In internal medicine, relapse or recidivism is a recurrence of a past (typically medical) condition. For example,

multiple sclerosis Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...

and

malaria Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms that typically include fever, tiredness, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or death. S ...

often exhibit peaks of activity and sometimes very long periods of dormancy, followed by relapse or

recrudescence Recrudescence is the revival of material or behavior that had previously been stabilized, settled, or diminished. In medicine, it is usually defined as the recurrence of symptoms after a period of remission or quiescence, in which sense it can som ...

. In

psychiatry Psychiatry is the medical specialty devoted to the diagnosis, prevention, and treatment of mental disorders. These include various maladaptations related to mood, behaviour, cognition, and perceptions. See glossary of psychiatry. Initial psych ...

, relapse or reinstatement of drug-seeking behavior, is the recurrence of pathological drug use, self harm or other symptoms after a period of recovery. Relapse is often observed in individuals who have developed a

drug addiction Addiction is a neuropsychological disorder characterized by a persistent and intense urge to engage in certain behaviors, one of which is the usage of a drug, despite substantial harm and other negative consequences. Repetitive drug use of ...

or a form of

drug dependence Substance dependence, also known as drug dependence, is a biopsychological situation whereby an individual's functionality is dependent on the necessitated re-consumption of a psychoactive substance because of an adaptive state that has develope ...

, as well as those who have a

mental disorder A mental disorder, also referred to as a mental illness or psychiatric disorder, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. Such features may be persistent, relapsing and remitti ...

Risk factors

Dopamine D2 receptor availability

The availability of the

dopamine receptor D2 Dopamine receptor D2, also known as D2R, is a protein that, in humans, is encoded by the ''DRD2'' gene. After work from Paul Greengard's lab had suggested that dopamine receptors were the site of action of antipsychotic drugs, several groups, in ...

plays a role in

self-administration Self-administration is, in its medical sense, the process of a subject administering a pharmacological substance to themself. A clinical example of this is the subcutaneous "self-injection" of insulin by a diabetic patient. In animal experimentati ...

and the reinforcing effects of

cocaine Cocaine (from , from , ultimately from Quechuan languages, Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly recreational drug use, used recreationally for its euphoria, euphoric effects. It is primarily obtained from t ...

and other

stimulants Stimulants (also often referred to as psychostimulants or colloquially as uppers) is an overarching term that covers many drugs including those that increase activity of the central nervous system and the body, drugs that are pleasurable and inv ...

. The D2 receptor availability has an

inverse relationship In statistics, there is a negative relationship or inverse relationship between two variables if higher values of one variable tend to be associated with lower values of the other. A negative relationship between two variables usually implies that ...

to the vulnerability of reinforcing effects of the

drug A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via insuffla ...

. With the D2 receptors becoming limited, the user becomes more susceptible to the reinforcing effects of cocaine. It is currently unknown if a predisposition to low D2 receptor availability is possible; however, most studies support the idea that changes in D2 receptor availability are a

result A result (also called upshot) is the final consequence of a sequence of actions or events expressed qualitatively or quantitatively. Possible results include advantage, disadvantage, gain, injury, loss, value and victory. There may be a range ...

, rather than a

precursor Precursor or Precursors may refer to: *Precursor (religion), a forerunner, predecessor ** The Precursor, John the Baptist Science and technology * Precursor (bird), a hypothesized genus of fossil birds that was composed of fossilized parts of unr ...

, of cocaine use. It has also been noted that D2 receptors may return to the level existing prior to drug exposure during long periods of

abstinence Abstinence is a self-enforced restraint from indulging in bodily activities that are widely experienced as giving pleasure. Most frequently, the term refers to sexual abstinence, but it can also mean abstinence from alcohol, drugs, food, etc. ...

, a fact which may have implications in relapse treatment.

Social hierarchy

Social interaction A social relation or also described as a social interaction or social experience is the fundamental unit of analysis within the social sciences, and describes any voluntary or involuntary interpersonal relationship between two or more individuals ...

s, such as the formation of linear dominance hierarchies, also play a role in vulnerability to substance use.

