Psychological dependence

Addiction and dependence glossary^[1]^[2]^[3]
Addiction and dependence glossary
	addiction – a biopsychosocial disorder characterized by persistent use of drugs (including alcohol) despite substantial harm and adverse consequences; addictive drug – psychoactive substances that with repeated use are associated with significantly higher rates of substance use disorders, due in large part to the drug's effect on brain reward systems; dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake); drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose; drug withdrawal – symptoms that occur upon cessation of repeated drug use; physical dependence – dependence that involves persistent physical–somatic withdrawal symptoms (e.g., fatigue and delirium tremens); psychological dependence – dependence socially seen as being extremely mild compared to physical dependence (e.g., with enough willpower it could be overcome); reinforcing stimuli – stimuli that increase the probability of repeating behaviors paired with them; rewarding stimuli – stimuli that the brain interprets as intrinsically positive and desirable or as something to approach; sensitization – an amplified response to a stimulus resulting from repeated exposure to it; substance use disorder – a condition in which the use of substances leads to clinically and functionally significant impairment or distress; tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose;
	v; t; e;

Psychological dependence is a cognitive disorder and a form of dependence that involves emotional–motivational withdrawal symptoms – such as anxiety or anhedonia – upon cessation of prolonged drug use or certain repetitive behaviors.^[4] It develops through consistent and frequent exposure to certain substances or behaviors, which leads to an individual requiring further exposure to avoid experiencing an unpleasant withdrawal syndrome upon cessation (negative reinforcement).^[5]^[6] 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] Environmental enrichment and physical activity can attenuate withdrawal symptoms.^[6]

Symptoms

Psychological withdrawal symptoms include:^[4]^[7]^[8]

Development

Psychological dependence develops through consistent and frequent exposure to a stimulus. After sufficient exposure to a stimulus capable of inducing psychological dependence (e.g., drug use), an adaptive state develops that results in the onset of withdrawal symptoms that negatively affect psychological function upon cessation of exposure.^[4]

Psychostimulants, such as amphetamine or cocaine, are an example of a drug class where only emotional psychological symptoms are observed during withdrawal, as opposed to somatic withdrawal symptoms that characterize cases of physical dependence.^[4] Whilst psychological dependence is often associated with effects of prolonged drug use, the development of a behavioral dependence-withdrawal syndrome is possible. For example, exercise dependence can develop in amateur and professional athletes whereby marked cognitive withdrawal symptoms are experienced during abstinence from physical activity, with the severity of symptoms often intensifying alongside the duration of abstinence.^[8]^[6] Other behaviors that can produce observable psychological withdrawal symptoms (i.e., cause psychological dependence) include shopping, sex and self-stimulation using pornography, and eating food with high sugar or fat content, among others.^[6]

The process responsible for the induction of psychological dependence is a negative feedback mechanism that involves neuronal-counter adaptation, leading to tolerance to the desirable effects of certain drugs or stimuli and a subsequent withdrawal syndrome upon abrupt cessation of exposure.^[5]^[7] While psychological dependence and addiction are distinct disease states mediated by opposite modes of reinforcement, they arise through partially overlapping biological processes.^[5]^[7] In the nucleus accumbens, both conditions involve overlapping signaling cascades that diverge at the CREB transcription factor. Upregulation of CREB expression in the nucleus accumbens plays a major role in mediating psychological dependence by inhibiting reward-related motivational salience, which mediates the onset of emotional-motivational withdrawal symptoms.^[5] Evidence indicates that the unpleasant nature of these withdrawal symptoms intensifies the desire to resume the associated drug or behavior.^[5]

Biomolecular mechanisms

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.^[9]

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.^[10]

Increased expression of AMPA receptors in nucleus accumbens MSNs is a potential mechanism of aversion produced by drug withdrawal.^[11]

Methods for reducing dependence

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.^[12]

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.^[13]

Distinction between psychological and physical dependence

Table 1: Drugs and Their Associated Dependence Syndrome^[4]^{[note 1]}
Physical dependence	Psychological dependence
Alcohols	SSRIs
Opioids	Hallucinogens
Barbiturates	Inhalants
Benzodiazepines	Psychostimulants
Caffeine
Cannabis products

The defining contrast between psychological dependence and physical dependence syndromes lies in the nature of the withdrawal symptoms experienced from removal of a particular stimulus following the development of tolerance.^[4] Psychological dependence is characterized by symptoms that are cognitive in nature and may include anxiety, dysphoria, exhaustion, hyperphagia, or irritability, among other symptoms.^[4]^[5] Conversely, physical dependence involves entirely somatic symptoms, such as diarrhea, myalgia, nausea, sweating, tremors, and other symptoms that are readily observable.^[4]^[14] Substance dependence is a general term that can refer to either psychological or physical dependence, or both, depending on the specific substance involved.^[4]

Notes

^ Substances listed under the physical dependence column are also capable of inducing psychological dependence. Conversely, substances listed under the psychological dependence column do not induce physical dependence.

