The treatment of physical dependence will be discussed with reference to the specific drug of abuse and dependence problems characteristic to each category: CNS depressants, including alcohol and other sedatives; nicotine and tobacco; opioids; psychostimulants, such as amphetamine and cocaine; cannabinoids; psychedelic drugs; and inhalants (volatile solvents, nitrous oxide, and ethyl ether). Abuse of combinations of drugs across these categories is common. Alcohol is so widely available that it is combined with practically all other categories. Some combinations reportedly are taken because of their interactive effects. An example is the combination of heroin and cocaine ("speedball"), which will be described with the opioid category. Alcohol and cocaine is another very common combination. When confronted with a patient exhibiting signs of overdose or withdrawal, the physician must be aware of these possible combinations because each drug may require specific treatment.
Ethanol. Experimentation with ethanol is almost universal, and a high proportion of users find the experience pleasant. More than 90% of American adults report experience with ethanol (commonly called "alcohol"), and ~70% report some level of current use. The lifetime prevalence of alcohol use disorders (alcoholism) in men is almost 20% and in women is 10-15% (Hasin et al., 2007). This drug is discussed more fully in Chapter 23. Ethanol is classified as a depressant because it indeed produces sedation and sleep. However, the initial effects of alcohol, particularly at lower doses, often are perceived as stimulation owing to a suppression of inhibitory systems. Those who perceive only sedation from alcohol generally choose not to drink when evaluated in a test procedure (de Wit et al., 1989).
Alcohol impairs recent memory and, in high doses, produces the phenomenon of "blackouts": the drinker has no memory of his or her behavior while intoxicated. The effects of alcohol on memory are unclear, but evidence suggests that reports from patients about their reasons for drinking and their behavior during a binge are not reliable. Alcohol-dependent persons often say that they drink to relieve anxiety or depression. When allowed to drink under observation, however, alcoholics typically become more dysphoric as drinking continues (Mendelson and Mello, 1979), thus not supporting the idea that alcoholics drink to relieve tension.
Tolerance, Physical Dependence, and Withdrawal. Mild intoxication by alcohol is familiar to almost everyone, but the symptoms vary among individuals. Some simply experience motor incoordination and sleepiness. Others initially become stimulated and garrulous. As the blood level increases, the sedating effects increase, with eventual coma and death occurring at high alcohol levels. The initial sensitivity (innate tolerance) to alcohol varies greatly among individuals and is related to family history of alcoholism (Wilhelmsen et al., 2003). Experience with alcohol can produce greater tolerance (acquired tolerance) such that extremely high blood levels (300-400 mg/dL) can be found in alcoholics who do not appear grossly sedated. In these cases, the lethal dose does not increase proportionately to the sedating dose, and thus the margin of safety (therapeutic index) is decreased.
Heavy consumers of alcohol not only acquire tolerance but also inevitably develop a state of physical dependence. This often leads to drinking in the morning to restore blood alcohol levels diminished during the night. Eventually, they may awaken during the night and take a drink to avoid the restlessness produced by falling alcohol levels. The alcohol-withdrawal syndrome (Table 24–4) generally depends on the size of the average daily dose and usually is "treated" by resumption of alcohol ingestion. Withdrawal symptoms are experienced frequently but usually are not severe or life-threatening until they occur in conjunction with other problems, such as infection, trauma, malnutrition, or electrolyte imbalance. In the setting of such complications, the syndrome of delirium tremens becomes likely.
Alcohol addiction produces cross-tolerance to other sedatives such as benzodiazepines. This tolerance is operative in abstinent alcoholics, but while the alcoholic is drinking, the sedating effects of alcohol add to those of other sedatives, making the combination more dangerous. This is particularly true for benzodiazepines, which are relatively safe in overdose when given alone but potentially are lethal in combination with alcohol.
The chronic use of alcohol and other sedatives is associated with the development of depression (McLellan et al., 1979), and the risk of suicide among alcoholics is one of the highest of any diagnostic category. Cognitive deficits have been reported in alcoholics tested while sober. These deficits usually improve after weeks to months of abstinence. More severe recent memory impairment is associated with specific brain damage caused by nutritional deficiencies common in alcoholics (e.g., thiamine deficiency).
Alcohol is toxic to many organ systems. As a result, the medical complications of alcohol abuse and dependence include liver disease, cardiovascular disease, endocrine and GI effects, and malnutrition, in addition to the CNS dysfunctions outlined earlier. Ethanol readily crosses the placental barrier, producing the fetal alcohol syndrome, a major cause of mental retardation (Chapter 23).
Detoxification. A patient who presents in a medical setting with an alcohol-withdrawal syndrome should be considered to have a potentially lethal condition. Although most mild cases of alcohol withdrawal never come to medical attention, severe cases require general evaluation; attention to hydration and electrolytes; vitamins, especially high-dose thiamine; and a sedating medication that has cross-tolerance with alcohol. To block or diminish the symptoms described in Table 24–4, a short-acting benzodiazepine such as oxazepam can be used at a dose of 15-30 mg every 6-8 hours according to the stage and severity of withdrawal; some authorities recommend a long-acting benzodiazepine unless there is demonstrated liver impairment. Anticonvulsants such as carbamazepine have been shown to be effective in alcohol withdrawal, although they appear not to relieve subjective symptoms as well as benzodiazepines. After medical evaluation, uncomplicated alcohol withdrawal can be treated effectively on an outpatient basis. When there are medical problems, a history of seizures, or simultaneous dependence on other drugs, hospitalization is required.
Pharmacotherapy. Detoxification is only the first step of treatment. Complete abstinence is the objective of long-term treatment, and this is accomplished mainly by behavioral approaches. Medications that aid in the prevention of relapse are under development. Disulfiram (antabuse; Chapter 23) has been useful in some programs that focus behavioral efforts on ingestion of the medication. Disulfiram blocks aldehyde dehydrogenase, the second step in ethanol metabolism, resulting in the accumulation of acetaldehyde, which produces an unpleasant flushing reaction when alcohol is ingested. Knowledge of this unpleasant reaction helps the patient to resist taking a drink. Although quite effective pharmacologically, disulfiram has not been found to be effective in controlled clinical trials because so many patients failed to ingest the medication.
Naltrexone (revia; Chapter 23), an opioid receptor antagonist that blocks the reinforcing properties of alcohol, is FDA- approved as an adjunct in the treatment of alcoholism. Chronic administration of naltrexone resulted in a decreased rate of relapse to alcohol drinking in the majority of published double-blind clinical trials (Pettinati et al., 2006). It works best in combination with behavioral treatment programs that encourage adherence to medication and abstinence from alcohol. A depot preparation with a duration of 30 days (vivitrol) was approved by the FDA in 2006; it greatly improves medication adherence, the major problem with the use of medications in alcoholism.
A significant development in identifying a potential endophenotype of alcoholism has grown out of the clinical experience with naltrexone. Animal studies have demonstrated that alcohol causes the release of endogenous opioids in brain reward systems and the disinhibition or activation of DA neurons, a condition common to all drugs of abuse. Blocking opioid receptors prevents this dopaminergic effect and results in less stimulation or reward from alcohol (Ray and Hutchison, 2007). A functional allele of the gene for the μ opioid receptor that naltrexone blocks has been associated with alcohol stimulation and with good response to naltrexone treatment among alcoholics (Anton et al., 2006).
Acamprosate (campral), another FDA-approved medication for alcoholism (Mason, 2003), is a competitive inhibitor of the N-methyl-D-aspartate (NMDA)–type glutamate receptor. The drug appears to normalize the dysregulated neurotransmission associated with chronic ethanol intake and thereby to attenuate one of the mechanisms that lead to relapse (Chapter 23).
