Psychological dependence is a cognitive disorder that involves emotional–motivational withdrawal symptoms – such as anxietyoranhedonia – upon cessation of prolonged drug abuse or certain repetitive behaviors.[4] It develops through frequent exposure to certain psychoactive substances or behaviors, which leads to an individual requiring further exposure to avoid withdrawal symptoms, as a result of negative reinforcement. Neuronal counter-adaptation is believed to play a role in generating withdrawal symptoms, which could be mediated through changes in neurotransmitter activity or altered receptor expression.[5][6][7][8][9] Environmental enrichment and physical activity can attenuate withdrawal symptoms.[10][11]
Addiction and dependence glossary[1][2][3] | |
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Symptoms of psychological dependence include:
Psychological dependence develops through consistent and frequent exposure to drug or behavioral activity.[12] After sufficient exposure to a stimulus capable of inducing psychological dependence (e.g., drug use), an adaptive state develops and results in the onset of withdrawal symptoms that negatively affect cognition upon disengagement.[4]
Psychostimulants, such as amphetamineorcocaine, are an example of a drug class where only emotional and motivational (i.e., cognitive) symptoms are observed in withdrawal, as opposed to somatic withdrawal in cases of physical dependence.[4] Whilst psychological dependence is often associated with effects of drug use, a behavioral dependence-withdrawal syndrome is possible. For example, exercise dependence can develop in amateur and professional athletes whereby marked cognitive withdrawal symptoms - associated with depressive symptoms and increased anxiety - are experienced when abstaining from experience for two weeks or longer.[13]
The mechanism that generates dependence involves a neuronal counter-adaptation, which is localized to areas of the brain responsible for a drug's positive reinforcement. This adaptation occurs as a change in neurotransmitter activity or in receptor expression.[5]
Two factors have been identified as playing pivotal roles in psychological dependence: the neuropeptide "corticotropin-releasing factor" (CRF) and the gene transcription factor "cAMP response element binding protein" (CREB).[1] The nucleus accumbens (NAcc) is one brain structure that has been implicated in the psychological component of drug dependence. In the NAcc, CREB is activated by cyclic adenosine monophosphate (cAMP) immediately after a high and triggers changes in gene expression that affect proteins such as dynorphin; dynorphin peptides reduce dopamine release into the NAcc by temporarily inhibiting the reward pathway. A sustained activation of CREB thus forces a larger dose to be taken to reach the same effect. In addition, it leaves the user feeling generally depressed and dissatisfied, and unable to find pleasure in previously enjoyable activities, often leading to a return to the drug for another dose.[14]
In addition to CREB, it is hypothesized that stress mechanisms play a role in dependence. Koob and Kreek have hypothesized that during drug use, CRF activates the hypothalamic–pituitary–adrenal axis (HPA axis) and other stress systems in the extended amygdala. This activation influences the dysregulated emotional state associated with psychological dependence. They found that as drug use escalates, so does the presence of CRF in human cerebrospinal fluid. In rat models, the separate use of CRF inhibitors and CRF receptor antagonists both decreased self-administration of the drug of study. Other studies in this review showed dysregulation of other neuropeptides that affect the HPA axis, including enkephalin which is an endogenous opioid peptide that regulates pain. It also appears that μ-opioid receptors, which enkephalin acts upon, is influential in the reward system and can regulate the expression of stress hormones.[15]
Increased expression of AMPA receptors in nucleus accumbens MSNs is a potential mechanism of aversion produced by drug withdrawal.[16]
Change in neurotransmitter activity
Studies have shown that in rats experiencing ethanol withdrawal, stimulant withdrawaloropioid withdrawal, the nucleus accumbens shows lower levels of serotonin and dopamine than controls. These decreases are associated with depression and anxiety.[6][7]
In anatomically distinct areas of the rat brain, withdrawal is linked to lower levels of GABA and neuropeptide Y as well as higher levels of dynorphin, corticotropin-releasing factor, and norepinephrine; these fluctuations can contribute to psychological dependence.[5]
Altered receptor expression
Changes in receptor expression have also been linked to various symptoms of drug withdrawal. For example, in a study of rats undergoing nicotine withdrawal there has been observed a down regulation of α6β2*n-icotinic acetylcholine receptors in the mesostriatal dopaminergic pathways.[8]
