Dr. Leddi Talks About: Tolerance

Some Research On Tolerance:

Tolerance occurs after protracted use of a psychoactive substance, in which physiological and behavioral reactions to the substance are altered such that additional amounts must be used in order to obtain equivalent effects. Alternatively, consistent intake levels of the same substance produce decreased action or impact. Tolerance is complicated by the fact that initial individual variations in susceptibility to a substance’s effect can easily be misconstrued as tolerance. In addition, the rate of tolerance growth is inconsistent between substances, and the same substance impacts various brain systems differentially in terms of the pace and degree of tolerance incurred (DSM-IV-TR, 2000). Julien et al. (2008) described “pharmacological” and “behavioral” factors involved in processes that cause tolerance. These authors indicated that physiological adaptations occur when a psychoactive substance is used over extended time periods. Included in these adjustments is the production of additional enzymes to metabolize the substance. The increased quantity of enzymes makes the disintegration and deactivation process more efficient, leaving less substance available in the system to elicit an effect. Therefore, greater amounts of the substance are required to generate a comparable response. “Down-regulation” or the physical adaptation of neurons to extended substance exposure manifests in a significant decline in receptor quantity and responsiveness. These structural modifications also create a situation where the response elicited during initial usage can only be maintained through the use of increased quantities of the substance. In addition to physiological tolerance, conditioning effects or behavioral adaptations in response to substance cues has also been found to contribute to the phenomenon of tolerance. It has been proposed that this becomes a conditioned stimuli-response effect, where the development and maintenance of tolerance is facilitated by external cues, which become directly associated with and counteract the effects of regular substance use. Julien et al. (2008, p. 34) explained, “The environmental cues routinely paired with drug administration will become conditioned stimuli that elicit a conditioned response that is opposite in direction to or compensation for the direct effects of the drug.”

Examples of rapid tolerance include cocaine and amphetamine induced appetite loss and increased level of substance required for overdose. In addition, some degree of tolerance to the cardiac effects of cocaine transpires over a short duration of time. Conversely, stimulant induced psychosis is not an aspect of substance use impacted by tolerance. Ethanol involves both physiological and conditioned tolerance and tolerance impacts the tranquilizing effect of sedatives, but not the anticonvulsant effects. Cannabis effects are impacted by tolerance, the psychoactive effects of ecstasy are prone to rapid tolerance, and short-term repetitive hallucinogen use induces tolerance (WHO, 2004).

Although the traditional use of the term tolerance emphasizes the impact of long-term substance use, short term or “acute” tolerance appears to occur. An almost immediate reduction of “m-opioid receptor (MOPr)” sensitivity has been identified and examined during opioid administration within experimental conditions. Although it appears that short-term desensitization or tolerance might transpire with particular substances and receptors, this level or form of tolerance does not incorporate all the physiological and behavioral substrates that classical tolerance encompasses (Christie, 2008).

Tabokoff and Hoffman (2004, p. 12) described processes underlying the development of immediate and long-term tolerance to ethanol ingestion. Tabokoff and Hoffman (2004) indicated that short-term or immediate levels of tolerance might transpire due to a process that adds phosphates to proteins, which alters the responsiveness of key “receptor-gated ion channels” (including “NMDA, nicotinic cholingergic, and GABA A receptors”). Persistent ingestion of ethanol causes “cyclic adenosine monophosphate (cAMP)” or second messenger alterations and more significant neuronal adaptations including changes in intracellular transcription of DNA and protein synthesis, which cause longer-term cellular tolerance.

Concerns Regarding Tolerance:

On one side…

Tolerance to a substance often facilitates an increased use of that substance. High levels of alcohol and/or substance use can impact the individual from a physiological perspective and ultimately can cause damage to major organ systems.

The nervous system, which includes the brain and spinal cord are impacted by high levels of substance use. The brain controls important cognitive and motor functions, allowing for movement, the processing of information, mood regulation, personality development and structure. Substances interfere with the regulation and control of these domains, and in severe cases can cause irreversible brain damage, impacting basic functioning, including memory and movement.

The lymphatic and immune system can be compromised by substance and alcohol usage. This can result in lowered immune system functioning. Hormone production, secretion and regulation through the endocrine and reproductive systems can also be impaired by substance use, reducing the reproductive and immune system’s efficacy as well as causing lower hormonal levels of estrogen and testosterone, as well as creating lipid and glucose imbalance. Sexual dysfunction can occur in both males and females due to these impacts.

Breathing is slowed and at times impaired by substance and alcohol usage. If the respiratory system is depressed to the point where the body is deprived of oxygen this can result in death or brain damage. The cardiovascular and circulatory system, which includes the heart and blood vessels, are also negatively impacted by usage, leading to chronic and serious issues such as high blood pressure, arrhythmia, reduced blood flow, and anemia.

The skeletal system including the human bone structure is impacted by alcohol consumption due to alcohol’s interference with calcium absorption and utilization, resulting in weakened bones that are prone to injury and skeletomuscular degenerative conditions. Muscle coordination and movement is also impacted by substance use. This can result in decreased muscle mass and in severe cases can lead to the breakdown of muscle fibers, which can then enter the bloodstream, causing kidney damage and failure.

The digestive system, including the mouth, stomach, liver and intestines are stressed by substances and alcohol usage. This stress interferes with nutrition absorption, can increase susceptibility to ulcers, gallstones, as well as other life threatening diseases such as cancers.

In addition, the kidney and other elimination organs can be negatively impacted by substance abuse, as it interferes with the effective functioning of these organs, which are crucial in eliminating toxins from the system. This toxicity can lead to infections as well as sepsis.

On the other side…

Tolerance leads to the need to use increased amounts of a substance to attempt to achieve the desired effect. This learned increase places individuals who have gone through treatment and have managed a period of sobriety at significant risk for overdose. Often these individuals do not account for the decrease in tolerance levels, relapse on the amount of substance used prior to treatment, and place themselves in grave danger for overdose.

Both sides…

Are part of the many reasons that at Evolutions Treatment Center we put together a strong relapse prevention plan for patients discharging from treatment. A comprehensive plan that factors in sober living, strong peer support, medication management, and continued care on a lower but accountable level of treatment, are crucial to support individuals continued ability to maintain abstinence and long term recovery.