Table 24-4Alcohol Withdrawal Syndrome ||Download (.pdf) Table 24-4 Alcohol Withdrawal Syndrome
|Alcohol craving |
|Tremor, irritability |
|Sleep disturbance |
|Perceptual distortion |
|Seizures (6-48 hours after last drink) |
|Visual (and occasionally auditory or tactile) hallucinations (12-48 hours after last drink) |
|Delirium tremens (48-96 hours after last drink; rare in uncomplicated withdrawal) |
| Severe agitation |
| Confusion |
| Fever, profuse sweating |
| Tachycardia |
| Nausea, diarrhea |
| Dilated pupils |
Benzodiazepines. Benzodiazepines are among the most commonly prescribed medications worldwide; they are used mainly for the treatment of anxiety disorders and insomnia (Chapters 15 and 17). Considering their widespread use, intentional abuse of prescription benzodiazepines is relatively uncommon. When a benzodiazepine is taken for up to several weeks, there is little tolerance and no difficulty in stopping the medication when the condition no longer warrants its use. After several months, the proportion of patients who become tolerant increases, and reducing the dose or stopping the medication produces withdrawal symptoms (Table 24–5).
Table 24-5Benzodiazepine Withdrawal Symptoms ||Download (.pdf) Table 24-5 Benzodiazepine Withdrawal Symptoms
|Following moderate dose usage |
| Anxiety, agitation |
| Increased sensitivity to light and sound |
| Paresthesias, strange sensations |
| Muscle cramps |
| Myoclonic jerks |
| Sleep disturbance |
| Dizziness |
|Following high-dose usage |
| Seizures |
| Delirium |
It can be difficult to distinguish withdrawal symptoms from the reappearance of the anxiety symptoms for which the benzodiazepine was prescribed initially. Some patients may increase their dose over time because tolerance definitely develops to the sedative effects. Many patients and their physicians, however, contend that anti-anxiety benefits continue to occur long after tolerance to the sedating effects. Moreover, these patients continue to take the medication for years according to medical directions without increasing their dose and are able to function very effectively as long as they take the benzodiazepine. The degree to which tolerance develops to the anxiolytic effects of benzodiazepines is a subject of controversy. There is, however, good evidence that significant tolerance does not develop to all benzodiazepine actions because some effects of acute doses on memory persist in patients who have taken benzodiazepines for years. According to a task force that reviewed the issues and published guidelines on the proper medical use of benzodiazepines (American Psychiatric Association, 1990), intermittent use only when symptoms occur retards the development of tolerance and therefore is preferable to daily use. Patients with a history of alcohol- or other drug-abuse problems have an increased risk for the development of benzodiazepine abuse and should rarely, if ever, be treated with benzodiazepines on a chronic basis.
While relatively few patients who receive benzodiazepines for medical indications abuse their medication, there are individuals who specifically seek benzodiazepines for their ability to produce a "high." Among these abusers, there are differences in drug popularity; benzodiazepines that have a rapid onset, such as diazepam and alprazolam, tend to be the most desirable. The drugs may be obtained by simulating a medical condition and deceiving physicians or simply through illicit channels. Unsupervised use can lead to self-administration of large doses and therefore tolerance to the benzodiazepine's sedating effects. For example, while 5-20 mg/day of diazepam is a typical dose for a patient receiving prescribed medication, abusers may take over 1000 mg/day and not appear grossly sedated.
Abusers may combine benzodiazepines with other drugs to increase the effect. For example, it is part of the "street lore" that taking diazepam 30 minutes after an oral dose of methadone will produce an augmented high not obtainable with either drug alone.
While there is some illicit use of benzodiazepines as a primary drug of abuse, most of the unsupervised use seems to be by abusers of other drugs who are attempting to self-medicate the side effects or withdrawal effects of their primary drug of abuse. Thus, cocaine addicts often take diazepam to relieve the irritability and agitation produced by cocaine binges, and opioid addicts find that diazepam and other benzodiazepines relieve some of the anxiety symptoms of opioid withdrawal when they are unable to obtain their preferred drug.
Pharmacological Interventions. If patients receiving long-term benzodiazepine treatment by prescription wish to stop their medication, the process may take months of gradual dose reduction. Withdrawal symptoms (Table 24–5) may occur during this outpatient detoxification, but in most cases the symptoms are mild. If anxiety symptoms return, a non-benzodiazepine such as buspirone may be prescribed, but this agent usually is less effective than benzodiazepines for treatment of anxiety in these patients. Some authorities recommend transferring the patient to a long t1/2 benzodiazepine during detoxification; others recommend the anticonvulsants carbamazepine and phenobarbital. Controlled studies comparing different treatment regimens are lacking. Since patients who have been on low doses of benzodiazepines for years usually have no adverse effects, the physician and patient should decide jointly whether detoxification and possible transfer to a new anxiolytic are worth the effort.
The specific benzodiazepine receptor antagonist flumazenil has been found useful in the treatment of overdose and in reversing the effects of long-acting benzodiazepines used in anesthesia. It has been used experimentally in the treatment of persistent withdrawal symptoms after cessation of long-term benzodiazepine treatment.
Deliberate abusers of high doses of benzodiazepines usually require inpatient detoxification. Frequently, benzodiazepine abuse is part of a combined dependence involving alcohol, opioids, and cocaine. Detoxification can be a complex clinical pharmacological problem requiring knowledge of the pharmacokinetics of each drug. The patient's history may be unreliable not simply because of lying but also because the patient frequently does not know the true identity or dose of drugs purchased on the street. Medication for detoxification should not be prescribed by the "cookbook" approach but by careful titration and patient observation. The withdrawal syndrome from diazepam, e.g., may not become evident until the patient develops a seizure in the second week of hospitalization. One approach to complex detoxification is to focus on the CNS-depressant drug and temporarily hold the opioid component constant with a low dose of methadone. Opioid detoxification can begin later. A long-acting benzodiazepine such as diazepam or clorazepate (tranxene, others) or a long-acting barbiturate such as phenobarbital can be used to block the sedative withdrawal symptoms. The phenobarbital dose should be determined by a series of test doses and subsequent observations to determine the level of tolerance. Most complex detoxifications can be accomplished using this phenobarbital loading-dose strategy (Robinson et al., 1981).
After detoxification, the prevention of relapse requires a long-term outpatient rehabilitation program similar to the treatment of alcoholism. No specific medications have been found to be useful in the rehabilitation of sedative abusers; but, of course, specific psychiatric disorders such as depression or schizophrenia, if present, require appropriate medications.
Barbiturates and Older Sedatives. The use of barbiturates and older non-benzodiazepine sedating medications (e.g., meprobamate, glutethimide, chloral hydrate) has declined greatly in recent years owing to the increased safety and to the efficacy of the benzodiazepines and the newer agents zolpidem, eszopiclone, zaleplon, and ramelteon (Chapters 15 and 17). Abuse problems with barbiturates resemble those seen with benzodiazepines in many ways. Treatment of abuse and addiction should be handled similarly to interventions for the abuse of alcohol and benzodiazepines. Because drugs in this category frequently are prescribed as hypnotics for patients complaining of insomnia, physicians should be aware of the problems that can develop when the hypnotic agent is withdrawn. Insomnia rarely should be treated with medication as a primary disorder except when produced by short-term stressful situations. Insomnia often is a symptom of an underlying chronic problem, such as depression or respiratory dysfunction, or may be due simply to a change in sleep requirements with age. Prescription of sedative medications, however, can change the physiology of sleep with subsequent tolerance to these medication effects. When the sedative is stopped, there is a rebound effect with worsened insomnia. This medication-induced insomnia requires detoxification by gradual dose reduction.
The basic pharmacology of nicotine and agents for smoking cessation are discussed in Chapter 11. Because nicotine provides the reinforcement for cigarette smoking, the most common cause of preventable death and disease in the U.S., it is arguably the most dangerous dependence-producing drug. The dependence produced by nicotine can be extremely durable, as exemplified by the high failure rate among smokers who try to quit. Although >80% of smokers express a desire to quit, only 35% try to stop each year, and fewer than 5% are successful in unaided attempts to quit (American Psychiatric Association, 2000).