References

^ ^a ^b Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 364–375. ISBN 9780071481274.
^ Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC 3898681. PMID 24459410. 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.
^ Volkow ND, Koob GF, McLellan AT (January 2016). "Neurobiologic Advances from the Brain Disease Model of Addiction". New England Journal of Medicine. 374 (4): 363–371. doi:10.1056/NEJMra1511480. PMC 6135257. PMID 26816013. 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.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ Malenka RC, Nestler EJ, Hyman SE, Holtzman DM (2015). "Chapter 16: Reinforcement and Addictive Disorders". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (3rd ed.). New York: McGraw-Hill Medical. ISBN 9780071827706. 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.
^ ^a ^b ^c ^d ^e ^f ^g Nestler EJ (2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. doi:10.31887/DCNS.2013.15.4/enestler. PMC 3898681. PMID 24459410. Stimulant and opiate drugs of abuse activate CREB in several brain regions important for addiction, including prominently in the NAc. ...
Drug activation of CREB in NAc has been shown to represent a classic negative feedback mechanism, whereby CREB serves to reduce an animal's sensitivity to the rewarding effects of these drugs (tolerance) and to mediate a negative emotional state during drug withdrawal (dependence). These effects have been shown recently to drive increased drug self-administration and relapse, presumably through a process of negative reinforcement.
^ ^a ^b ^c ^d ^e Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–1122. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101.
^ ^a ^b ^c ^d Koob, George F.; Le Moal, Michel (2008). "Addiction and the brain antireward system". Annual Review of Psychology. 59: 29–53. doi:10.1146/annurev.psych.59.103006.093548. ISSN 0066-4308. PMID 18154498.
^ ^a ^b Weinstein AA, Koehmstedt C, Kop WJ (November 2017). "Mental health consequences of exercise withdrawal: A systematic review". General Hospital Psychiatry. 49: 11–18. doi:10.1016/j.genhosppsych.2017.06.001. ISSN 1873-7714. PMID 28625704. 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).
^ AJ Giannini, RQ Quinones, DM Martin. Role of beta-endorphin and cAMP in addiction and mania. Society for Neuroscience Abstracts. 15:149, 1998.
^ Koob G, Kreek MJ (August 2007). "Stress, dysregulation of drug reward pathways, and the transition to drug dependence". The American Journal of Psychiatry. 164 (8): 1149–59. doi:10.1176/appi.ajp.2007.05030503. PMC 2837343. PMID 17671276.
^ Carlezon WA, Thomas MJ (2009). "Biological substrates of reward and aversion: a nucleus accumbens activity hypothesis". Neuropharmacology. 56 (Suppl 1): 122–32. doi:10.1016/j.neuropharm.2008.06.075. PMC 2635333. PMID 18675281.
^ Hammami-Abrand Abadi, Arezoo; Miladi-Gorji, Hossein; Bigdeli, Imanollah (April 2016). "Effect of environmental enrichment on physical and psychological dependence signs and voluntary morphine consumption in morphine-dependent and morphine-withdrawn rats". Behavioural Pharmacology. 27 (2 and 3 - Special Issue): 270–278. doi:10.1097/fbp.0000000000000197. ISSN 0955-8810. PMID 26397757. S2CID 11212134.
^ Fadaei, Atefeh; Gorji, Hossein Miladi; Hosseini, Shahrokh Makvand (2015-01-15). "Swimming reduces the severity of physical and psychological dependence and voluntary morphine consumption in morphine dependent rats". European Journal of Pharmacology. 747: 88–95. doi:10.1016/j.ejphar.2014.11.042. ISSN 1879-0712. PMID 25498794.
^ Volkow ND, Bianco C (2020-01-02). "Medications for opioid use disorders: clinical and pharmacological considerations". The Journal of Clinical Investigation. 130 (1). doi:10.1172/JCI134708. PMC 6934219. PMID 31763992.

