Reverse tolerance (drug sensitization) is a pharmacological phenomenon where there is an increase in the potency of a drug caused by factors like the drug-taking individual becoming more sensitive or less tolerant to the effects of the substance; the presence of a disease; organ damage; or toxic reactions. The phenomenon manifests as the individual experiencing exaggerated effects of the drugs even without increasing the dosage.

The causes of reverse tolerance include intermittent exposure to substances of abuse in high doses; history of drug exposure; and the presence of health issues like impaired liver functionality. Other causes include cross-sensitization; accumulation of a drug in the body; individual genetic differences; chronic stress; and environmental cues.

The symptoms of reverse tolerance are anxiety, agitation, increased sweating, seizures, tremors, and psychosis. These symptoms are essentially those that develop due to the consumption of an addictive substance.

The mechanism of reverse tolerance (drug sensitization) is influenced by one or more factors like an upregulation of neural receptors; an increased efficiency of receptors; behavioral or learned sensitization; or the presence of a disease.

The risks of reverse tolerance are the development of drug cravings; intense adverse effects of the drug; increased risk of relapsing even after a prolonged period of abstinence; intoxication that has the potential to cause self-harm and accidents; and overdosing.

What is reverse tolerance (drug sensitization)?

Reverse tolerance (drug sensitization) refers to a pharmacological phenomenon that manifests as a progressive amplification of response to a drug of abuse due to repeated or continuous exposure. In laboratory experiments, reverse tolerance manifests as a drug eliciting a response that is more than what was recorded when it was administered for the first time and without increasing dosage. It is an increase in the potency of a drug due to a decrease in tolerance or an increase in sensitivity to the substance exhibited by the drug user. The other likely reasons for an increase in a drug’s potency after repeated administration include toxic reactions to the drug, damage to the organ that is involved in the metabolization of the drug, and the presence of a disease in the drug-taking individual. Reverse tolerance is associated with learning and memory and is believed to be caused by neural adaptations to repeated drug exposure.

Which drugs are subject to reverse tolerance?

The drugs which are subject to reverse tolerance are listed below.

• Alcohol: It is believed that reverse tolerance or sensitization causes alcohol hangovers to increase in severity as the frequency of these episodes increases. Authors Verster et al., in a 2019 article titled “The Association between Alcohol Hangover Frequency and Severity: Evidence for Reverse Tolerance?” published in the Journal of Clinical Medicine believe that reverse tolerance exerts a protective effect by compelling individuals to drink less in the future.
• Cocaine: It is believed that cocaine sensitization is associated with taking the substance intermittently, a common pattern during the early drug abuse phase, according to a 2013 article by Calipari et al., published in the journal Neuropsychopharmacology, titled “Temporal Pattern of Cocaine Intake Determines Tolerance vs Sensitization of Cocaine Effects at the Dopamine Transporter.”
• Opiates: Evidence from experimental animal studies suggests that chronic opioid usage is associated with reverse tolerance to specific behavioral manifestations, especially in the motivational neural systems, according to a 2009 article by M. J. Christie published in the British Journal of Pharmacology, titled “Cellular neuroadaptations to chronic opioids: tolerance, withdrawal and addiction.”
• Amphetamines: Repeated amphetamine usage is associated with reverse tolerance.Authors O’Daly et al., in their 2014 article titled “Amphetamine Sensitization Alters Reward Processing in the Human Striatum and Amygdala” published in the journal PLoSOne note that significant sensitization effects are noticed in the amygdala and caudate nucleus regions of the brain.
• Cannabis: It is believed that a phenomenon called “dispositional tolerance” contributes to the development of reverse tolerance to cannabis, according to a 1976 article by A. Wikler published in the Annals of the New York Academy of Sciences, titled “Aspects of tolerance to and dependence on cannabis.” Dispositional tolerance refers to an enzyme-mediated increase in the rate of metabolism of THC (tetrahydrocannabinol), a compound that occurs in cannabis plants.

How common is reverse tolerance in addiction?