Cigarette (nicotine) addiction is influenced by multiple variables. Nicotine itself produces reinforcement; users compare nicotine to stimulants such as cocaine or amphetamine, although its effects are of lower magnitude. While there are many casual users of alcohol and cocaine, few individuals who smoke cigarettes smoke a small enough quantity (≤5 cigarettes per day) to avoid dependence. Nicotine is absorbed readily through the skin, mucous membranes, and lungs. The pulmonary route produces discernible CNS effects in as little as 7 seconds. Thus, each puff produces some discrete reinforcement. With 10 puffs per cigarette, the one-pack-per-day smoker reinforces the habit 200 times daily. The timing, setting, situation, and preparation all become associated repetitively with the effects of nicotine.
Nicotine has both stimulant and depressant actions. The smoker feels alert, yet there is some muscle relaxation. Nicotine activates the nucleus accumbens reward system in the brain; increased extracellular DA has been found in this region after nicotine injections in rats. Nicotine affects other systems as well, including the release of endogenous opioids and glucocorticoids.
There is evidence for tolerance to the subjective effects of nicotine. Smokers typically report that the first cigarette of the day after a night of abstinence gives the "best" feeling. Smokers who return to cigarettes after a period of abstinence may experience nausea if they return immediately to their previous dose. Persons naive to the effects of nicotine will experience nausea at low nicotine blood levels, and smokers will experience nausea if nicotine levels are raised above their accustomed levels.
Negative reinforcement refers to the benefits obtained from the termination of an unpleasant state. In dependent smokers, the urge to smoke correlates with a low blood nicotine level, as though smoking were a means to achieve a certain nicotine level and thus avoid withdrawal symptoms. Some smokers even awaken during the night to have a cigarette, which ameliorates the effect of low nicotine blood levels that could disrupt sleep. If the nicotine level is maintained artificially by a slow intravenous infusion, the number of cigarettes smoked and in the number of puffs decrease. Thus, smokers may be smoking to achieve the reward of nicotine effects, to avoid the pain of nicotine withdrawal, or most likely a combination of the two. Nicotine withdrawal symptoms are listed in Table 24–6.
Depressed mood (dysthymic disorder, affective disorder) is associated with nicotine dependence, but it is not known whether depression predisposes one to begin smoking or depression develops during the course of nicotine dependence. Depression increases significantly during smoking withdrawal, and this is cited as one reason for relapse.
Pharmacological Interventions. The nicotine withdrawal syndrome can be alleviated by nicotine-replacement therapy, available with a prescription (e.g., NICOTROL inhaler and nasal spray) or without (e.g., NICORETTE gum and others; COMMIT lozenges and others; and NICODERM CQ transdermal patch and others). Figure 24–3 shows the blood nicotine concentrations achieved by different methods of nicotine delivery. Because nicotine gum and a nicotine patch do not achieve the peak levels seen with cigarettes, they do not produce the same magnitude of subjective effects as smoking. These methods do, however, suppress the symptoms of nicotine withdrawal. Thus, smokers should be able to transfer their dependence to the alternative delivery system and gradually reduce the daily nicotine dose with minimal symptoms. Although this results in more smokers achieving abstinence, most resume smoking over the ensuing weeks or months. Comparisons with placebo treatment show large benefits of nicotine replacement at 6 weeks, but the effect diminishes with time. The nicotine patch produces a steady blood level (Figure 24–3) and seems to have better patient compliance than that observed with nicotine gum. Verified abstinence rates at 12 months are reported to be in the range of 20%. The necessary goal of complete abstinence contributes to the poor success rate; when ex-smokers "slip" and begin smoking a little, they usually relapse quickly to their prior level of dependence.
The search for better medications to treat nicotine addiction has become an important goal of the pharmaceutical industry, and other types of medication have been tested in clinical trials. A sustained-release preparation of the antidepressant bupropion (zyban; Chapter 15), improves abstinence rates among smokers and remains a useful option. The cannabinoid CB1 receptor inverse agonist rimonabant improves abstinence rates and reduces the weight gain seen frequently in ex-smokers. Unfortunately, the CB1 inverse agonist mechanism led to a high frequency of depressive and neurologic symptoms, ending its development in the U.S. Varenicline, a partial agonist at the α4β2 subtype of the nicotinic acetylcholine receptor, improves abstinence rates but has also been linked to risk of developing suicidal ideation. Varenicline partially stimulates nicotinic receptors, thereby reducing craving and preventing most withdrawal symptoms. It has high receptor affinity, thus blocking access to nicotine, so if the treated smoker relapses, there is little reward and abstinence is more likely to be maintained. In one recent clinical trial, the abstinence rate for varenicline at 1 year was 36.7% versus 7.9% for placebo (Williams et al., 2007).
Table 24-6Nicotine Withdrawal Symptoms ||Download (.pdf) Table 24-6 Nicotine Withdrawal Symptoms
|Irritability, impatience, hostility |
|Dysphoric or depressed mood |
|Difficulty concentrating |
|Decreased heart rate |
|Increased appetite or weight gain |
Opioid drugs are used primarily for the treatment of pain (Chapter 18). Some of the CNS mechanisms that reduce the perception of pain also produce a state of well-being or euphoria. Thus, opioid drugs also are taken outside medical channels for the purpose of obtaining the effects on mood. This potential for abuse has generated much research on separating the mechanism of analgesia from that of euphoria in the hope of eventually developing a potent analgesic that does not activate the brain reward systems. Although this research has led to advances in understanding the physiology of pain, the standard medications for severe pain remain the derivatives of the opium poppy (opiates) and synthetic drugs that activate the same receptors (opioids). Drugs modeled after the endogenous opioid peptides may one day provide more specific options for the treatment of pain, but none of these currently is available for clinical use. Analgesic medications that do not act at opioid receptors, such as the nonsteroidal anti-inflammatory drugs (NSAIDs), have an important role in mild to moderate types of pain, but for severe pain, the opioid drugs are most effective. Progress in pain control stems from a greater understanding of the mechanism of tolerance to μ opiate receptor–mediated analgesia, which involves NMDA receptors (Trujillo and Akil, 1991). Experimentally, by combining morphine with dextromethorphan, an NMDA- receptor antagonist, tolerance is impaired and analgesia is enhanced without an increase in the dose of opioid.
The subjective effects of opioid drugs are useful in the management of acute pain. This is particularly true in high-anxiety situations, such as the crushing chest pain of myocardial infarction, when the relaxing, anxiolytic effects complement the analgesia. Normal volunteers with no pain given opioids in the laboratory may report the effects as unpleasant because of side effects such as nausea, vomiting, and sedation. Patients with pain usually do not develop abuse or addiction problems. Of course, patients receiving opioids over time develop tolerance routinely, and if the medication is stopped abruptly, they will show the signs of an opioid-withdrawal syndrome, the evidence for physical dependence.
Opioids should never be withheld from patients with cancer out of fear of producing addiction. If chronic opioid medication is indicated, it is preferable to prescribe an orally active, slow-onset opioid with a long duration of action. These qualities reduce the likelihood of producing euphoria at onset and withdrawal symptoms as the medication wears off. In selected patients, methadone is an excellent choice for the management of chronic severe pain. Controlled-release oral morphine (ms contin, others) and controlled-release oxycodone (oxycontin, others) are other possibilities. Rapid-onset, short-duration opioids are excellent for acute short-term use, such as during the postoperative period. As tolerance and physical dependence develop, however, the patient may experience the early symptoms of withdrawal between doses, and during withdrawal, the threshold for pain decreases. Thus, for chronic administration, long-acting opioids are preferred. While methadone is long acting because of its metabolism to active metabolites, the long-acting version of oxycodone has been formulated to release slowly, thereby changing a short-acting opioid into a long-acting one. Unfortunately, this mechanism can be subverted by breaking the tablet and making the full dose of oxycodone immediately available. This has led to diversion of oxycodone to illicit traffic because high-dose oxycodone produces euphoria that is sought by opiate abusers. The diversion of prescription opioids such as oxycodone and hydrocodone to illegal markets has become an important source of opiate abuse in the U.S.