A study examined how rats experienced morphine withdrawal in different surroundings. The rats were either placed in a standard environment (SE) or in an enriched environment (EE). The study concluded that EE reduced depression and anxiety withdrawal symptoms.[10]
Another study tested whether swimming exercises affected the intensity of perceivable psychological symptoms in rodents during morphine withdrawal. It concluded that the anxious and depressive states of the withdrawal were reduced in rats from the exercise group.[11]
Physical dependence | Psychological dependence |
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Alcohols | SSRIs |
Opioids | Hallucinogens |
Barbiturates | Inhalants |
Benzodiazepines | Psychostimulants |
Caffeine | |
Cannabis products |
The defining contrast between psychological dependence and physical dependence syndromes is based upon the set of withdrawal symptoms occurs upon removal of a particular stimulus after induction of an adaptive state (i.e., tolerance).[4] Withdrawal symptoms associated with psychological dependence are cognitive in nature and involve emotional and motivational impairment in particular, which may present as anhedonia, anxiety, dysphoria, or irritability, among other symptoms.[4] In contrast, physical dependence presents entirely somatic symptoms, such as diarrhea, myalgia, nausea, sweating, tremors, and other symptoms that are readily observable.[4][17] Substance dependence, the more general concept, is an umbrella term that can entail either or both states, depending on the subtance (see table 1).[4]
Although psychological dependence and physical dependence are distinct entities, they should not be characterized as mutually exclusive. Empirical studies have shown that cravings, which are traditionally associated with psychological dependence, involve a physiological element.[18][19]
Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41. ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict.
Substance-use disorder: A diagnostic term in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) referring to recurrent use of alcohol or other drugs that causes clinically and functionally significant impairment, such as health problems, disability, and failure to meet major responsibilities at work, school, or home. Depending on the level of severity, this disorder is classified as mild, moderate, or severe.
Addiction: A term used to indicate the most severe, chronic stage of substance-use disorder, in which there is a substantial loss of self-control, as indicated by compulsive drug taking despite the desire to stop taking the drug. In the DSM-5, the term addiction is synonymous with the classification of severe substance-use disorder.
Dependence is defined as an adaptive state that develops in response to repeated drug administration, and is unmasked during withdrawal, which occurs when drug taking stops. Dependence resulting from long-term drug use may have both a somatic component, manifested by physical symptoms, and an emotional–motivational component, manifested by dysphoria and anhedonic symptoms, that occur when a drug is discontinued. While physical dependence and withdrawal occur dramatically with some drugs of abuse (opiates, ethanol), these phenomena are not useful in the diagnosis of an addiction because they do not occur as robustly with other drugs of abuse (cocaine, amphetamine) and can occur with many drugs that are not abused (propranolol, clonidine). The official diagnosis of drug addiction by the Diagnostic and Statistical Manual of Mental Disorders (2013), which uses the term substance use disorder, is flawed. Criteria used to make the diagnosis of substance use disorders include tolerance and somatic dependence/withdrawal, even though these processes are not integral to addiction as noted. As previously discussed, cessation of cocaine use and the use of other psychostimulants in dependent individuals does not produce a physical withdrawal syndrome but may produce dysphoria, anhedonia, and an intense desire to reinitiate drug use. ...
Long-term caffeine use can lead to mild physical dependence.
Results showed a consistent pattern for adverse effects of exercise withdrawal on these mental health measures, particularly depressive symptoms and anxiety. For the studies reviewed, depressive symptoms consistently occurred following the cessation of exercise. Depressive symptoms includes a variety of complaints, including fatigue, tension, confusion, lower self-esteem, insomnia, and irritability. However, the severity of these symptoms did not reach the level of a clinical diagnosis. Exercise deprivation also consistently resulted in an increase in general anxiety (state anxiety), but no information was provided regarding anxiety disorders based on clinical diagnostic criteria. Regarding general mood symptoms and general well-being, results indicated consistent negative changes in both general mood and wellbeing. The most frequently reported feelings were guilt, irritability, anger, confusion, restlessness, tension, frustration, stress, and sluggishness (loss of vigor).