By the end of class, you will be able to:
Compare and contrast the mechanisms underlying the development of drug tolerance, dependence, withdrawal symptoms, and addiction.
Relate the mechanisms of action of abused substances to their withdrawal symptoms and signs of intoxication.
Summarize the molecular mechanisms of common substance-use disorders, including alcohol, opioid, sedative, cannabis and stimulant-used disorders.
Evaluate reasons why some substances have more chronic abuse potential than others.
Categorize pharmacological treatments used for drug addiction into drugs used for intoxication, alleviate withdrawal symptoms, mimic the abused drugs to a lesser extent, and reverse the addiction process itself.
Evaluate the most likely cause of substance abuse symptoms, including determining overdose, intoxication or withdrawal, based on drug mechanism of action and signs and symptoms, patient history and drug paraphernalia.
Compare and contrast treatment strategies for treatment of drug intoxication and overcoming addiction for commonly used substances of abuse.
Addiction involves a pattern of substance use leading to significant impairment or distress. Addiction is often confused with tolerance and dependence, but they are different. The key characteristic is drug-seeking behavior.
Tolerance occurs when the effectiveness of a substance decreases with continuous use. Patients need larger amounts to produce the same effect. The dose response curve shifts to the right, demonstrating reduced potency. Although the dose response curve changes, the drug toxicity curve does not. Thus, increasing the dose to achieve therapeutic effects can also increase side effects. Cross-tolerance can also occur between drugs that act on the same receptor. For example, patients tolerant to fentanyl will also be tolerant to morphine.
The mechanisms of tolerance vary and depend on both the substance and the individual. Individuals may have innate drug tolerance due to their environment or their genetics. Repeated drug administration can also lead to tolerance. Acquired tolerance can involve pharmacokinetics, which can increase metabolism or excretion. This is often due to the induction of metabolic enzymes such as cytochrome P450. Pharmacodynamic tolerance may involve:
increased synaptic removal.
decreased neurotransmitter release.
decreased receptor sensitivity.
decreased receptor number.
modified signal conduction.
Long term exposure may alter gene expression. This can increase or decrease the number of receptors or metabolic enzyme production. These neuroadaptive changes are like the processes involved in learning and memory. This might explain why cravings may occur long after the discontinuation of a drug.
Dependence involves withdrawal symptoms when use of the drug stops. Withdrawal symptoms may cause drug cravings, but dependence is not the same as addiction. While addiction is a psychological response, dependence is physical. Withdrawal symptoms differ from drug to drug and depend on the drug mechanism. Withdrawal symptoms involve the opposite effect of the drug itself. For example, withdrawal from sedatives involves increased CNS activity, anxiety and even seizures. Withdrawal from catecholamines results in fatigue, dysphoria, and depression.
Chronic self-administration of drugs causes permanent long-term changes in the nervous system. This is due to the adaptation of the reward pathways in the brain. The emotional baseline state (i.e., in the absence of the drug) of an addict becomes diminished. The addict cannot experience emotions the way that they did before drug exposure. Their desire to recapture their previous normal state often fuels drug seeking.
Drug-seeking behavior begins for various reasons. Positive reinforcement (such as euphoria) drives drug use for some people. For others negative reinforcement (e.g., drinking to relieve anxiety) may encourage drug-seeking. Motivation for substance use changes as the substance use disorder progresses. Positive reinforcement is rare after years of use. People keep using the drug to prevent withdrawal symptoms or return to how they felt before using the drug. Development of substance use disorders depends on drug nature, environmental and individual factors.
Pharmacokinetic factors of drugs are especially important in determining reward activity. Drugs with rapid increases in concentration are more likely to activate reward pathways. For example, many substances of abuse readily cross the blood-brain barrier. Injection of drugs also increases the chance of reward. Drugs absorbed over a large surface area (such as the lungs) are more likely to activate reward. Drugs that have a shorter duration of action tend to be more addictive. This is because their rapid removal is more likely to trigger withdrawal symptoms.
There are several factors that may predispose a person to substance use disorder. Some of these risk factors include:
Resistance or sensitivity to the specific drug of abuse.
Genetic differences in drug metabolism.
The genetic potential for neuroadaptive changes.
Personality traits and coexisting psychiatric disorders.
Acquired physical disability and painful illness.