Animal studies Animal studies is a recently recognised field in which animals are studied in a variety of cross-disciplinary ways. Scholars who engage in animal studies may be formally trained in a number of diverse fields, including geography, art history, ant ...

suggest that there exists a difference in D2 receptor availability between dominant and subordinate animals within a

social hierarchy Social stratification refers to a society's categorization of its people into groups based on socioeconomic factors like wealth, income, race, education, ethnicity, gender, occupation, social status, or derived power (social and political). As su ...

as well as a difference in the function of cocaine to

reinforce In behavioral psychology, reinforcement is a consequence applied that will strengthen an organism's future behavior whenever that behavior is preceded by a specific antecedent stimulus. This strengthening effect may be measured as a higher freq ...

self-administration in these animal groups. Socially dominant animals exhibit higher availability of D2 receptors and fail to maintain self-administration.

Triggers

Drug taking and relapse are heavily influenced by a number of factors including the

pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...

, dose, and

neurochemistry Neurochemistry is the study of chemicals, including neurotransmitters and other molecules such as psychopharmaceuticals and neuropeptides, that control and influence the physiology of the nervous system. This particular field within neuroscience e ...

of the drug itself as well as the drug taker’s

environment Environment most often refers to: __NOTOC__ * Natural environment, all living and non-living things occurring naturally * Biophysical environment, the physical and biological factors along with their chemical interactions that affect an organism or ...

and drug-related history. Reinstatement of drug use after a period of non-use or abstinence is typically initiated by one or a combination of the three main triggers:

stress Stress may refer to: Science and medicine * Stress (biology), an organism's response to a stressor such as an environmental condition * Stress (linguistics), relative emphasis or prominence given to a syllable in a word, or to a word in a phrase ...

, re-exposure to the drug or drug-priming, and environmental cues. These factors may induce a

neurochemical A neurochemical is a small organic molecule or peptide that participates in neural activity. The science of neurochemistry studies the functions of neurochemicals. Prominent neurochemicals Neurotransmitters and neuromodulators *Glutamate is the ...

response in the drug taker that mimics the drug and thus triggers reinstatement. These cues may lead to a strong desire or intention to use the drug, a feeling termed craving by

Abraham Wikler Abraham Wikler (October 12, 1910 – March 7, 1981). was an American psychiatrist and neurologist who made important discoveries in drug addiction. He was one of the first to promote a view of addiction as conditioned behavior, and made the fir ...

in 1948. The propensity for craving is heavily influenced by all three triggers to relapse and is now an accepted hallmark of

substance dependence Substance dependence, also known as drug dependence, is a biopsychological situation whereby an individual's functionality is dependent on the necessitated re-consumption of a psychoactive substance because of an adaptive state that has develope ...

. Stress is one of the most powerful stimuli for reinstating drug use because stress cues stimulate craving and drug-seeking behavior during

. Stress-induced craving is also predictive of time to relapse. Comparably, addicted individuals show an increased susceptibility to

stressor A stressor is a chemical or biological agent, environmental condition, external stimulus or an event seen as causing stress to an organism. Psychologically speaking, a stressor can be events or environments that individuals might consider demandin ...

s than do non-addicted controls. Examples of stressors that may induce reinstatement include emotions of

fear Fear is an intensely unpleasant emotion in response to perceiving or recognizing a danger or threat. Fear causes physiological changes that may produce behavioral reactions such as mounting an aggressive response or fleeing the threat. Fear ...

sadness Sadness is an emotional pain associated with, or characterized by, feelings of disadvantage, loss, despair, grief, helplessness, disappointment and sorrow. An individual experiencing sadness may become quiet or lethargic, and withdraw thems ...

, or

anger Anger, also known as wrath or rage, is an intense emotional state involving a strong uncomfortable and non-cooperative response to a perceived provocation, hurt or threat. A person experiencing anger will often experience physical effects, su ...

, a physical stressor such as a footshock or elevated sound level, or a social event. Drug-priming is exposing the abstinent user to the addictive substances, which will induce reinstatement of the drug-seeking behavior and drug self-administration. Stimuli that have a pre-existing association with a given drug or with use of that drug can trigger both craving and reinstatement. These cues include any items, places, or people associated with the drug.

