Inhalants – Background, Behavioral and Neural Effects

Have you ever heard the word “resistoleros”? If you have, it was probably in reference to a Bay Area punk rock band that goes by A that name. But there is another, more disturbing, use of the word. In many parts of Latin America, resistoleros are street children who are habitual glue sniffers. Their name comes from Resistol, which is a contact cement and shoemaker’s glue that is widely sold in Latin American countries and favored by many young glue sniffers.

According to the International Assembly of the National Council for the Social Studies (2004), millions of homeless Latin American children are sniffing glues such as Resistol. Glue sniffing gives the children a temporary “high” that helps them cope with their precarious existence, but it can also cause many long-term health problems including damage to the brain and other vital organs.

Glues belong to a broader class of abused substances known as inhalants. Most inhalants are perfectly legal, can easily be purchased at retail stores by people of any age, and are readily accessible in the home by anyone who can reach into a medicine cabinet or kitchen drawer, or who can walk down the stairs to the basement or open the door to the garage. Moreover, in recent years these substances have been responsible for the abrupt death of a number of children and teenagers in many countries, including the United States. Indeed, the parents of children who have died from abusing inhalants invariably say that they never knew how dangerous these substances could be.

Where inhalants come from, how they affect behavioral and neural functioning, and what health risks they pose. Next will cover y-hydroxybutyrate (GHB) and anabolic-androgenic steroids. Although inhalants, GHB, and steroids differ in their mechanisms of action, they share the fact that they are all newcomers to the drug abuse scene relative to many other substances such as alcohol, cannabis, tobacco, opiates, and the plant-derived hallucinogens.

The third category, gases, includes several gases found in domestic or commercial products as well as anesthetic agents used in human and veterinary medicine. Sources of gaseous inhalants include whipped cream dispensers (which contain nitrous oxide, also known as “laughing gas”), propane tanks, butane lighters, and appliances that contain refrigerants such as refrigerators, freezers, and air-conditioners. Table 1 lists some abused inhalants that fall within these three classes.

A fourth group of inhalants, called nitrites, is often placed in a separate category apart from the solvents, aerosols, and gases. Whereas most inhalants are taken in order to obtain a euphoric effect, or “high,” nitrites are typically used to heighten sexual arousal and pleasure. Furthermore, unlike other inhalants, which are thought to act directly on nerve cells, nitrites produce their subjective effects primarily by dilating blood vessels and causing muscle relaxation. Members of this group include amyl nitrite (“poppers”), butyl nitrite, and cyclohexyl nitrite. In the remainder of this section, we will focus on the first three classes of inhalants.

Background

Inhalants represent a novel group of abused substances. These substances, which often come from everyday household items, have the following characteristics:

1. They are either volatile (easily vaporized) liquids or gases at room temperature.

2. They are used by either sniffing fumes from a container of the substance, inhaling the substance from a balloon, inhaling fumes from a rag saturated with the substance (“huffing”), inhaling fumes of the substance inside of a plastic or paper bag, or spraying an aerosol of the substance directly into one’s nose or mouth.

3. They do not belong to another defined class of abused substances (for example, nicotine, THC, or cocaine, all of which can be inhaled through smoking).

Most inhalants can be categorized as volatile solvents, aerosols, or gases. Volatile solvents are chemicals that are liquid at room temperature but give off fumes that can be inhaled. Solvents are found in numerous household and industrial products, including adhesives, correction fluids, ink used in felt-tip marking pens, paint thinners and paint removers, dry-cleaning fluids, gasoline, and industrial degreasing agents. Aerosols are sprays that contain various solvents and propellants. Examples are hair sprays, deodorant sprays, spray paints, vegetable oil sprays used in cooking, and sprays used for household cleaning.

TABLE 1 Some Commonly Abused Inhalants

Compound Principal uses
Acetone Nail polish remover, adhesives, general solvent
Aliphatic and aromatic hydrocarbons Gasoline, white spirits
Bromochlorodifluoromethane (BCF) Fire extinguishers
n-Butane Cigarette lighters, bottled fuel gas
Butanone (methyl ethyl ketone, MEK) Adhesives, general solvent
Carbon tetrachloride Grain fumigant, laboratory solvent
Chlorodifluoromethane Aerosol propellant
(Halon 122 or Freon 22)
Chloroform Laboratory solvent
Dichlorodifluoromethane Aerosol propellant, refrigerant
(Halon or Freon 12)
Dichlorotetrafluoroethane Aerosol propellant
(Halon 242 or Freon 114)
Diethyl ether Laboratory solvent
Enflurane Anesthetic
Ethyl acetate Adhesives
Halothane Anesthetic
n-Hexane General solvent
Isoflurane Anesthetic
Methyl isobutyl ketone (MIBK) General solvent
Nitrous oxide Anesthetic, whipped cream dispensers
Propane Botded fuel gas
Tetrachloroethylene (perchloroethylene) Dry-cleaning and degreasing agent
Toluene Adhesives, acrylic paints, paint stripper
Trichloroethane (methylchloroform) Dry-cleaning and degreasing agent, correction fluid
Trichloroethylene Dry-cleaning and degreasing agent, chewing gum remover
Trichlorofluoromethane Aerosol propellant, refrigerant
(Halon or Freon 11)
Xylene Woodwork adhesives, histology clearing agent

