Drug Tolerance, Dependence, and Addiction

Focus shifts from drug classes to addiction-related processes: drug tolerance, withdrawal, physical dependence, and addiction criteria.
Global prevalence of addiction to six commonly used psychoactive drugs is examined.
Tobacco and alcohol have the highest global prevalence of addiction, significantly exceeding other drug classes.
Tobacco's prevalence is nearly 10 times that of alcohol but is not to scale on the Y axis.
Tobacco and alcohol have the greatest negative impacts and death rates worldwide, surpassing all other drugs combined.

Drug-addicted individuals are typically habitual drug users, but not all habitual users are addicted.
Individuals reliant on pain medications may use them habitually without being addicted, due to a genuine need and ability to stop.
Criteria beyond high frequency and intensity of drug use are necessary to determine addiction.

DSM-IV divided criteria into abuse and dependence; DSM-5 aggregates them into one.
DSM-IV abuse criteria focused on problems in the individual's life, such as:
- Hazardous use (e.g., drink driving).
- Social and interpersonal problems (e.g., relationship satisfaction, occupational stressors, financial burden).
- Neglect of major roles (e.g., family, domestic, work, study functioning).
- Legal problems.
DSM-IV dependence criteria address the mechanisms behind addiction, including:
- Withdrawal symptoms.
- Tolerance (needing more of the drug for the same effect or using larger amounts/longer periods).
- Repeated attempts to quit or impaired control over use.
- Time spent using.
- Physical and psychological problems related to use.
- Activities given up to use.
DSM-5 aggregates above criteria and includes craving.
Craving is clinically experienced as a maladaptive wanting, a sense of need and compulsion beyond just desire.
Craving reflects the neurobiological understanding of dependence models, especially pursuing pleasure while still feeling a need.

Drug tolerance is a key feature in the development of addiction.
It involves decreased sensitivity to a drug's effects with increasing and prolonged exposure.
A greater amount of the drug is needed to achieve the same effect over time, depicted via dose response curves.
Tolerance can apply to some but not all effects of a drug.
- For example, tolerance to the inebriation effect of alcohol doesn't reduce the burden on the liver.
Multiple mechanisms and features of tolerance exist.

The drug is broken down and eliminated faster before reaching the site of action.
Results in a lower spike in blood concentration (e.g., alcohol is metabolized more quickly).

Reduced reactivity at the site of action, such as neural receptors in the brain reward circuit.
Neuroadaptation occurs at the synapse level (between pre- and postsynaptic neurons).
Chronic drinkers may not appear as intoxicated due to downregulated neural receptors, even with high blood alcohol levels.

Over time, the effect of an initial dose is blunted due to the development of an opponent process (internal opposition).
The body compensates for the drug's effects to maintain a steady state.
Tolerance and withdrawal go hand in hand because the body seeks to restore balance disrupted by chronic drug use, per the equal and opposite reaction principle.
Withdrawal symptoms are essentially equal and opposite to the drug effects.

Example: MDMA releases a cascade of monoamines (dopamine, norepinephrine, serotonin), overstimulating receptors.
Receptor density and availability decrease via retraction.
Changes occur in the amount of neurotransmitters released.
Functional tolerance leads to an habituation effect, reducing the drug effect over time.

Functional tolerance is the basis of a compensatory reaction, involving conditioning and anticipatory learning.
Example: Coffee drinkers' bodies anticipate caffeine intake via cues (smell, sight, taste), slowing down the heart rate as an equal and opposite reaction.
Following MDMA use, receptors can downregulate, disrupting monoamine production, leading to depressive effects and redosing tendencies.
Withdrawal, tolerance, and craving drive the transition from recreational to habitual to addictive drug use.

Functional tolerance can also be referred to as pharmacodynamic tolerance because it involves the effect of the drug on the body, specifically at the neurotransmitter or receptor level.
Similar observations occur with cocaine, where the first line provides the greatest euphoria, with diminishing reward from subsequent lines.

The degree of short-term memory interference depends on whether blood alcohol levels are rising or falling.
Greater impairment occurs when blood alcohol is rising due to functional tolerance at the receptor level.

Tolerance depends on the order in which a stimulus is presented.
Experiment: Rats were given alcohol and a convulsive shock in different orders.
Results: Tolerance to the shock was contingent on whether alcohol was administered before or after the shock.

Pharmacokinetic tolerance involves increased metabolism, where a drug is moved faster through the body.
Emphasis is on how quickly the drug reaches the nervous system.
Liver enzyme tests can index liver activity, indicating the level of drug metabolism.

Regular use of one drug affects the dose of another due to a common biochemical mechanism.
Tolerance to LSD can occur alongside tolerance to psilocybin.
Tolerance to alcohol can lead to tolerance to benzodiazepines.

Individuals learn to compensate for drug effects consciously or subconsciously.
Seasoned drinkers adapt to coordination impairment by walking with a lower center of gravity.

Classical conditioning principles apply, where repeated priming allows the brain to respond efficiently to maintain homeostasis.
Example: Smell of coffee interferes with heart rate due to anticipatory effects of caffeine.

Chronic alcohol consumption leads to an initial drop in body temperature (e.g., 1.5 degrees).
With repeated dosing, there is less of a hypothermic response due to tolerance.
Upon cessation, the adaptation leads to a withdrawal effect of the same magnitude in the opposite direction.
The compensatory response theory explains how the equal and opposite effect of tolerance manifests as withdrawal.

The brain recognizes situational and contextual factors, leading to conditioned responses.
In opioid abuse, individuals have pharmacokinetic changes based on their usual dosing environment.
Taking the same dose in a new environment can lead to overdose because the brain doesn't make the same compensatory adjustments.

Injections of alcohol will result in a similar drop in body temperature. $\approx 1.36$ degrees
If one subject receives 20 injections in the same environment, there will be no change in body temperature.
However, a subject in a new enivornment, injected with alcohol will have a body temperature drop as described above. This is due to the the fact that the body doesn't have those anticipatory mechanisms to work against that to have that tolerance.

Chronic consumption leads to physical dependence through neuroadaptations.
Sudden cessation (detox) can promote adverse effects: physical, emotional, cognitive, sexual.
Withdrawal symptoms span various areas and are equal and opposite to the effects of tolerance.