The risk for addiction is highest in patients complaining of pain with no clear physical explanation or in patients with evidence of a chronic, non-life-threatening disorder. Examples are chronic headaches, backaches, abdominal pain, or peripheral neuropathy. Even in these cases, an opioid may be considered as a brief emergency treatment, but long-term treatment with opioids should be used only after other alternatives have been exhausted. In the relatively rare patient who develops abuse, the transition from legitimate use to abuse often begins when the patient returns to his physician earlier than scheduled, asking for a new prescription, or visits emergency rooms of multiple hospitals, complaining of acute pain and asking for an opioid injection.
Heroin is the most frequently abused opiate. There is no legal supply of heroin for clinical use in the U.S. Despite claims that heroin has unique analgesic properties for the treatment of severe pain, double-blind trials have found it to be no more effective than hydromorphone. However, heroin is widely available on the illicit market, and its price dropped sharply in the 1990s, continuing to the present, with purity increased 10-fold.
Previously, street heroin in the U.S. was highly diluted: Each 100-mg bag of powder had only ~4 mg heroin (range: 0-8 mg), and the rest was filler such as quinine. In the mid-1990s, street heroin reached 45-75% purity in many large cities, with some samples testing as high as 90%. This increase in purity has led to increased levels of physical dependence among heroin addicts. Users who interrupt regular dosing develop more severe withdrawal symptoms. Whereas heroin previously required intravenous injection, the more potent supplies can be smoked or administered nasally (snorted), making the initiation of heroin use accessible to people who would not insert a needle into their veins. There is no accurate way to count the number of heroin addicts, but based on extrapolation from overdose deaths, number of applicants for treatment, and number of heroin addicts arrested, the estimates range from 800,000 to 1 million in the U.S.; based on a stratified national sample of adults, ~1 in 4 individuals who report any use of heroin become addicted (Anthony et al., 1994). Recent law enforcement actions may presage the emergence of a domestic supply of heroin precursor (raw opium) harvested from Papaver somniferum grown in the Pacific Northwest of the U.S. (Baer, 2009).
Tolerance, Dependence, and Withdrawal. Injection of a heroin solution produces a variety of sensations described as warmth, taste, or high and intense pleasure ("rush") often compared with sexual orgasm. There are some differences among the opioids in their acute effects, with morphine producing more of a histamine-releasing effect and meperidine producing more excitation or confusion. Even experienced opioid addicts, however, cannot distinguish between heroin and hydromorphone in double-blind tests.
Thus, the popularity of heroin may be due to its availability on the illicit market and its rapid onset. After intravenous injection, the effects begin in less than a minute. Heroin has high lipid solubility, crosses the blood-brain barrier quickly, and is deacetylated to the active metabolites 6-monoacetyl morphine and morphine. After the intense euphoria, which lasts from 45 seconds to several minutes, there is a period of sedation and tranquility ("on the nod") lasting up to an hour. The effects of heroin wear off in 3-5 hours, depending on the dose. Experienced users may inject two to four times per day. Thus, the heroin addict is constantly oscillating between being "high" and feeling the sickness of early withdrawal (Figure 24–4). This produces many problems in the homeostatic systems regulated at least in part by endogenous opioids. For example, the hypothalamic-pituitary-gonadal axis and the hypothalamic-pituitary-adrenal axis are abnormal in heroin addicts. Women on heroin have irregular menses, and men have a variety of sexual performance problems. Mood also is affected. Heroin addicts are relatively docile and compliant after taking heroin, but during withdrawal, they become irritable and aggressive.
Based on patient reports, tolerance develops early to the euphoria-producing effects of opioids. There also is tolerance to the respiratory depressant, analgesic, sedative, and emetic properties. Heroin users tend to increase their daily dose, depending on their financial resources and the availability of the drug. If a supply is available, the dose can be increased progressively 100 times. Even in highly tolerant individuals, the possibility of overdose remains if tolerance is exceeded. Overdose is likely to occur when potency of the street sample is unexpectedly high or when the heroin is mixed with a far more potent opioid, such as fentanyl (sublimaze, others).
Addiction to heroin or other short-acting opioids produces behavioral disruptions and usually becomes incompatible with a productive life. There is a significant risk for opioid abuse and dependence among physicians and other health care workers who have access to potent opioids, tempting them toward unsupervised experimentation. Physicians often begin by assuming that they can manage their own dose, and they may rationalize their behavior based on the beneficial effects of the drug. Over time, however, the typical unsupervised opioid user loses control, and behavioral changes are observed by family and co-workers. Apart from the behavioral changes and the risk of overdose, especially with very potent opioids, chronic use of opioids is relatively nontoxic.
Opioids frequently are used in combinations with other drugs. A common combination is heroin and cocaine ("speedball"). Users report an improved euphoria because of the combination, and there is evidence of an interaction, because cocaine reduces the signs of opiate withdrawal, and heroin may reduce the irritability seen in chronic cocaine users.
The mortality rate for street heroin users is very high. Early death comes from involvement in crime to support the habit; from the uncertain dose, purity, and even identity of what is purchased on the street; and from serious infections associated with nonsterile drugs and sharing of injection paraphernalia. Heroin users commonly acquire bacterial infections producing skin abscesses; endocarditis; pulmonary infections, especially tuberculosis; and viral infections producing hepatitis C and acquired immune deficiency syndrome (AIDS).
As with other addictions, the first stage of treatment addresses physical dependence and consists of detoxification (Kosten and O'Conner, 2003). The opioid-withdrawal syndrome (Table 24–7) is very unpleasant but not life-threatening. It begins within 6-12 hours after the last dose of a short-acting opioid and as long as 72-84 hours after a very long-acting opioid medication. Heroin addicts go through early stages of this syndrome frequently when heroin is scarce or expensive. Some therapeutic communities as a matter of policy elect not to treat withdrawal so that the addict can experience the suffering while being given group support. The duration and intensity of the syndrome are related to the clearance of the individual drug. Heroin withdrawal is brief (5-10 days) and intense. Methadone withdrawal is slower in onset and lasts longer. Protracted withdrawal also is likely to be longer with methadone. (See more detailed discussions of protracted withdrawal under "Long-Term Management" later in the chapter.)
Pharmacological Interventions. Opioid withdrawal signs and symptoms can be treated by three different approaches. The first and most commonly used approach depends on cross-tolerance and consists of transfer to a prescription opioid medication and then gradual dose reduction. The same principles of detoxification apply as for other types of physical dependence. It is convenient to change the patient from a short-acting opioid such as heroin to a long-acting one such as methadone. Detoxification and subsequent maintenance of opiate dependence with methadone is specifically limited to accredited opioid treatment programs (OTPs) and is regulated by Federal Opioid Treatment Standards. The initial dose of methadone is typically 20-30 mg. This is a test dose to determine the level needed to reduce observed withdrawal symptoms. The first day's total dose then can be calculated depending on the response and then reduced by 20% per day during the course of detoxification.
A second approach to detoxification involves the use of oral clonidine (catapres, others), a medication approved only for the treatment of hypertension. Clonidine is an α2 adrenergic agonist that decreases adrenergic neurotransmission from the locus ceruleus. Many of the autonomic symptoms of opioid withdrawal such as nausea, vomiting, cramps, sweating, tachycardia, and hypertension result from the loss of opioid suppression of the locus ceruleus system during the abstinence syndrome. Clonidine, acting upon distinct receptors but by cellular mechanisms that mimic opioid effects, can alleviate many of the symptoms of opioid withdrawal, but not the generalized aches and opioid craving. When using clonidine to treat withdrawal, the dose must be titrated according to the stage and severity of withdrawal, beginning with 0.2 mg orally; postural hypotension is commonly a side effect. A similar drug, lofexidine (currently in clinical trials in the U.S.), has greater selectivity for α2A adrenergic receptors and is associated with less of the hypotension that limits the usefulness of clonidine in this setting.