Treatment

Relapse treatment is somewhat of a

misnomer A misnomer is a name that is incorrectly or unsuitably applied. Misnomers often arise because something was named long before its correct nature was known, or because an earlier form of something has been replaced by a later form to which the name ...

because relapse itself is a treatment failure; however there exist three main approaches that are currently used to reduce the likelihood of drug relapse. These include

pharmacotherapy Pharmacotherapy is therapy using pharmaceutical drugs, as distinguished from therapy using surgery (surgical therapy), radiation (radiation therapy), movement ( physical therapy), or other modes. Among physicians, sometimes the term ''medical the ...

, cognitive behavioral techniques, and

contingency management Contingency management (CM) is the application of the three-term contingency (or operant conditioning), which uses stimulus control and consequences to change behavior. CM originally derived from the science of applied behavior analysis (ABA), bu ...

. The main goals of treating substance dependence and preventing relapse are to identify the

needs A need is dissatisfaction at a point of time and in a given context. Needs are distinguished from wants. In the case of a need, a deficiency causes a clear adverse outcome: a dysfunction or death. In other words, a need is something required for a ...

that were previously met by use of the drug and to develop the skills needed to meet those needs in an alternative way.

Pharmacotherapy

:''Related article:

Drug rehabilitation Drug rehabilitation is the process of medical or psychotherapeutic treatment for dependency on psychoactive substances such as alcohol, prescription drugs, and street drugs such as cannabis, cocaine, heroin or amphetamines. The general inte ...

Various

medications A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and rel ...

are used to stabilize an addicted user, reduce the initial drug use, and prevent reinstatement of the drug. Medications can normalize the long-term changes that occur in the

brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...

and

nervous system In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes th ...

as a result of prolonged drug use. This method of therapy is complex and multi-faceted because the brain target for the desire to use the drug may be different from the target induced by the drug itself. The availability of various

neurotransmitter receptor A neurotransmitter receptor (also known as a neuroreceptor) is a membrane receptor protein that is activated by a neurotransmitter. Chemicals on the outside of the cell, such as a neurotransmitter, can bump into the cell's membrane, in which the ...

s, such as the

, and changes in the

medial prefrontal cortex In mammalian brain anatomy, the prefrontal cortex (PFC) covers the front part of the frontal lobe of the cerebral cortex. The PFC contains the Brodmann areas BA8, BA9, BA10, BA11, BA12, BA13, BA14, BA24, BA25, BA32, BA44, BA45, BA46, ...

are prominent targets for pharmacotherapy to prevent relapse because they are heavily linked to drug-induced, stress-induced, and cue-induced relapse. Receptor recovery can be

upregulated In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary proce ...

by administration of

receptor antagonists A receptor antagonist is a type of Receptor (biochemistry), receptor ligand (biochemistry), ligand or drug that blocks or dampens a biological response by binding to and blocking a Receptor (biochemistry), receptor rather than activating it like ...

, while pharmacotherapeutic treatments for neruoadaptations in the medial prefrontal cortex are still relatively ineffective due to lacking knowledge of these

adaptations In biology, adaptation has three related meanings. Firstly, it is the dynamic evolutionary process of natural selection that fits organisms to their environment, enhancing their evolutionary fitness. Secondly, it is a state reached by the p ...

on the

molecular A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioche ...

and

cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery ...

ular level.

Cognitive behavioral techniques

The various behavioral approaches to treating relapse focus on the precursors and consequences of drug-taking and reinstatement. Cognitive-behavioral techniques (CBT) incorporate

Pavlovian conditioning Classical conditioning (also known as Pavlovian or respondent conditioning) is a behavioral procedure in which a biologically potent stimulus (e.g. food) is paired with a previously neutral stimulus (e.g. a triangle). It also refers to the learni ...

and

operant conditioning Operant conditioning, also called instrumental conditioning, is a learning process where behaviors are modified through the association of stimuli with reinforcement or punishment. In it, operants—behaviors that affect one's environment—are c ...

, characterized by

positive reinforcement In behavioral psychology, reinforcement is a consequence applied that will strengthen an organism's future behavior whenever that behavior is preceded by a specific antecedent stimulus. This strengthening effect may be measured as a higher freq ...

and

negative reinforcement In behavioral psychology, reinforcement is a consequence applied that will strengthen an organism's future behavior whenever that behavior is preceded by a specific antecedent stimulus. This strengthening effect may be measured as a higher freq ...