Reverse tolerance in addiction is not common. However, several studies report a high percentage of cases where tolerance to alcohol decreased as addiction progressed over time, according to a 1995 article by Ziolkowski et al., in the journal Drug and Alcohol Dependence, titled “Decrease in alcohol tolerance: clinical significance in alcohol dependence.” In a study performed on 237 male patients with alcohol dependence, 54% (126 patients) showed a reduction in tolerance to alcohol. This phenomenon was prevalent more among elderly patients and those in the later stages of dependence. The authors suggest that reverse tolerance to alcohol is more prevalent after about a decade of excessive drinking than in the early stages of alcohol dependence when there is an increase in tolerance.

What is the difference between drug tolerance and reverse tolerance?

The difference between drug tolerance and reverse tolerance stems from the contradictory effects produced by substances like drugs and alcohol in the body. The development of tolerance and sensitization is determined by diverse factors like the dose of the drug taken, the frequency of taking the drug or the interval between two doses, and specific environmental factors.

Drug tolerance is a condition that manifests as a reduction in physical and/or psychological response to a particular substance after repeated use. On the other hand, reverse tolerance or sensitization is a phenomenon where there is an increase in the potency of the substance stemming from repeated usage. It manifests as the user exhibiting an increased physiological and/or behavioral response to the substance they have been abusing without increasing the dosage.

When an individual develops drug tolerance, they need to take more of the drug to feel the same effects as earlier. When they develop reverse tolerance, they experience magnified effects of the drug at the same or a smaller dosage.

Tolerance to the therapeutic effects of a drug means that the drug loses its efficacy over time and fails to produce the desired or expected health benefits to the individual. On the other hand, developing sensitization to the side effects of a drug increases the risk that continuing to use the drug will aggravate the problem.

Animal studies involving cocaine and amphetamines suggest that continuous exposure to a substance of abuse produces drug tolerance. In contrast, repeated intermittent exposure produces sensitization, also referred to as “reverse tolerance,” according to a 2004 article by Trujillo et al., published in the journal Pharmacology Biochemistry and Behavior, titled “Continuous administration of opioids produces locomotor sensitization.”

What causes reverse tolerance?

The causes of reverse tolerance are listed below.

• Intermittent drug exposure in high doses: Authors Robinson et al., in the chapter titled “Incentive Salience and the Transition to Addiction” from the 2013 book Biological Research on Addiction note that intermittent exposure to drugs in high doses generates the strongest possibility of sensitization. It has also been observed that intermittent exposure to psychostimulants like cocaine and amphetamine contributes to the development of sensitization, according to a 2004 article by Trujillo et al., published in the journal Pharmacology Biochemistry and Behavior, titled “Continuous administration of opioids produces locomotor sensitization.” However, this causal relationship has not been observed with opiates.
• Past drug exposure: It has been observed from animal studies carried out with cocaine and amphetamine that past drug exposure contributes to increased drug effects, or sensitization, upon successive exposures to the same substance.
• Presence of health issues: The presence of medical issues like organ damage or a disease state affects drug responsiveness. For instance, an alcoholic with liver cirrhosis exhibits a heightened response to alcoholic beverages because their liver, the primary organ that metabolizes alcohol, is damaged.
• Cross-sensitization: Sensitization to one drug has been found to be associated with sensitization to another drug, as in the case of cocaine and heroin (Robinson et al., 2013). Authors Becker et al., in the chapter titled “Neuroadaptive Changes that Result from Chronic Drug Exposure” from the 2013 book Biological Research on Addiction note that there is cross-sensitization between ethanol and cocaine and between amphetamine and morphine.
• Persistence of the drug in the body: Reverse tolerance due to this phenomenon has been observed in the case of marijuana wherein users have reported being able to decrease their dosage of the drug to experience the earlier degree of high. It is believed that marijuana tends to persist in the body and chronic usage leads to an accumulation of its psychoactive components that contributes to reverse tolerance.
• Chronic stress: There is cross-sensitization between chronic stress and drug responsiveness. For instance, it was found that repeated experiences of stressful events or injections of the stress hormone corticosterone produced behavioral and neurochemical sensitization to cocaine (Becker et al., 2013).
• Environmental context: The expression of drug sensitization has been found to be associated with environmental context. The presence of drug-related cues in the environment has the ability to increase the sensitivity of the dopaminergic or reward circuitry of the brain in subjects who have used the drug before and whose brains thus are able to form positive correlations between drug use and the feel-good response elicited by a dopamine surge (Robinson et al., 2013).
• Genetic makeup: Studies on experimental animals suggest that individual genetic makeup contributes to the development of drug sensitization. Variations in the functioning of the mesolimbic dopamine circuit caused by genetic differences contribute to variations in acute responsiveness to drugs (Robinson et al., 2013). This explains why the same drug causes rapid and robust sensitization in one group of users and little to no sensitization in another group.