A third method of treating opioid withdrawal involves activation of the endogenous opioid system without medication. The techniques proposed include acupuncture and several methods of CNS activation using transcutaneous electrical stimulation. While attractive theoretically, this has not yet been found to be practical. Rapid antagonist-precipitated opioid detoxification under general anesthesia has received considerable publicity because it promises detoxification in several hours while the patient is unconscious and not experiencing withdrawal discomfort. A mixture of medications has been used, but morbidity and mortality as reported in the lay press are unacceptable, with no demonstrated advantage in long-term outcome (Collins et al., 2005).
Long-Term Management. If patients are simply discharged from the hospital after withdrawal from opioids, there is a high probability of a quick return to compulsive opioid use. Addiction is a chronic disorder that requires long-term treatment. Numerous factors influence relapse. One factor is that the withdrawal syndrome does not end in 5-7 days. There are subtle signs and symptoms often called the protracted withdrawal syndrome (Table 24–7) that persist for up to 6 months. Physiological measures tend to oscillate as though a new set point were being established; during this phase, outpatient drug-free treatment has a low probability of success, even when the patient has received intensive prior treatment while protected from relapse in a residential program.
The most successful treatment for heroin addiction consists of stabilization on methadone in accordance with state and federal regulations. Patients who relapse repeatedly during drug-free treatment can be transferred directly to methadone without requiring detoxification. The dose of methadone must be sufficient to prevent withdrawal symptoms for at least 24 hours. The introduction of buprenorphine, a partial agonist at μ opioid receptors (Chapter 18), represents a major change in the treatment of opiate addiction. This drug produces minimal withdrawal symptoms when discontinued and has a low potential for overdose, a long duration of action, and the ability to block heroin effects. Treatment can take place in a qualified physician's private office rather than in a special center, as required for methadone. When taken sublingually, buprenorphine (subutex) is active, but it also has the potential to be dissolved and injected (abused). A buprenorphine-naloxone combination (suboxone) is also available. When taken orally (sublingually), the naloxone moiety is not effective, but if the patient abuses the medication by injecting, the naloxone will block or diminish the subjective high that could be produced by buprenorphine alone.
Agonist or Partial-Agonist Maintenance. Patients receiving methadone or buprenorphine will not experience the ups and downs produced by heroin (Figure 24–4). Drug craving diminishes and may disappear. Neuroendocrine rhythms eventually are restored (Kreek et al., 2002). Because of cross-tolerance (from methadone to heroin), patients who inject street heroin report a reduced effect from usual heroin doses. This cross-tolerance effect is dose-related, so higher methadone maintenance doses result in less illicit opioid use, as determined by random urine testing. Buprenorphine, as a partial agonist, has a ceiling effect at ~16 mg of the sublingual tablet equaling no more than 60 mg methadone. If the patient has a higher level of physical dependence, a full agonist (methadone) must be used. Patients become tolerant to the sedating effects of methadone and can attend school or function in a job. Opioids also have a persistent, mild, stimulating effect noticeable after tolerance to the sedating effect, such that reaction time is quicker and vigilance is increased while on a stable dose of methadone.
Antagonist Treatment. Another pharmacological option is opioid antagonist treatment. Naltrexone (revia, others; Chapter 18) is an antagonist with a high affinity for the μ opioid receptor (MOR); it will competitively block the effects of heroin or other MOR agonists. Naltrexone has almost no agonist effects of its own and will not satisfy craving or relieve protracted withdrawal symptoms. For these reasons, naltrexone treatment does not appeal to the average heroin addict, but it can be used after detoxification for patients with high motivation to remain opioid-free. Physicians, nurses, and pharmacists who have frequent access to opioid drugs make excellent candidates for this treatment approach. A depot formulation of naltrexone that provides 30 days of medication after a single injection (vivitrol) has been approved for the treatment of alcoholism. This formulation eliminates the necessity of daily pill-taking and prevent relapse when the recently detoxified patient leaves a protected environment.
Differences in responses to heroin and methadone. A person who injects heroin (↑) several times per day oscillates (red line) between being sick and being high. In contrast, the typical methadone patient (purple line) remains in the "normal" range (indicated in blue) with little fluctuation after dosing once per day. The ordinate values represent the subject's mental and physical state, not plasma levels of the drug.
Table 24-7Characteristics of Opioid Withdrawal ||Download (.pdf) Table 24-7 Characteristics of Opioid Withdrawal
|SYMPTOMS ||SIGNS |
|Regular withdrawal |
|Craving for opioids ||Pupillary dilation |
|Restlessness, irritability ||Sweating |
|Increased sensitivity to ||Piloerection ("gooseflesh") |
|pain ||Tachycardia |
|Nausea, cramps ||Vomiting, diarrhea |
|Muscle aches ||Increased blood pressure |
|Dysphoric mood ||Yawning |
|Insomnia, anxiety ||Fever |
|Protracted withdrawal |
|Anxiety ||Cyclic changes in weight, |
|Insomnia ||pupil size, respiratory |
|Drug craving ||center sensitivity |
Cocaine and Other Psychostimulants
Cocaine. More than 23 million Americans have used cocaine at some time. Although chronic use and use by high school students has declined, the number of frequent users (at least weekly) has remained steady since 1991 at ~600,000. Not all users become addicts, and the variables that influence this risk are discussed at the beginning of this chapter. A key factor is the widespread availability of relatively inexpensive cocaine in the alkaloidal form (free base, "crack") suitable for smoking and in the hydrochloride powder form suitable for nasal or intravenous use. Drug abuse in men occurs about twice as frequently as in women. However, free basing is particularly common in young women of child-bearing age, who may use cocaine in this manner as commonly as do men.
The reinforcing effects of cocaine and cocaine analogs correlate best with their effectiveness in blocking the transporter that recovers DA from the synapse. This leads to increased DA concentrations at critical brain sites (Ritz et al., 1987). However, cocaine also blocks both NE and 5-HT reuptake, and chronic use of cocaine leads to reductions in the neurotransmitter metabolites 3-methoxy-4 hydroxyphenethyleneglycol (MOPEG or MHPG) and 5-hydroxyindoleacetic acid (5-HIAA).
The general pharmacology and medicinal use of cocaine as a local anesthetic are discussed in Chapter 20. Cocaine produces a dose-dependent increase in heart rate and blood pressure accompanied by increased arousal, improved performance on tasks of vigilance and alertness, and a sense of self-confidence and well-being. Higher doses produce euphoria, which has a brief duration and often is followed by a desire for more drug. Repeated doses may lead to involuntary motor activity, stereotyped behavior, and paranoia. Irritability and increased risk of violence are found among heavy chronic users. The t1/2 of cocaine in plasma is ~50 minutes, but inhalant (crack) users typically desire more cocaine after 10-30 minutes. Intranasal and intravenous uses also result in a high of shorter duration than would be predicted by plasma cocaine levels, suggesting that a declining plasma concentration is associated with termination of the high and resumption of cocaine seeking. This theory is supported by positron-emission tomographic imaging studies using 11C-labeled cocaine, which show that the time course of subjective euphoria parallels the accumulation and decline of the drug in the corpus striatum (Volkow et al., 2003).
The major route for cocaine metabolism involves hydrolysis of each of its two ester groups. Benzoylecgonine, produced on loss of the methyl group, represents the major urinary metabolite and can be found in the urine for 2-5 days after a binge. As a result, the benzoylecgonine test is a valid method for detecting cocaine use; the metabolite remains detectable in the urine of heavy users for up to 10 days. Cocaine frequently is used in combination with other drugs, as discussed previously. Ethanol is frequently abused with cocaine, as it reduces the irritability induced by cocaine. Dual addiction to alcohol and cocaine is common. When cocaine and alcohol are taken concurrently, cocaine may be transesterified to cocaethylene, which is equipotent to cocaine in blocking DA reuptake (Hearn et al., 1991).