Behavioral and Neural Effects

Many inhalant effects are similar to alcohol intoxication

The acute effects of volatile and gaseous inhalants are often compared to those seen with alcohol intoxication. The user initially experiences euphoria, stimulation, and disinhibition, which are followed by drowsiness and lightheadedness. Heavier exposure causes stronger depressant effects, characterized by slurred speech, poor coordination, ataxia, and lethargy. Sensory distortions, even hallucinations, may occur. Very high doses can lead to anesthesia, loss of consciousness, and coma.

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A British study by Evans and Raistrick (1987) surveyed groups of young people (mean ages of 15 or 16) who had abused either toluene-containing adhesives (“glue sniffing”) or butane gas. Both groups reported behaving as though they were drunk while under inhalant intoxication. Euphoria was experienced in nearly all cases, but other mood changes (for example, feelings of depression or fearfulness) also occurred some of the time. Visual or auditory hallucinations were quite common. Less common but more dangerous were reports by some users of delusional ideas, including the delusion that one could fly. Users who thought they could fly actually jumped out of windows or trees, leading to at least one broken bone and various minor injuries but fortunately no fatalities.

Repeated use of inhalants can lead to tolerance, and thus a need to take higher doses in order to obtain the expected euphoric effect. Some investigators have also proposed the existence of an inhalant withdrawal syndrome with symptoms such as nausea, tremors, irritability, and sleep disturbances. However, this remains controversial at the present time.

Rewarding and reinforcing effects have been demonstrated in animals

Inhalants appear to be reinforcing, thereby linking them with most other substances of abuse. We know from subjective reports that people take inhalants to obtain pleasurable effects, but it is always valuable for researchers to have an animal model of reward or reinforcement to study. This has long been a technically challenging problem for scientists working with inhalants, but progress is being made, as indicated by the recent study of Funada et al. (2002). These Japanese researchers tested the rewarding properties of toluene by means of a place-conditioning procedure using an airtight inhalation shuttlebox. As is standard for place- conditioning studies, the two compartments of the apparatus differed in the sensory cues they presented to the animals. Mice were given 10 conditioning sessions over 5 days, 1 session each day in the toluene-containing compartment, and an additional session in the compartment that just contained air. Exposure to 700 parts per million (ppm) or more of toluene led to a significant preference for the toluene-associated side of the apparatus.

Inhalants reduce central nervous system (CNS) excitability by acting on specific ionotropic receptors

Because of their more recent arrival on the scene, less is known about the mechanism of action of inhalants than of other abused substances. Furthermore, all inhalants may not work the same way, due to their chemical diversity. Nevertheless, our understanding of these substances is increasing and several important findings have been made.

With respect to pharmacokinetics, inhalants are rapidly absorbed from the lungs into the bloodstream and quickly enter the brain due to their high lipid solubility. Madina Gerasimov and her colleagues at the Brookhaven National Laboratory recently used positron emission tomography (PET) to investigate the localization of [uC]toluene that had been administered to baboons (Gerasimov et al., 2002). The radiolabeled toluene reached all parts of the brain, but its distribution was not uniform. Quantitative measurements of the striatum, frontal cortex, thalamus, cerebellum, and white matter showed particularly high uptake in the striatum, thalamus, and deep cerebellar nuclei. These findings indicate that localization of inhalants within the brain needs to be taken into account in trying to understand how these substances affect brain function and behavior.

The CNS-depressant actions of inhalants can best be explained by their effects on various ionotropic receptors. A number of studies have found that volatile solvents as well as anesthetics enhance the function of inhibitory GABAA and glycine receptors and inhibit the activity of excitatory NMDA glutamate receptors. A similar profile of ionotropic receptor effects has been demonstrated for other depressant drugs, particularly ethanol. Thus, it appears that inhalants reduce CNS excitability and cause behavioral impairment in much the same way as does alcohol.