, in order to alter the cognitions,

thoughts In their most common sense, the terms thought and thinking refer to conscious cognitive processes that can happen independently of sensory stimulation. Their most paradigmatic forms are judging, reasoning, concept formation, problem solving, an ...

, and

emotions Emotions are mental states brought on by neurophysiological changes, variously associated with thoughts, feelings, behavioral responses, and a degree of pleasure or displeasure. There is currently no scientific consensus on a definition. ...

associated with drug-taking behavior. A main approach of CBT is cue exposure, during which the abstinent user is repeatedly exposed to the most salient triggers without exposure to the substance in hopes that the substance will gradually lose the ability to induce drug-seeking behavior. This approach is likely to reduce the severity of a relapse than to prevent one from occurring altogether. Another method teaches addicts basic coping mechanisms to avoid using the

illicit drug The prohibition of drugs through sumptuary legislation or religious law is a common means of attempting to prevent the recreational use of certain intoxicating substances. While some drugs are illegal to possess, many governments regulate the ...

. It is important to address any deficits in

coping skills Coping refers to conscious strategies used to reduce unpleasant emotions. Coping strategies can be cognitions or behaviours and can be individual or social. Theories of coping Hundreds of coping strategies have been proposed in an attempt to ...

, to identify the needs that likely induce drug-seeking, and to develop another way to meet them.

Relapse prevention

Relapse prevention Relapse prevention (RP) is a cognitive-behavioral approach to relapse with the goal of identifying and preventing high-risk situations such as unhealthy substance use, obsessive-compulsive behavior, sexual offending, obesity, and depression.Witki ...

attempts to group the factors that contribute to relapse into two broad categories: immediate determinants and covert antecedents. Immediate determinants are the environmental and emotional situations that are associated with relapse, including high-risk situations that threaten an individual’s sense of control,

coping strategies Coping refers to conscious strategies used to reduce unpleasant emotions. Coping strategies can be cognitions or behaviours and can be individual or social. Theories of coping Hundreds of coping strategies have been proposed in an attempt to ...

, and outcome expectancies. Covert antecedents, which are less obvious factors influencing relapse, include lifestyle factors such as stress level and balance, and urges and cravings. The relapse prevention model teaches addicts to anticipate relapse by recognizing and coping with various immediate determinants and covert antecedents. The RP model shows the greatest success with treatment of

alcoholism Alcoholism is, broadly, any drinking of alcohol (drug), alcohol that results in significant Mental health, mental or physical health problems. Because there is disagreement on the definition of the word ''alcoholism'', it is not a recognize ...

but it has not been proven superior to other treatment options. Relapse may also be more likely to occur during certain times, such as the holiday season when stress levels are typically higher. So, emphasizing relapse prevention strategies during these times is ideal.

Contingency management

In contrast to the behavioral approaches above,

concentrates on the consequences of drug use as opposed to its precursors. Addict behavior is reinforced, by reward or

punishment Punishment, commonly, is the imposition of an undesirable or unpleasant outcome upon a group or individual, meted out by an authority—in contexts ranging from child discipline to criminal law—as a response and deterrent to a particular acti ...

, based on ability to remain abstinent. A common example of contingency management is a token or voucher system, in which abstinence is rewarded with tokens or vouchers that individuals can redeem for various retail items.

Animal models

There are vast ethical limitations in

research because humans cannot be allowed to self-administer drugs for the purpose of being studied. However, much can be learned about drugs and the neurobiology of drug taking by the examination of laboratory animals. Most studies are performed on rodents or non-human primates with the latter being most comparable to humans in

anatomy Anatomy () is the branch of biology concerned with the study of the structure of organisms and their parts. Anatomy is a branch of natural science that deals with the structural organization of living things. It is an old science, having its ...

of the

prefrontal cortex In mammalian brain anatomy, the prefrontal cortex (PFC) covers the front part of the frontal lobe of the cerebral cortex. The PFC contains the Brodmann areas BA8, BA9, BA10, BA11, BA12, BA13, BA14, BA24, BA25, BA32, BA44, BA45, BA46, ...

social behavior Social behavior is behavior among two or more organisms within the same species, and encompasses any behavior in which one member affects the other. This is due to an interaction among those members. Social behavior can be seen as similar to an ...