Can health issues cause reverse tolerance?

Yes, health issues can cause reverse tolerance. For example, one reason for the manifestation of reverse tolerance in individuals with chronic alcoholism is damage to the liver. The liver is the primary organ of alcohol metabolism. When the functionality of the liver is reduced, the individual experiences increased effects of alcohol. They become intoxicated on much smaller quantities of alcohol than an individual who drinks only infrequently.

Who is most likely to develop reverse tolerance?

Individuals who are most likely to develop reverse tolerance include those who intermittently consume an addictive substance in high doses, have a history of drug use, and are suffering from a health condition, such as liver impairment, that slows down the metabolism of drugs. Due to a phenomenon known as cross-sensitization, individuals who are sensitized to heroin or ethanol tend to develop reverse tolerance to cocaine and those who are sensitized to amphetamine also exhibit sensitization to morphine. Individuals experiencing chronic stress and those who have genetic peculiarities that affect the functioning of the reward circuitry in their brains are also likely to develop reverse tolerance.

What are the symptoms of reverse tolerance?

The symptoms of reverse tolerance are listed below.

• Anxiety: Feelings of anxiety accompanied by irritability and restlessness are known to trigger paranoia in individuals with reverse tolerance to stimulants.
• Agitation: Agitation, manifesting as restlessness accompanied by a feeling of anxiety, is a common symptom of intoxication. Individuals who develop reverse tolerance tend to become intoxicated on previously tolerated levels of a substance and exhibit intense symptoms associated with taking that particular drug.
• Profuse sweating: Sweating is caused by a dysfunction of the body’s temperature regulation mechanism and is associated with the consumption of addictive substances like heroin and cocaine.
• Tremors: Drug-induced tremors manifest as involuntary shaking of the arms, hand, or head and are associated with the taking of substances like amphetamines, alcohol, and nicotine.
• Seizures: Drugs of abuse trigger seizures by directly affecting the brain or in the case of individuals with epilepsy, by interacting with their seizure medications.
• Psychosis: Animal studies suggest that the schizophrenia-like psychotic symptoms in humans induced by the chronic abuse of amphetamine are associated with the development of reverse tolerance, according to a 1990 article by S. Tadokoro and H. Kuribara published in the journal Nihon Yakurigaku Zasshi, titled “[Modification of the behavioral effects of drugs after repeated administration–special reference to the reverse tolerance of amphetamines].”

What is the mechanism of reverse tolerance (drug sensitization)?

The mechanism of reverse tolerance (drug sensitization) is explained by varied factors like an upregulation of receptors, an increase in the efficacy or affinity of receptors, medical reasons like organ damage or the presence of a disease, and behavioral or learned sensitization. These factors are, in turn, influenced by the dosage of the drug; timing, and frequency of drug use; the environmental context in which drug use takes place; and individual characteristics of the user, such as their genetic makeup, gender, hormonal status, and stress levels, according to authors Robinson et al., in the chapter titled “Incentive Salience and the Transition to Addiction” from the 2013 book Biological Research on Addiction.