Relatively little is known about the neural mechanisms underlying inhalant reinforcement. In previous posts, we saw that dopamine (DA) plays a role in the reinforcing properties of many abused drugs. Riegel and French (2002) found that inhaled toluene activated dopaminergic neurons in the ventral tegmental area, which suggests that DA may also be involved in inhalant reinforcement. It will be important to determine whether DA receptor antagonists can block the rewarding effects of toluene in model systems such as the place-conditioning paradigm.

Significant health risks are associated with inhalant abuse

It is not uncommon for inhalants to be the first substances tried by children, even sooner than alcohol, tobacco, or marijuana. Solvents and aerosols in particular can be obtained legally and inexpensively (in fact, there are almost certainly plenty of them at home already in the kitchen, basement, or garage), and it may be difficult for parents and teachers to detect the use of inhalants if the child is careful. Government surveys indicate that about 6% of children in this country have tried inhalants at least once by the fourth grade and that inhalant use typically peaks during the seventh through the ninth grades. Indeed, inhalants were found to be the most popular substances for 12-year-olds, exceeding marijuana. This is not to say that adults don’t use inhalants, because obviously some do. Nevertheless, this class of substances is unusual in its special attractiveness to children and teenagers.

The health risks of inhalant use are significant. Even a single use can lead to a fatal cardiac arrhythmia, which means a loss of normal heart rhythm. This reaction has been termed sudden sniffing death syndrome. Although most users obviously don’t suffer heart failure, repeated inhalant use can damage the liver, kidneys, and lungs. The brain is particularly vulnerable to inhalant toxicity. Several magnetic resonance imaging (MRI) studies have shown white-matter abnormalities indicative of damage to the myelin sheaths surrounding nerve cell axons in many brain areas. One recent study compared MRI scans of chronic inhalant abusers with individuals who abused various other drugs such as cocaine, marijuana, alcohol, amphetamines, or opiates. The results indicated many more subcortical abnormalities in the inhalant-abusing group (Rosenberg et al., 2002). Moreover, the inhalant abusers also performed more poorly than the other drug abusers on several neuropsychological tests. These results suggest that chronic inhalant abuse can have damaging effects on the brain that are manifested in cognitive impairment.

Many parts of the United States have had problems with inhalant abuse, but none more than Alaska. As many as 22% of high school students surveyed in Alaska admitted to having tried inhalants, and a number of deaths have occurred. Unlike for other substances, there is little information on treatment for inhalant abuse. However, in 2001 the federal government began funding the nation’s first treatment center for inhalant users, the Tundra Swan Inhalant Treatment Center, in Bethel, Alaska. Although Tundra Swan is only a small facility at this time, substance abuse workers hope that the lessons learned there will help us better understand the nature of this problem and how to treat it effectively.

Post Summary

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. Volatile solvents are chemicals that are liquid at room temperature but release fumes that can be inhaled. Aerosols are sprays that contain one or more solvents or propellants. There are also gaseous inhalants, which include some gases used commercially as well as anesthetic agents like nitrous oxide. Nitrites represent a fourth group of inhalants that differ from the previous types in that they are taken specifically to enhance sexual arousal.

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, and sleepiness. Very high doses may cause loss of consciousness and even coma. Repeated inhalant use leads to tolerance, although the existence of an inhalant withdrawal syndrome has not yet been conclusively established. Inhalants are reinforcing to humans due to their euphoric effects, and animal studies have also begun to establish the rewarding and reinforcing properties of these substances under controlled laboratory conditions.

Inhalants are rapidly absorbed from the lungs and quickly enter the brain from the bloodstream due to their high lipid solubility. Distribution within the brain does not appear to be uniform, which may influence the behavioral effects of these substances. The depressant effects of inhalants can be attributed mainly to enhancement of inhibitory GABAA and glycine receptor activity, as well as inhibition of excitatory NMDA receptors. Inhalant reinforcement may also involve release of DA due to activation of dopaminergic neurons in the ventral tegmental area.

Because of their legal status and ready availability in the home, inhalants are sometimes the first abused substances taken by children. Surveys show that inhalant use peaks during the seventh through the ninth grades. Inhalants present serious health risks involving damage to the liver, kidneys, lungs, and brain. Solvent abusers show cognitive impairment that may be related to white-matter abnormalities seen on MRI scans. There is also a rare disorder called sudden sniffing death syndrome, which is a fatal cardiac arrhythmia resulting from inhalant use. Although inhalant use and abuse is found throughout the United States, the greatest problem is found in Alaska. Little is known about the most effective treatments for inhalant abusers, but useful information will hopefully be gleaned from the treatment center that was established several years ago in Alaska.

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