The euphoric effects of opioids are most likely due to the activity of the μ receptor. Opioids inhibit GABAergic neurons that keep dopamine neurons of the reward pathways “switched off”. By inhibiting GABA neurons, dopaminergic neurons activate, producing the reward effects. There are many neural circuits involved in reward. Addiction to combinations of drugs with different mechanisms is possible (e.g., cocaine/heroin – “speedball”). This also increases the risk of life-threatening complications.
Some opioids have a higher potential to cause drug-seeking behavior than others. Opioids with the fastest rise in brain concentration, have the highest abuse potential. This is why intravenous opioids are frequently abused. Hydrophobic drugs diffuse across the blood brain barrier. This also increases the potential for abuse. Abuse of heroin is more likely than abuse of morphine because of these factors.
Treatment
Naloxone is a fast-acting opioid antagonist that can treat severe overdose. Naltrexone is another opioid antagonist. It has a slower-onset and is longer acting than naloxone. Naltrexone can help with treatment of opioid use disorder. Although naltrexone prevents opioids-associated reward, it does not prevent withdrawal symptoms. Another drug can be given with naloxone to treat withdrawal symptoms. Buprenorphine is an opioid partial agonist. It has two benefits. First, it reduces cravings. Second, buprenorphine reduces the reward-effects of the substance of abuse. This makes the abused opioid less appealing to the addict.
Methadone is a very long-acting opioid. It does not produce a sharp increase in plasma levels compared to heroin and morphine. It can help reduce cravings and withdrawal symptoms. Unfortunately, methadone itself has a high abuse potential. The euphoric effects often need high doses to achieve. This has resulted in cases of overdose from patients attempting to reach euphoria. Methadone is only used in controlled circumstances.
Initial onset of action of benzodiazepines and barbiturates can cause euphoria and anxiolytic effects. This may underlie their abuse potential. Chronic use of GABA potentiators can down-regulate GABA pathways through neuroadaptation. Withdrawal causes under-inhibition of the brain. This increases the risk of delirium and seizures. Central sympathetic pathways become hyperactive. This causes physical symptoms associated with fear, anxiety, and panic. An antagonist of the benzodiazepine site called flumazenil, is useful for overdose. However, it is very short acting. Barbiturates are less selective than benzodiazepines, which results in more severe withdrawal symptoms.
Alcohol-use disorder is the most prevalent drug problem. Alcohol is accessible and inexpensive. There are two types of alcohol use disorder. Type I alcohol use disorder usually occurs later in life (after age 25). It involves fewer incidents of spontaneous drinking and antisocial behavior than type II. Guilt over drinking behaviors and a desire for approval from others are common. Type II alcohol use disorder usually occurs before age 25. It involves spontaneous drinking and antisocial behavior. There is little concern about the consequences of the disorder. Loss of control is common.
Ethanol has polymodal mechanisms of action including potentiation of GABA-A receptors. Mechanisms also include inhibition of NMDA receptors and activation of cannabinoid receptors. Dependence mechanisms are like other GABA receptor potentiators. Alcohol inhibits NMDA receptors involved in long-term potentiation. This may cause neuroadaptive changes with long-term use. Finally, activation of cannabinoid receptors enhances dopaminergic activity in the mesolimbic reward pathway.
Disulfiram is an inhibitor of aldehyde dehydrogenase. It interferes with the metabolism of alcohol. The result is accumulation of a toxic metabolite. This results in headaches, nausea, and hypotension. These symptoms can last for several hours, followed by fatigue. These effects act as a deterrent to further drinking. Unfortunately, compliance in taking disulfiram is often low.
Nicotine has strong direct effects on the dopaminergic neurons of reward pathways. Activation of presynaptic nicotinic acetylcholine receptors facilitates the release of dopamine. Decreased plasma levels of nicotine can produce strong withdrawal symptoms. Withdrawal symptoms of nicotine include anxiety, irritability, increased autonomic activity and strong cravings. Nicotine addiction treatment includes replacement therapy. Additionally, a nicotinic acetylcholine receptor partial agonist called varenicline is useful.