Receptor upregulation refers to the phenomenon where prolonged exposure to a substance causes an increase in the number of receptors on the surface of a cell. Upregulation causes an increase in the cell’s response to a specific substance. So, the substance tends to produce increased effects at the same dosage. An increase in the number of receptors also tends to induce receptor supersensitivity or hypersensitivity, a condition where the same dose of a drug produces a magnified physiological response. This phenomenon occurs when the newly synthesized receptors do not have enough of the drug to interact with.

Drug sensitization is believed to be a manifestation of learning and memory, according to a 1993 article by J. Stewart and A. Badiani published in the journal Behavioural Pharmacology, titled “Tolerance and sensitization to the behavioral effects of drugs.” For instance, users of cannabis have reported reverse tolerance. In this case, shared cultural beliefs and learnings are believed to contribute to how individuals tend to interpret and label psychological states induced by cannabis use. So, it is probable that the reactions of an individual after consuming marijuana are partly learned behaviors because they require time to learn to anticipate specific drug-related reactions.

What is the role of reinforcing stimuli in drug sensitization?

The role of reinforcing stimuli in drug sensitization is to recondition the neural systems associated with rewards and motivations in multiple ways that raise the likelihood of future drug-taking behavior. It is known that intermittent exposure to drugs in high doses is a powerful contributor to drug sensitization, according to authors Robinson et al., in the chapter titled “Incentive Salience and the Transition to Addiction” from the 2013 book Biological Research on Addiction.

In the context of drug-use behavior, the reinforcing stimulus is the surge of dopamine that follows the use of an addictive substance. Drugs of abuse like cocaine, opioids, or nicotine, flood the reward circuitry of the brain with 10 times more dopamine than a natural reward. The brain associates the pleasurable feelings triggered by the surge of dopamine with the addictive substance via a process known as associative learning. The repeated use of these addictive substances causes changes that make the neural systems increasingly, and often, permanently sensitized to drugs and drug-related stimuli, according to a 1993 article by Terry E. Robinson and Kent C. Berridge published in the journal Brain Research Reviews, titled “The neural basis of drug craving: an incentive-sensitization theory of addiction.” This hypersensitive state of the neural system also produces incentive salience or an increase in drug “wanting,” which is a psychological state that makes addicts excessively motivated to seek drugs, according to a 2010 article by Louk J. M. J. Vanderschuren and R. Christopher Pierce published in the journal Current Topics in Behavioral Neurosciences, titled “Sensitization processes in drug addiction.”

How do the rewarding stimuli contribute to drug sensitization?

Rewarding stimuli contribute to drug sensitization by triggering individuals to exhibit drug-seeking behavior. Repeated exposure to substances of abuse has the possibility to cause drug sensitization, according to authors Robinson et al., in the chapter titled “Incentive Salience and the Transition to Addiction” from the 2013 book Biological Research on Addiction.

In the context of drug addiction, rewarding stimuli are substances that produce a desirable outcome, such as the pleasurable feelings produced by a surge of dopamine in the brain’s reward circuitry or the relief felt when there is a decrease in physical pain. According to authors Stauffer et al., in their 2015 article titled “Components and characteristics of the dopamine reward utility signal” published in The Journal of Comparative Neurology,rewards are “positive reinforcers” that produce approach behavior. Individuals are thus motivated to seek drugs to experience their rewarding effects. In genetically susceptible or otherwise vulnerable individuals with previous drug exposure, addictive substances have the ability to make the reward circuitry hyperactive or sensitized. As a result, “rewards” and reward-related cues tend to cause an increased amount of dopamine release, according to authors Warlow et al., in the chapter titled “Sensitization of Incentive Salience and the Transition to Addiction” from the book The Cambridge Handbook of Substance and Behavioral Addictions published in July 2020.

What are the risks of reverse tolerance?

The risks of reverse tolerance are listed below.