[Dependencetable-14] Substances listed under the physical dependence column are also capable of inducing psychological dependence. Conversely, substances listed under the psychological dependence column do not induce physical dependence.

[Addiction_glossary-1] Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 364–375. ISBN 9780071481274.

[Cellular_basis-2] Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC 3898681. PMID 24459410. 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.

[Brain_disease-3] Volkow ND, Koob GF, McLellan AT (January 2016). "Neurobiologic Advances from the Brain Disease Model of Addiction". New England Journal of Medicine. 374 (4): 363–371. doi:10.1056/NEJMra1511480. PMC 6135257. PMID 26816013. 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.

[NHMH_3e-Physical_withdrawal_and_psychostimulant_dependence-4] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ Malenka RC, Nestler EJ, Hyman SE, Holtzman DM (2015). "Chapter 16: Reinforcement and Addictive Disorders". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (3rd ed.). New York: McGraw-Hill Medical. ISBN 9780071827706. 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.

[:1-5] ^ ^a ^b ^c ^d ^e ^f ^g Nestler EJ (2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. doi:10.31887/DCNS.2013.15.4/enestler. PMC 3898681. PMID 24459410. Stimulant and opiate drugs of abuse activate CREB in several brain regions important for addiction, including prominently in the NAc. ...
Drug activation of CREB in NAc has been shown to represent a classic negative feedback mechanism, whereby CREB serves to reduce an animal's sensitivity to the rewarding effects of these drugs (tolerance) and to mediate a negative emotional state during drug withdrawal (dependence). These effects have been shown recently to drive increased drug self-administration and relapse, presumably through a process of negative reinforcement.

[Natural_and_drug_addictions-6] Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–1122. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101.

[:5-7] Koob, George F.; Le Moal, Michel (2008). "Addiction and the brain antireward system". Annual Review of Psychology. 59: 29–53. doi:10.1146/annurev.psych.59.103006.093548. ISSN 0066-4308. PMID 18154498.

[:8-8] Weinstein AA, Koehmstedt C, Kop WJ (November 2017). "Mental health consequences of exercise withdrawal: A systematic review". General Hospital Psychiatry. 49: 11–18. doi:10.1016/j.genhosppsych.2017.06.001. ISSN 1873-7714. PMID 28625704. 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).

[9] AJ Giannini, RQ Quinones, DM Martin. Role of beta-endorphin and cAMP in addiction and mania. Society for Neuroscience Abstracts. 15:149, 1998.

[Koob_and_Kreek-10] Koob G, Kreek MJ (August 2007). "Stress, dysregulation of drug reward pathways, and the transition to drug dependence". The American Journal of Psychiatry. 164 (8): 1149–59. doi:10.1176/appi.ajp.2007.05030503. PMC 2837343. PMID 17671276.

[11] Carlezon WA, Thomas MJ (2009). "Biological substrates of reward and aversion: a nucleus accumbens activity hypothesis". Neuropharmacology. 56 (Suppl 1): 122–32. doi:10.1016/j.neuropharm.2008.06.075. PMC 2635333. PMID 18675281.

[:2-12] Hammami-Abrand Abadi, Arezoo; Miladi-Gorji, Hossein; Bigdeli, Imanollah (April 2016). "Effect of environmental enrichment on physical and psychological dependence signs and voluntary morphine consumption in morphine-dependent and morphine-withdrawn rats". Behavioural Pharmacology. 27 (2 and 3 - Special Issue): 270–278. doi:10.1097/fbp.0000000000000197. ISSN 0955-8810. PMID 26397757. S2CID 11212134.

[:3-13] Fadaei, Atefeh; Gorji, Hossein Miladi; Hosseini, Shahrokh Makvand (2015-01-15). "Swimming reduces the severity of physical and psychological dependence and voluntary morphine consumption in morphine dependent rats". European Journal of Pharmacology. 747: 88–95. doi:10.1016/j.ejphar.2014.11.042. ISSN 1879-0712. PMID 25498794.

[15] Volkow ND, Bianco C (2020-01-02). "Medications for opioid use disorders: clinical and pharmacological considerations". The Journal of Clinical Investigation. 130 (1). doi:10.1172/JCI134708. PMC 6934219. PMID 31763992.

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