, and life span. Other advantages to studying relapse in non-human primates include the ability of the animal to reinstate

, and to learn complex behaviors in order to obtain the drug. Animal studies have shown that a reduction in negative withdrawal symptoms is not necessary to maintain drug taking in laboratory animals; the key to these studies is operant conditioning and reinforcement.

Protocols

Self-administration

To self-administer the drug of interest the animal is implanted with an intravenous

catheter In medicine, a catheter (/ˈkæθətər/) is a thin tube made from medical grade materials serving a broad range of functions. Catheters are medical devices that can be inserted in the body to treat diseases or perform a surgical procedure. Cath ...

and seated in a primate chair equipped with a response lever. The animal is seated in a ventilated chamber and trained on a schedule of drug self-administration. In many studies the self-administration task begins with presentation of a stimulus light (located near the response panel) that may change colors or turn off upon completion of the operant task. The change in visual stimulus is accompanied by an injection of the given drug through the implanted catheter. This schedule is maintained until the animals learn the task.

Extinction

Extinction Extinction is the termination of a kind of organism or of a group of kinds (taxon), usually a species. The moment of extinction is generally considered to be the death of the last individual of the species, although the capacity to breed and ...

in non-human primates is analogous, with some limitations, to abstinence in humans. In order to extinguish drug-seeking behavior the drug is substituted with a saline solution. When the animal performs the task it has been trained to perform it is no longer reinforced with an injection of the drug. The visual stimulus associated with the drug and completion of the task is also removed. The extinction sessions are continued until the animal ceases the drug-seeking behavior by pressing the lever.

Reinstatement

After the animal’s drug-seeking behavior is extinguished, a stimulus is presented to promote the reinstatement of that same drug-seeking behavior (i.e., relapse). For example, if the animal receives an injection of the drug in question it will likely begin working on the operant task for which it was previously reinforced. The stimulus may be the drug itself, the visual stimulus that was initially paired with the drug intake, or a stressor such as an acoustic startle or foot shock. However, the stimulus used to trigger reinstatement can influence the psychological processes involved.

Neuroimaging

Neuroimaging Neuroimaging is the use of quantitative (computational) techniques to study the structure and function of the central nervous system, developed as an objective way of scientifically studying the healthy human brain in a non-invasive manner. Incre ...

has contributed to the identification of the

neural In Biology, biology, the nervous system is the Complex system, highly complex part of an animal that coordinates its Behavior, actions and Sense, sensory information by transmitting action potential, signals to and from different parts of its ...

components involved in drug reinstatement as well as drug-taking determinants such as the pharmokinetics,

, and dose of the drug. The neuroimaging techniques used in non-human primates include

positron emission tomography Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in Metabolism, metabolic processes, and in other physiological activities including bl ...

(PET), which uses

radiolabeled A radioactive tracer, radiotracer, or radioactive label is a chemical compound in which one or more atoms have been replaced by a radionuclide so by virtue of its radioactive decay it can be used to explore the mechanism of chemical reactions by tr ...

ligand In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...

tracers to measure neurochemistry

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

and

single-photon emission computed tomography Single-photon emission computed tomography (SPECT, or less commonly, SPET) is a nuclear medicine tomographic imaging technique using gamma rays. It is very similar to conventional nuclear medicine planar imaging using a gamma camera (that is, ...

(SPECT).

Functional magnetic resonance imaging Functional magnetic resonance imaging or functional MRI (fMRI) measures brain activity by detecting changes associated with blood flow. This technique relies on the fact that cerebral blood flow and neuronal activation are coupled. When an area o ...

(fMRI) is widely used in human subjects because it has much higher resolution and eliminates exposure to

radiation In physics, radiation is the emission or transmission of energy in the form of waves or particles through space or through a material medium. This includes: * ''electromagnetic radiation'', such as radio waves, microwaves, infrared, visi ...