Cocaine produces greater euphoric effects than amphetamine. The euphoric effects of amphetamine last longer than those produced by cocaine. Cocaine and amphetamines block or reverse the direction of monoamine neurotransmitter transporters. The result is an increase in synaptic concentrations of dopamine, norepinephrine, and/or serotonin. Norepinephrine neurons in the brain maintain alertness and responsiveness to unexpected stimuli. Cocaine and amphetamines enhance arousal by increasing norepinephrine levels. Withdrawal symptoms include bradycardia, sleepiness, and fatigue. Psychological symptoms, such as dysphoria and inability to experience pleasure also occur. Administration of more cocaine or amphetamine does not ease these symptoms. Psychological symptoms may even occur when plasma concentrations are high. This most likely occurs because of adaptive depletion of the neurotransmitter(s).
Methylenedioxymethamphetamine (MDMA, “Ecstasy”), has a similar molecular structure to methamphetamine. It also produces similar stimulant effects on dopaminergic and serotonergic neurons. MDMA also has hallucinogenic properties and may be toxic to serotonergic neurons. MDMA also has anticholinergic effects which can cause hyperthermia in overdose. Dantrolene is a drug that can reverse MDMA induced hyperthermia.
The primary psychoactive ingredient in marijuana is D9-tetrahydrocannabinol (THC). It is a partial agonist of cannabinoid-1 (CB1) G-protein coupled receptors. CB1 receptors are widely distributed throughout the brain. Activation of CB1 receptors activates the dopaminergic neurons of the mesolimbic reward pathway. Cannabinoid use causes rapid euphoria associated with laughter, giddiness, and depersonalization. After 1–2 hours, cognitive functions decrease, and the user has difficulty concentrating. This “mellowing” phase results in relaxation and even sleep. High doses of marijuana can cause anxiety, panic, and perceptual distortions. It can even cause psychosis in susceptible individuals. Cannabinoids induce blood vessel dilation and increase blood flow to the eyes. The appearance of red eyes is one of the key features of cannabis intoxication. Synthetic “street” cannabinoids (for example, “Spice”) can cause severe psychological symptoms. Use of synthetic cannabinoids has resulted in misdiagnosis of psychotic disorders. Tolerance occurs due to down-regulation of CB1 receptors and reduced signal transduction. Marijuana has a high volume of distribution and long elimination half-life. This is why withdrawal is generally mild. Withdrawal symptoms include insomnia, loss of appetite, irritability, and anxiety.
Hallucinogens
Hallucinogens such as LSD seem to have a lower potential for chronic abuse. There does not seem to be any significant withdrawal symptoms or physical dependence. Despite this, some individuals are still susceptible to psychological addiction. Hallucinogens do not have a direct effect on dopamine pathways. This may be why they have a lower abuse potential than many other substances of abuse. Rapid, but temporary tolerance to hallucinogens may also prevent addiction. Daily administration of LSD leads to complete loss of sensitivity to the effects of the drug by day 4.
Methylxanthines include caffeine, theophylline, and theobromine. They are present in coffee, tea, cola, “energy” drinks and chocolate. Methylxanthines are also present in many prescribed and over-the-counter medications. Methylxanthines block presynaptic adenosine receptors on many neurons, including dopaminergic and adrenergic neurons. This prevents the inhibition of dopamine and norepinephrine release. The result is an increase in synaptic dopamine and norepinephrine concentrations. Through this mechanism, methylxanthines act as stimulants. Withdrawal symptoms from caffeine include lethargy, irritability, and a characteristic headache. While dependence on caffeine is common, addiction is rare.
Inhalants are volatile organic compounds. These include gasoline, toluene, ethyl ether, fluorocarbons, and volatile nitrates. Inhalation (sometimes called huffing) of volatile organic compounds causes psychoactive effects. At low doses, inhalants produce mood changes and ataxia. At high doses, they may produce dissociative states and hallucinations. The mechanisms of action of inhalants vary. Inhalants can cause hepatotoxicity, neurotoxicity, and suffocation, making them extremely dangerous.
The first step in the treatment of substance-use disorder is detoxification. This allows the body to adapt to the absence of the abused drug. During this time, patients slowly taper off the substance. Administration of a longer acting drug with cross-tolerance can reduce withdrawal symptoms. Other drugs, such as clonidine, can treat some of the peripheral withdrawal symptoms.
Another approach is to treat the dysfunctional reward mechanisms. For example, bupropion inhibits the reuptake of CNS catecholamines including dopamine. This decreases the withdrawal symptoms associated with several substance use disorders. Bupropion may be effective for non-substance related addiction disorders such as gambling disorders.