Addiction is the most common complication of cocaine abuse. Intranasal users can continue intermittent use for years. Others become compulsive users despite elaborate methods to maintain control. In general, stimulants tend to be abused much more irregularly than opioids, nicotine, and alcohol. Binge use is very common, and a binge may last hours to days, terminating only when supplies of the drug are exhausted.
Toxicity. Other risks of cocaine, beyond the potential for addiction, include cardiac arrhythmias, myocardial ischemia, myocarditis, aortic dissection, cerebral vasoconstriction, and seizures. Death from trauma also is associated with cocaine use. Cocaine may induce premature labor and abruptio placentae (Chasnoff et al., 1989). The developmental abnormalities reported in infants born to cocaine users may be the result of cocaine effects as well as multiple other factors (the infant's prematurity, multiple-drug and alcohol exposure, and inadequate pre- and postnatal care).
Cocaine has been reported to produce a prolonged and intense orgasm if taken prior to intercourse, and users often indulge in compulsive and promiscuous sexual activity. However, chronic cocaine use reduces sexual drive. Chronic use is also associated with psychiatric disorders, including anxiety, depression, and psychosis, and while some of these disorders undoubtedly existed prior to addiction, many are likely attributable to the drug (McLellan et al., 1979).
Tolerance, Dependence, and Withdrawal. Sensitization, a consistent finding in animal studies of cocaine and other stimulants, is produced by intermittent use and typically is manifested as behavioral hyperactivity. In human cocaine users, the euphoric effect typically is not subject to sensitization. On the contrary, most experienced users become desensitized and, over time, require more cocaine to obtain euphoria, i.e., tolerance develops. In the laboratory, tolerance is rapidly induced by repeated administration of the same dose in one session (tachyphylaxis). Sensitization may involve conditioning (Figure 24–2). Cocaine users often report a strong response on seeing cocaine before it is administered, consisting of physiological arousal and increased drug craving with concomitant activation of brain limbic structures (Childress et al., 1999). Sensitization in humans has been linked to paranoid, psychotic manifestations of cocaine use (Satel et al., 1991). Since cocaine typically is used intermittently, even heavy users go through frequent periods of withdrawal or "crash." The symptoms of withdrawal seen in users admitted to hospitals are listed in Table 24–8. Careful studies of cocaine users during withdrawal show gradual diminution of these symptoms over 1-3 weeks (Weddington et al., 1990). Residual depression, often seen after cocaine withdrawal, should be treated with antidepressant agents if it persists (Chapter 15).
Pharmacological Interventions. Since cocaine withdrawal is generally mild, treatment of withdrawal symptoms usually is not required. The major problem in treatment is not detoxification but helping the patient to resist the urge to resume compulsive cocaine use. Rehabilitation programs involving individual and group psychotherapy based on the principles of Alcoholics Anonymous, and behavioral treatments based on reinforcing cocaine-free urine tests, result in significant improvement in the majority of cocaine users (Alterman et al., 1994; Higgins et al., 1994). Nonetheless, there is great interest in finding a medication that can aid in the rehabilitation of cocaine addicts.
Numerous medications have been tried in placebo-controlled clinical trials with cocaine addicts, but no medication has yet consistently improved upon the results of behavior therapy alone. Animal models suggest that enhancing GABAergic inhibition can reduce reinstatement of cocaine self-administration, and a controlled clinical trial of topiramate (topamax) showed a significant reduction in cocaine use. Topiramate also reduced the relapse rate in alcoholics, prompting current studies in patients dually dependent on cocaine and alcohol. Baclofen (lioresal, others), a GABAB agonist, was found in a single-site trial to reduce relapse in cocaine addicts, but was not effective in a multisite trial. A different approach was taken using modafinil (provigil), a medication that increases alertness and is approved for the treatment of narcolepsy. This medication was found to reduce the euphoria produced by cocaine and to relieve cocaine withdrawal symptoms. Modafinil is currently being tested in clinical trials of cocaine, methamphetamine, alcohol, and other substance abuse disorders. A novel approach to cocaine addiction employs a vaccine that produces cocaine-binding antibodies. Preliminary studies showed some success in reducing cocaine use. Larger trials are in progress. For now, behavioral therapy remains the treatment of choice, with medication indicated for specific co-existing disorders such as depression.
Table 24-8Cocaine Withdrawal Symptoms and Signs
Amphetamine and Related Agents. Subjective effects similar to those of cocaine are produced by amphetamine, dextroamphetamine, methamphetamine, phenmetrazine, methylphenidate, and diethylpropion. Amphetamines increase synaptic DA, NE, and 5-HT primarily by stimulating pre-synaptic release rather than by blockade of reuptake, as is the case with cocaine. Intravenous or smoked methamphetamine produces an abuse/dependence syndrome similar to that of cocaine, although clinical deterioration may progress more rapidly. In animal studies, methamphetamine in doses comparable with those used by human abusers produces neurotoxic effects, as reflected by histologic changes in dopaminergic and serotonergic neurons.
Methamphetamine can be synthesized from ephedrine in small, clandestine laboratories. Methamphetamine addiction has become a major public health problem, particularly in the western half of the U.S. Behavioral and medical treatments for methamphetamine addiction are similar to those used for cocaine. Until recently, ephedrine was a widely available nonprescription stimulant (a "wake-up" pill). Oral stimulants, such as those prescribed in a weight-reduction program, have short-term efficacy because of tolerance development. Only a small proportion of patients introduced to these appetite suppressants subsequently exhibits dose escalation or drug-seeking from various physicians; such patients may meet diagnostic criteria for abuse or addiction.
Caffeine. Caffeine, a mild stimulant, is the most widely used psychoactive drug in the world. It is present in soft drinks, coffee, tea, cocoa, chocolate, and numerous prescription and over-the-counter drugs. It mildly increases NE and DA release and enhances neural activity in numerous brain areas. Caffeine is absorbed from the digestive tract and is distributed rapidly throughout all tissues and easily crosses the placental barrier. Many of caffeine's effects are believed to occur by means of competitive antagonism at adenosine receptors; as a methylxanthine, caffeine also inhibits cyclic nucleotide phosphodiesterases. Adenosine is a neuromodulator that influences a number of functions in the CNS, as is cyclic AMP (Chapter 14). The mild sedating effects that occur when adenosine activates particular adenosine-receptor subtypes can be antagonized by caffeine.
Tolerance occurs rapidly to the stimulating effects of caffeine. Thus, a mild withdrawal syndrome has been produced in controlled studies by abruptly discontinuing the intake of as little as one to two cups of coffee per day. Caffeine withdrawal consists of feelings of fatigue and sedation. With higher doses, headaches and nausea have been reported during withdrawal; vomiting is rare (Silverman et al., 1992). Although a withdrawal syndrome can be demonstrated, few caffeine users report loss of control of caffeine intake or significant difficulty in reducing or stopping caffeine, if desired (Dews et al., 1999). Thus, caffeine is not listed in the category of addicting stimulants (American Psychiatric Association, 2000).
The cannabis plant has been cultivated for centuries both for the production of hemp fiber and for its presumed medicinal and psychoactive properties. The smoke from burning cannabis contains many chemicals, including 61 different cannabinoids that have been identified. One of these, Δ-9-tetrahydrocannabinol (Δ-9-THC), produces most of the characteristic pharmacological effects of smoked marijuana.
Marijuana is the most commonly used illegal drug in the U.S. Surveys over the period 2006-2009 report that ~32% of highschool seniors have tied marijuana, down from a high of 51% in 1974, but up from 22% in 1992 (Johnston et al., 2010).