Limitations

Although the reinstatement

protocols Protocol may refer to: Sociology and politics * Protocol (politics), a formal agreement between nation states * Protocol (diplomacy), the etiquette of diplomacy and affairs of state * Etiquette, a code of personal behavior Science and technology ...

are used frequently in

laboratory A laboratory (; ; colloquially lab) is a facility that provides controlled conditions in which scientific or technological research, experiments, and measurement may be performed. Laboratory services are provided in a variety of settings: physicia ...

settings there are some limitations to the

validity Validity or Valid may refer to: Science/mathematics/statistics: * Validity (logic), a property of a logical argument * Scientific: ** Internal validity, the validity of causal inferences within scientific studies, usually based on experiments ** ...

of the procedures as a model of craving and relapse in humans. The primary limiting factor is that in humans, relapse rarely follows the strict

extinction Extinction is the termination of a kind of organism or of a group of kinds (taxon), usually a species. The moment of extinction is generally considered to be the death of the last individual of the species, although the capacity to breed and ...

of drug-seeking behavior. Additionally, human self-reports show that drug-associated

stimuli A stimulus is something that causes a physiological response. It may refer to: * Stimulation ** Stimulus (physiology), something external that influences an activity ** Stimulus (psychology), a concept in behaviorism and perception * Stimulus (eco ...

play a lesser role in craving in humans than in the laboratory models. The

of the model can be examined in three ways:

formal equivalence The terms dynamic equivalence and formal equivalence, coined by Eugene Nida, are associated with two dissimilar translation approaches that are employed to achieve different levels of literalness between the source and target text, as evidenc ...

, correlational models, and functional equivalence. There is moderate formal equivalence, or

face validity Face validity is the extent to which a test is subjectively viewed as covering the concept it purports to measure. It refers to the transparency or relevance of a test as it appears to test participants. In other words, a test can be said to have fa ...

, meaning that the model somewhat resembles relapse as it occurs outside of the laboratory setting; however, there is little face validity for the procedures as a model of craving. The

predictive validity In psychometrics, predictive validity is the extent to which a score on a scale or test predicts scores on some criterion measure. For example, the validity of a cognitive test for job performance is the correlation between test scores and, for e ...

, which is assessed by correlational models, has yet to be determined for the procedures. There is sound functional equivalence for the model, which suggests that relapse in the laboratory is reasonably similar to that in nature. Further research into other manipulations or reinforcements that could limit drug-taking in non-human primates would be extremely beneficial to the field.

Differences between sexes

There exists a higher rate of relapse, shorter periods of

, and higher responsiveness to drug-related cues in women as compared to men. One study suggests that the ovarian hormones,

estradiol Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development of f ...

and

progesterone Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the m ...

, that exist in females at fluctuating levels throughout the

menstrual cycle The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that make pregnancy possible. The ovarian cycle controls the production and release of eggs a ...

(or

estrous cycle The estrous cycle (, originally ) is the set of recurring physiological changes that are induced by reproductive hormones in most mammalian therian females. Estrous cycles start after sexual maturity in females and are interrupted by anestrous p ...

in rodents), play a significant role in drug-primed relapse. There is a marked increase in progesterone levels and a decrease in estradiol levels during the

luteal phase The corpus luteum (Latin for "yellow body"; plural corpora lutea) is a temporary endocrine structure in female ovaries involved in the production of relatively high levels of progesterone, and moderate levels of estradiol, and inhibin A. It is t ...

Anxiety Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...

, irritability, and depression, three symptoms of both

withdrawal Withdrawal means "an act of taking out" and may refer to: * Anchoresis (withdrawal from the world for religious or ethical reasons) * ''Coitus interruptus'' (the withdrawal method) * Drug withdrawal * Social withdrawal * Taking of money from a ban ...

and the human menstrual cycle, are most severe in the luteal phase. Symptoms of withdrawal not associated with the cycle, such as hunger, are also enhanced during the luteal phase, which suggests the role of estradiol and progesterone in enhancing symptoms above the naturally occurring level of the menstrual cycle. The symptoms of craving also increase during the luteal phase in humans (it is important to note that the opposite result occurs in female subjects with cocaine addiction suggesting that cyclic changes may be specific for different addictive substances). Further, the drug-primed response is decreased during the luteal phase suggesting a time in the cycle during which the urge to continue use may be reduced. These findings implicate a cyclic, hormone-based timing for quitting an addictive substance and preparing for magnified symptoms of withdrawal or susceptibility to relapse.

References

{{Authority control Behavioral neuroscience Addiction Substance dependence Substance-related disorders de:Rezidiv ru:Рецидив (медицина)