are the experiences sought after by typical recreational users of GHB, GBL, or 1,4-BD. Higher doses of these compounds are associated with stronger sedating effects, as well as dizziness, nausea, vomiting, and memory impairment. Severe overdosing with GHB causes severe respiratory depression, unconsciousness, and even coma.
• Animals treated with GHB exhibit sedation, reduced locomotor activity, decreased anxiety behavior, and catalepsy at high doses. Impaired spatial learning has also been reported, which may be related to neurotoxic effects on the hippocampus.
• High doses of GHB can lead to EEG excitation resembling absence (petit mal) seizures in humans. A rat model of absence seizures has been developed based on administration of the appropriate doses of GHB or GBL.
• In regular users of sedative–hypnotic drugs, GHB ingestion produced positive subjective effects similar to those produced by ethanol. In laboratory animals, GHB and its precursors exert rewarding and reinforcing effects when tested under the appropriate dose and experimental conditions. However, these effects are not as robust as those seen with many other major drugs of abuse.
• The functional effects of GHB are mediated by multiple mechanisms. The low levels of endogenous GHB are believed to act on putative high-affinity GBH-specific receptors and on extrasynaptic GABA_A receptors containing α4, β, and δ subunits. High levels of exogenously administered GHB are additionally capable of activating GABA_B receptors, which mediate many of the behavioral and physiological effects observed in GHB-treated animals.
• The sodium salt of GHB (also called sodium oxybate; trade name Xyrem) is approved in the United States for the treatment of the sleep disorder narcolepsy. This treatment improves nighttime sleep and reduces the incidence of daytime sleepiness and attacks of catalepsy. In several European countries, sodium oxybate is approved for use as an IV anesthetic or for the treatment of alcoholism. In the latter application, the drug has been shown to ameliorate alcohol withdrawal symptoms and to reduce craving during abstinence from alcohol.
• Recreational GHB users reportedly experience euphoria, heightened sexuality, and feelings of relaxation during drug intoxication. In several respects, GHB intoxication resembles the state of alcohol intoxication, including impairment of psychomotor function and even loss of consciousness with overdose. The “comedown” following GHB use is characterized by sluggishness, mental confusion and amnesia, weakness, and increased arousal.
• Repeated GHB use can lead to tolerance, dependence, and withdrawal. Consumption patterns may escalate to dosing every 2 to 4 hours around the clock. In heavy GHB users, withdrawal symptoms can start within a few hours after the last dose and can persist for up to a few weeks. Typical withdrawal symptoms include insomnia, anxiety, and tremors, although use of extremely high doses can apparently cause a psychotic reaction involving hallucinations, delirium, and extreme agitation.
• Patients diagnosed with GHB dependence are typically treated with high doses of a benzodiazepine such as diazepam to help them get through the withdrawal period. However, an alternative approach developed in the Netherlands is to administer Xyrem starting with a high dose and then gradually tapering the medication until the patient is symptom free. Unfortunately, the majority of dependent users were found to relapse within 3 months after Xyrem treatment.