• Development of drug cravings: In vulnerable individuals who have been exposed to drugs, repeated use of addictive substances sensitizes the reward circuitry and makes it hyperactive, according to authors Warlow et al., in the chapter titled “Sensitization of Incentive Salience and the Transition to Addiction” from the book The Cambridge Handbook of Substance and Behavioral Addictions published in July 2020. The “reward” value of drugs is thus perceived to be greater than they really are. Drug-related cues evoke more dopamine release and hence, the individuals experience more cravings. “Sensitized” cravings are challenging to resist and contribute to the maintenance of addiction.
• Relapse: The incentive sensitization theory of addiction explains how reverse tolerance contributes to relapse, according to a 2010 article by Louk J. M. J. Vanderschuren and R. Christopher Pierce published in the journal Current Topics in Behavioral Neurosciences, titled “Sensitization processes in drug addiction.” Repeated use of drugs makes the motivational circuitry of the brain hyperactive and causes the individual to exhibit “incentive salience.” Incentive salience is a psychological phenomenon that makes the drug user perceive drug-related cues as being more attractive and “wanted,” according to a 1993 article by Terry E. Robinson and Kent C. Berridge published in the journal Brain Research Reviews, titled “The neural basis of drug craving: an incentive-sensitization theory of addiction.” Incentive salience is dampened during the expression of full-blown addiction when the individual takes large amounts of drugs. However, it surfaces during detoxification and when the symptoms of tolerance and withdrawal subside and thereby, contributes to a relapse even after the individual has been abstinent for an extended period.
• Intense adverse symptoms: The increase in the body’s response to a substance from a consistent dose has the possibility of triggering intense adverse effects. For instance, it has been found that individuals with decreased tolerance to alcohol due to impaired alcohol metabolism have higher concentrations of the substance in their blood, according to a 1995 article by Ziolkowski et al., in the journal Drug and Alcohol Dependence, titled “Decrease in alcohol tolerance: clinical significance in alcohol dependence.” The presence of increased amounts of alcohol in the blood coupled with the body’s intensified response to the substance causes adverse effects that are more severe than those that individuals with no reverse tolerance tend to exhibit.
• Drug intoxication: Individuals with reverse tolerance have an increased risk of getting intoxicated even with small amounts of the drug. Intoxication, in turn, increases the risk of the individual getting involved in accidents that harm them or others who interact with them.
• Overdose: The manifestation of drug tolerance varies widely across individuals, depending on multiple factors like individual genetic makeup, disease state, age, and the nature of the substance being used. Thus, reverse tolerance creates a situation where the drug user exhibits unpredictable drug sensitivity. Even a previously tolerable level of the drug has the possibility to overwhelm the physiological systems of an individual with decreased tolerance and cause a potentially fatal overdose.

How does reverse tolerance affect withdrawal?

Reverse tolerance affects withdrawal in multiple ways, such as by triggering the development of symptoms that are usually associated with the withdrawal phase or by dampening the withdrawal effects of select drugs. Reverse tolerance manifests as decreased tolerance to the effects of a drug due to reasons like impaired liver functioning or aging in the case of alcohol. An individual with reverse tolerance to alcohol has higher levels of alcohol in their bloodstream.

Individuals with decreased tolerance to alcohol manifest psychotic symptoms like transient hallucinations, mental confusion, and delirium at an increased frequency, according to a 1995 article by Ziolkowski et al., in the journal Drug and Alcohol Dependence, titled “Decrease in alcohol tolerance: clinical significance in alcohol dependence.” These symptoms are also associated with alcohol withdrawal.

It has been found that chronic morphine exposure leads to sensitization and enhanced morphine reward. The neural adaptations produced by this sensitization cause a dampening of the effects of drug withdrawal after naloxone is administered, according to Wendy Wenderski and Ian Maze in the chapter titled “Epigenetic Mechanisms of Drug Addiction Vulnerability” from the book Epigenetics in Psychiatry published in 2014.

Are treatments available for reverse tolerance?

No, there are no targeted treatments available for reverse tolerance. Stopping drug use to allow the body to reset its tolerance level is the only way to manage the symptoms of reverse tolerance. However, the treatment should encompass a holistic approach that includes medical monitoring during the detoxification phase when abrupt changes in the patient’s sensitivity to the drug have the possibility to trigger uncomfortable symptoms. Behavioral therapies should also be delivered to complement pharmacological therapies to support and quicken recovery.

 

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