Cannabinoid receptors CB1 (mainly CNS) and CB2 (peripheral) have been identified and cloned. An arachidonic acid derivative, anandamide, has been proposed as an endogenous ligand for CB receptors. While the physiological function of these receptors and their endogenous ligands are incompletely understood, they are likely to have important functions because they are dispersed widely with high densities in the cerebral cortex, hippocampus, striatum, and cerebellum (Iversen, 2003). Specific CB1 antagonists have been developed and tested in controlled clinical trials. One of these, rimonabant, was found to reduce relapse in cigarette smokers and to produce weight loss in obese patients; however, its development has been abandoned because of depressive and neurologic side effects.
The pharmacological effects of Δ-9-THC vary with the dose, route of administration, experience of the user, vulnerability to psychoactive effects, and setting of use. Intoxication with marijuana produces changes in mood, perception, and motivation, but the effect most frequently sought is the "high" and "mellowing out." This effect is described as different from the high produced by a stimulant or opiate. Effects vary with dose, but typically last ~2 hours. During the high, cognitive functions, perception, reaction time, learning, and memory are impaired. Coordination and tracking behavior may be impaired for several hours beyond the perception of the high, with obvious implications for the operation of a motor vehicle and performance in the workplace or at school.
Marijuana also produces complex behavioral changes such as giddiness and increased hunger. There are unsubstantiated claims of increased pleasure from sex and increased insight during a marijuana high. Unpleasant reactions such as panic or hallucinations and even acute psychosis may occur; several surveys indicate that 50-60% of marijuana users have reported at least one anxiety experience. These reactions are seen commonly with higher doses and with oral ingestion rather than smoked marijuana, because smoking permits the titration of dose according to the effects. While there is no convincing evidence that marijuana can produce a lasting schizophrenia-like syndrome, association studies suggest a correlation of early marijuana use with an increased risk of later developing schizophrenia. Numerous clinical reports suggest that marijuana use may precipitate a recurrence of psychosis in people with a history of schizophrenia.
One of the most controversial of the reputed effects of marijuana is the production of an "amotivational syndrome." This syndrome is not an official diagnosis, but it has been used to describe young people who drop out of social activities and show little interest in school, work, or other goal-directed activity. When heavy marijuana use accompanies these symptoms, the drug often is cited as the cause, even though there are no data that demonstrate a causal relationship between marijuana smoking and these behavioral characteristics. There is no evidence that marijuana damages brain cells or produces any permanent functional changes, although there are animal data indicating impairment of maze learning that persists for weeks after the last dose. These findings are consistent with clinical reports of gradual improvement in mental state after cessation of chronic high-dose marijuana use.
Marijuana has medicinal effects, including anti-emetic properties that relieve side effects of anticancer chemotherapy. It also has muscle-relaxing effects, anticonvulsant properties, and the capacity to reduce the elevated intraocular pressure of glaucoma. These medical benefits come at the cost of the psychoactive effects that often impair normal activities. Thus, there is no clear advantage of marijuana over conventional treatments for any of these indications (Joy et al., 1999). An oral capsule containing Δ-9-THC (dronabinol; MARINOL, others) is approved for anorexia associated with weight loss in patients with HIV infection and for cancer chemotherapy-induced nausea and vomiting. With the cloning of cannabinoid receptors, the discovery of endogenous ligands, and the synthesis of specific agonists and antagonists, it is likely that new orally effective medications will be developed without the undesirable properties of smoked marijuana and without the deleterious effects of inhaling smoke particles and the chemical products of high-temperature combustion.
Tolerance, Dependence, and Withdrawal. Tolerance to most of the effects of marijuana can develop rapidly after only a few doses, but also disappears rapidly (Martin et al., 2004). Tolerance to large doses persists in experimental animals for long periods after cessation of drug use. Withdrawal symptoms and signs typically are not seen in clinical populations. In fact, few patients ever seek treatment for marijuana addiction. Human subjects develop a withdrawal syndrome when they receive regular oral doses of the agent (Table 24–9). This syndrome, however, is only seen clinically in persons who use marijuana on a daily basis and then suddenly stop.
Pharmacological Interventions. Marijuana abuse and addiction have no specific treatments. Heavy users may suffer from accompanying depression and thus may respond to antidepressant medication, but this should be decided on an individual basis considering the severity of the affective symptoms after the marijuana effects have dissipated. The residual drug effects may continue for several weeks. The CB1 receptor antagonist rimonabant has been reported to block the acute effects of smoked marijuana, but development of this drug has been halted due to safety concerns (discussed under "Pharmacological Interventions" in the nicotine section earlier in the chapter).
Table 24-9Marijuana Withdrawal Syndrome ||Download (.pdf) Table 24-9 Marijuana Withdrawal Syndrome
|Mild agitation |
|Sleep EEG disturbance |
|Nausea, cramping |
Perceptual distortions that include hallucinations, illusions, and disorders of thinking such as paranoia can be produced by toxic doses of many drugs. These phenomena also may follow withdrawal from toxic sedatives such as alcohol. There are, however, certain drugs that have as their primary effect the production of disturbances of perception, thought, or mood at low doses with minimal effects on memory and orientation. These are commonly called hallucinogenic drugs, but their use does not always result in frank hallucinations. In the late 1990s, the use of "club drugs" at all-night dance parties became popular. Such drugs include methylenedioxymethamphetamine (MDMA, "ecstasy"), lysergic acid diethylamide (LSD), phencyclidine (PCP), and ketamine (ketalar). They often are used in association with illegal sedatives such as flunitrazepam (rohypnol) or γ-hydroxybutyrate (GHB). The latter drug has the reputation of being particularly effective in preventing memory storage, and has been implicated in "date rapes."
While psychedelic effects can be produced by a variety of different drugs, there are two main categories of psychedelic compounds, indoleamines and phenethylamines. The indoleamine hallucinogens include LSD, N,N-dimethyltryptamine (DMT), and psilocybin. The phenethylamines include mescaline, dimethoxymethylamphetamine (DOM), methylenedioxyamphetamine (MDA), and MDMA. Both groups have a relatively high affinity for 5-HT2 receptors (Chapter 13), but they differ in their affinity for other subtypes of 5-HT receptors. There is a good correlation between the relative affinity of these compounds for 5-HT2 receptors and their potency as hallucinogens in humans (Titeler et al., 1988). The 5-HT2 receptor is further implicated in the mechanism of hallucinations by the observation that antagonists of that receptor, such as ritanserin, are effective in blocking the behavioral and electrophysiological effects of hallucinogenic drugs in animal models. However, LSD interacts with many receptor subtypes at nanomolar concentrations, and it is not possible to attribute the psychedelic effects to any single 5-HT receptor subtype (Peroutka, 1994).
LSD. LSD is the most potent hallucinogenic drug and produces significant psychedelic effects with a total dose of as little as 25-50 μg. This drug is > 3000 times more potent than mescaline. LSD is sold on the illicit market in a variety of forms. A popular contemporary system involves postage stamp-sized papers impregnated with varying doses of LSD (50-300 μg or more). While most street samples sold as LSD actually contain LSD, samples of mushrooms and other botanicals sold as sources of psilocybin and other psychedelics have a low probability of containing the advertised hallucinogen.
The effects of hallucinogenic drugs are variable, even in the same individual on different occasions. LSD is absorbed rapidly after oral administration, with effects beginning at 40-60 minutes, peaking at 2-4 hours, and gradually returning to baseline over 6-8 hours. At a dose of 100 μg, LSD produces perceptual distortions and sometimes hallucinations; mood changes, including elation, paranoia, or depression; intense arousal; and sometimes a feeling of panic. Signs of LSD ingestion include pupillary dilation, increased blood pressure and pulse, flushing, salivation, lacrimation, and hyperreflexia. Visual effects are prominent. Colors seem more intense, and shapes may appear altered. The subject may focus attention on unusual items such as the pattern of hairs on the back of the hand.