Anabolic–Androgenic Steroids

Background and History

Pharmacology of Anabolic–Androgenic Steroids

• Anabolic–androgenic steroids (AAS) are hormones that increase muscle mass and strength and also produce masculinizing effects in the user. These substances either contain the naturally occurring male sex hormone testosterone or are similar to testosterone in their chemical structure. Some AAS are taken orally, others by intramuscular injection.
• AAS were initially developed for their musclebuilding and performance-enhancing effects, but some current users take these substances mainly to attain a more muscular physical appearance. The Soviet Union was the first country in which steroids were administered to athletic competitors; however, the practice quickly spread to other countries. When the use and abuse of these substances became more widespread and numerous adverse side effects began to emerge, steroids were classified as Schedule III controlled substances in the United States. They were also banned by a variety of national and international athletic organizations.
• AAS are usually taken in specific patterns and combinations. In the case of cycling, the steroid is taken in alternating on and off periods. Cycling can be combined with pyramiding, in which the dose is increased during the early part of the cycle and then is gradually decreased after the peak dose is reached at the midpoint of the cycle. Bridging is a pattern that avoids periods of abstinence, since the user continues to take a low steroid dose in between the high doses of one cycle and the next. Some users also engage in stacking, which refers to combining two or more steroids (often one that is injected and another that is taken orally). Steroid users frequently practice polypharmacy, in which additional substances (e.g., stimulants or masking agents like diuretics) are taken along with the steroid.
• Controlled studies have confirmed that AAS such as testosterone dose-dependently enhance muscle fiber size, muscle mass, and strength. These effects are mediated by intracellular androgen receptors and involve increased protein synthesis, proliferation of satellite cells that can form new myotubes, and differentiation of local stem cells into muscle cells.
• There are a number of adverse side effects of AAS. Chronic steroid users may exhibit cardiovascular problems such as abnormalities in heart structure and function, high blood pressure, and reduced circulating HDL. Other physiological side effects may include renal toxicity, skin and hair problems (e.g., severe acne), liver toxicity (particularly with the use of certain oral steroids), and risk of stunted growth in young users. Women are vulnerable to significant masculinizing effects of AAS use.
• Reproductive function can be disrupted by AAS use. Men show suppressed release of LH and FSH from the pituitary gland because the androgenic properties of AAS activate the negative feedback system that controls gonadotropin release. Chronically reduced LH and FSH causes testicular shrinkage, low circulating testosterone, and low sperm counts, which can lead to infertility.
• AAS have also been associated with a variety of psychological side effects. Mood shifts may range from depression to mania. Some individuals suffer from an unusual male body image disorder known as muscle dysmorphia. Case reports as well as controlled and naturalistic studies have also linked AAS with heightened irritability and aggressiveness in a significant percentage of users. In rare cases, a heavy AAS user may exhibit severe aggressive outbursts colloquially known as “roid rage.”
• Research with experimental animals has yielded important information regarding the neurobiological mechanisms of AAS-related aggression. A particularly well-studied model involves daily administration of an AAS mixture to adolescent male Syrian hamsters, after which the animals are tested in the resident–intruder paradigm. The treated animals show substantially elevated amounts of aggressive behaviors compared with controls, and they additionally show increased anxiety-like behaviors. Researchers have identified a complex neural circuit mediating these behaviors, with the anterior hypothalamus serving as a point of convergence of both aggression- and anxiety related neural pathways.
• A certain percentage of steroid users develop a characteristic pattern of dependence and withdrawal related to these substances. Feelings of anxiety are frequently experienced either at the end of a cycle of AAS use or after a period of prolonged abstinence and withdrawal. Intravenous and intracerebroventricular steroid self-administration have been demonstrated in laboratory animals, although steroids are not as strongly reinforcing as classical addictive drugs like cocaine or heroin. The mechanisms underlying steroid reinforcement are not yet well understood; however, several possible mechanisms can be considered. These mechanisms include activation of the following: the classical intracellular androgen receptor, a membrane form of the receptor, estrogen receptors after conversion of androgens (e.g., testosterone) to estrogens (e.g., estradiol) by aromatase, and receptors for neurotransmitters such as GABA.
• Testosterone has an important medical role in the treatment of male hypogonadism. Primary hypogonadism occurs when the testes are unresponsive to LH and FSH. Secondary hypogonadism occurs when an abnormal condition causes reduced secretion of LH and FSH. Both types of hypogonadism result in low testosterone levels, which in turn can cause poor libido, erectile dysfunction, sterility, and loss of muscle mass and bone density. Fortunately, these symptoms are usually responsive to testosterone replacement therapy. Besides the severe hypogonadism that may develop at a relatively young age, a more moderate reduction in circulating testosterone typically occurs in elderly men, who may seek medical attention if the symptoms are sufficiently distressing. Researchers are additionally beginning to consider the potential benefits of testosterone administration for improving sexual function and musculoskeletal health in postmenopausal women.