A "bad trip" usually consists of severe anxiety, although at times it is marked by intense depression and suicidal thoughts. Visual disturbances usually are prominent. The bad trip from LSD may be difficult to distinguish from reactions to anticholinergic drugs and phencyclidine. There are no documented toxic fatalities from LSD use, but fatal accidents and suicides have occurred during or shortly after intoxication. Prolonged psychotic reactions lasting 2 days or more may occur after the ingestion of a hallucinogen. Schizophrenic episodes may be precipitated in susceptible individuals, and there is some evidence that chronic use of these drugs is associated with the development of persistent psychotic disorders (McLellan et al., 1979).
Claims about the potential of psychedelic drugs for enhancing psychotherapy and for treating addictions and other mental disorders have not been supported by controlled treatment outcome studies. Consequently, there is no current indication for these drugs as medications.
Tolerance, Physical Dependence, and Withdrawal. Frequent, repeated use of psychedelic drugs is unusual, and thus tolerance is not commonly seen. Tolerance does develop to the behavioral effects of LSD after three or four daily doses, but no withdrawal syndrome has been observed. Cross-tolerance among LSD, mescaline, and psilocybin has been demonstrated in animal models.
Pharmacological Intervention. Because of the unpredictability of psychedelic drug effects, any use carries some risk. Dependence and addiction do not occur, but users may require medical attention because of "bad trips." Severe agitation may respond to diazepam (20 mg orally). "Talking down" by reassurance also is effective and is the management of first choice. Antipsychotic medications (Chapter 16) may intensify the experience and thus are not indicated.
A particularly troubling after-effect of the use of LSD and similar drugs is the occasional occurrence of episodic visual disturbances. These originally were called "flashbacks" and resembled the experiences of prior LSD trips. Flashbacks belong to an official diagnostic category called the hallucinogen persisting perception disorder (HPPD; American Psychiatric Association, 1994). The symptoms include false fleeting perceptions in the peripheral fields, flashes of color, geometric pseudohallucinations, and positive afterimages (Abraham and Aldridge, 1993). The visual disorder appears stable in half the cases and represents an apparently permanent alteration of the visual system. Precipitants include stress, fatigue, emergence into a dark environment, marijuana, antipsychotic agents, and anxiety states.
MDMA ("Ecstasy") and MDA. MDMA and MDA are phenylethylamines that have stimulant as well as psychedelic effects. MDMA became popular during the 1980s on college campuses because of testimonials that it enhances insight and self-knowledge. It was recommended by some psychotherapists as an aid to the process of therapy, although no controlled data exist to support this contention. Acute effects are dose-dependent and include feelings of energy, altered sense of time, and pleasant sensory experiences with enhanced perception. Negative effects include tachycardia, dry mouth, jaw clenching, and muscle aches. At higher doses, visual hallucinations, agitation, hyperthermia, and panic attacks have been reported. A typical oral dose is one or two 100-mg tablets and lasts 3-6 hours, although dosage and potency of street samples are variable (~100 mg per tablet).
MDA and MDMA produce degeneration of serotonergic nerve cells and axons in rats. While nerve degeneration has not been demonstrated in humans, the cerebrospinal fluid of chronic MDMA users has low levels of serotonin metabolites (Ricaurte et al., 2000). Thus, there is possible neurotoxicity with no evidence that the claimed benefits of MDMA actually occur.
Phencyclidine (PCP). PCP deserves special mention because of its widespread availability and because its pharmacological effects are different from those of the psychedelics such as LSD. PCP was developed originally as an anesthetic in the 1950s and later was abandoned because of a high frequency of postoperative delirium with hallucinations. It was classified as a dissociative anesthetic because, in the anesthetized state, the patient remains conscious with staring gaze, flat facies, and rigid muscles. PCP became a drug of abuse in the 1970s, first in an oral form and then in a smoked version enabling a better regulation of the dose. The effects of PCP have been observed in normal volunteers under controlled conditions. As little as 50 μg/kg produces emotional withdrawal, concrete thinking, and bizarre responses to projective testing. Catatonic posturing also is produced and resembles that of schizophrenia. Abusers taking higher doses may appear to be reacting to hallucinations and may exhibit hostile or assaultive behavior. Anesthetic effects increase with dosage; stupor or coma may occur with muscular rigidity, rhabdomyolysis, and hyperthermia. Intoxicated patients in the emergency room may progress from aggressive behavior to coma, with elevated blood pressure and enlarged nonreactive pupils.
PCP binds with high affinity to sites located in the cortex and limbic structures, resulting in blocking of N-methyl-D-aspartate (NMDA)–type glutamate receptors (Chapter 14). LSD and other psychedelics do not bind to NMDA receptors. There is evidence that NMDA receptors are involved in ischemic neuronal death caused by high levels of excitatory amino acids; as a result, there is interest in PCP analogs that block NMDA receptors but with fewer psychoactive effects. Both PCP and ketamine ("Special K"), another "club drug," produce similar effects by altering the distribution of the neurotransmitter glutamate.
Tolerance, Dependence, and Withdrawal. PCP is reinforcing in monkeys, as evidenced by self-administration patterns that produce continuous intoxication. Humans tend to use PCP intermittently, but a small fraction may use it daily. Tolerance to the behavioral effects of PCP develops in animals, but this has not been studied systematically in humans. Signs of a PCP withdrawal syndrome have been observed in monkeys after interruption of daily access to the drug, and include somnolence, tremor, seizures, diarrhea, piloerection, bruxism, and vocalizations.
Pharmacological Intervention. Overdose must be treated by life support because there is no antagonist of PCP effects and no proven way to enhance excretion, although acidification of the urine has been proposed. PCP coma may last 7-10 days. The agitated or psychotic state produced by PCP can be treated with diazepam. Prolonged psychotic behavior requires antipsychotic medication. Because of the anticholinergic activity of PCP, antipsychotic agents with significant anticholinergic effects such as chlorpromazine should be avoided.
Abused inhalants consist of many different categories of chemicals that are volatile at room temperature and produce abrupt changes in mental state when inhaled. Examples include toluene (from model airplane glue), kerosene, gasoline, carbon tetrachloride, amyl nitrite, and nitrous oxide. There are characteristic patterns of response for each substance. Solvents such as toluene typically are used by children. The material usually is placed in a plastic bag and the vapors inhaled. After several minutes of inhalation, dizziness and intoxication occur. Aerosol sprays containing fluorocarbon propellants are another source of solvent intoxication. Prolonged exposure or daily use may result in damage to several organ systems. Clinical problems include cardiac arrhythmias, bone marrow depression, cerebral degeneration, and damage to liver, kidney, and peripheral nerves. Death occasionally has been attributed to inhalant abuse, probably from cardiac arrhythmias, especially accompanying exercise or upper airway obstruction.
Amyl nitrite produces dilation of smooth muscle, has been used in the past for the treatment of angina, and continues to be available by prescription as a component of cyanide antidote kits and for certain diagnostic procedures. It is a yellow, volatile, flammable liquid with a fruity odor. In recent years, amyl nitrite and butyl nitrite have been used to relax smooth muscle and enhance orgasm, particularly by male homosexuals. These agents are commercially available as room deodorizers and can produce a feeling of "rush," flushing, and dizziness. Adverse effects include palpitations, postural hypotension, and headache progressing to loss of consciousness.
Anesthetic gases such as nitrous oxide and halothane sometimes are used as intoxicants by medical personnel. Nitrous oxide also is abused by food-service employees because it is supplied for use as a propellant in disposable aluminum mini tanks for whipping cream canisters. Nitrous oxide produces euphoria and analgesia and then loss of consciousness. Compulsive use and chronic toxicity are reported rarely, but there are obvious risks of overdose (coma) and chronic use (neuropathy) associated with the abuse of this anesthetic.