Treatment and management of addiction

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Treatment and management of addiction encompass the range of approaches aimed at helping individuals overcome addiction, most commonly in the form of substance use disorders and behavioral addictions. Effective treatment often includes a combination of medical, psychological, and social interventions tailored to the specific needs of the individual. Common practices to this end include detoxification, counseling, behavioral therapy, medication-assisted treatment, and support groups. The goal of addiction treatment is to reduce dependence, improve quality of life, and ultimately support long-term recovery. Comprehensive management addresses both the physical and psychological aspects of addiction, recognizing it as a chronic but treatable condition.

Contents

To be effective, treatment for addiction that is pharmacological or biologically based need to be accompanied by other interventions such as cognitive behavioral therapy (CBT), individual and group psychotherapy, behavior modification strategies, twelve-step programs, and residential treatment facilities. [1] [2] The TTM can be used to determine when treatment can begin and which method will be most effective. If treatment begins too early, it can cause a person to become defensive and resistant to change. [3] [4]

A biosocial approach to the treatment of addiction brings to the fore the social determinants of illness and wellbeing and considers the dynamic and reciprocal relationships that exist for, and influence, the individual's experience. [5]

The work of A.V. Schlosser (2018) aims to pronounce the individual lived experiences of women receiving medication-assisted treatment (e.g., methadone, naltrexone, burprenorphine) in a long-term rehabilitation setting, through a twenty month long ethnographic fieldwork investigation. This person-centered research shows how the experiences of these women "emerge from stable systems of inequality based in intersectional gender, race, and class marginalization entangled with processes of intra-action." [6] Viewing addiction treatment through this lens highlights the importance of framing clients' own bodies as "social flesh". As Schlosser (2018) points out, "client bodies" as well as the "embodied experiences of self and social belonging emerge in and through the structures, temporalities, and expectations of the treatment centre." [6]

Biotechnologies make up a large portion of the future treatments for addiction [7] including deep-brain stimulation, agonist and antagonist implants and hapten conjugate vaccines. Vaccinations against addiction specifically overlaps with the belief that memory plays a large role in the damaging effects of addiction and relapses.[ medical citation needed ] Hapten conjugate vaccines are designed to block opioid receptors in one area, while allowing other receptors to behave normally. Essentially, once a high can no longer be achieved in relation to a traumatic event, the relation of drugs to a traumatic memory can be disconnected and therapy can play a role in treatment. [8]

Behavioral therapy

CBT proposes four assumptions essential to the approach to treatment: addiction is a learned behavior, it emerges in an environmental context, it is developed and maintained by particular thought patterns and processes, and CBT can be integrated well with other treatment and management approaches as they all have similar goals. [3] CBT, (e.g., relapse prevention), motivational interviewing, and a community reinforcement approach are effective interventions with moderate effect sizes. [9]

Interventions focusing on impulsivity and sensation seeking are successful in decreasing substance use. [10] Cue exposure uses ideas from classical conditioning theory to change the learned behavioral response of someone addicted to a cue or trigger. Contingency management uses ideas from operant conditioning to use meaningful positive reinforcements to influence addiction behaviors towards sobriety. [3]

Addiction recovery groups draw on different methods and models and rely on the success of vicarious learning, where people imitate behavior they observe as rewarding among their own social group or status as well as those perceived as being of a higher status. [3]

Substance addiction in children is complex and requires multifacted behavioral therapy. Family therapy and school-based interventions have had minor but lasting results. Innovative treatments are still needed for areas where relevant therapies are unavailable. [2]

Consistent aerobic exercise, especially endurance exercise (e.g., marathon running), prevents the development of certain drug addictions and is an effective adjunct treatment for drug addiction, and for psychostimulant addiction in particular. [11] [12] [13] [14] [15] Consistent aerobic exercise magnitude-dependently (i.e., by duration and intensity) reduces drug addiction risk, which appears to occur through the reversal of drug induced addiction-related neuroplasticity. [11] [13] Exercise may prevent the development of drug addiction by altering ΔFosB or c-Fos immunoreactivity in the striatum or other parts of the reward system. [15] Aerobic exercise decreases drug self-administration, reduces the likelihood of relapse, and induces opposite effects on striatal dopamine receptor D2 (DRD2) signaling (increased DRD2 density) to those induced by addictions to several drug classes (decreased DRD2 density). [11] [13] Consequently, consistent aerobic exercise may lead to better treatment outcomes when used as an adjunct treatment for drug addiction. [11] [13] [14]

With a combination of tools such as behavioral therapy, a balanced lifestyle, and individualized relapse plans, relapse is can be more successfully avoided. [3]

Medication

Alcohol addiction

Alcohol, like opioids, can induce a severe state of physical dependence and produce withdrawal symptoms such as delirium tremens . Because of this, treatment for alcohol addiction usually involves a combined approach dealing with dependence and addiction simultaneously. Benzodiazepines have the largest and the best evidence base in the treatment of alcohol withdrawal and are considered the gold standard of alcohol detoxification. [16]

Pharmacological treatments for alcohol addiction include drugs like naltrexone (opioid antagonist), disulfiram, acamprosate, and topiramate. [17] [18] Rather than substituting for alcohol, these drugs are intended to affect the desire to drink, either by directly reducing cravings as with acamprosate and topiramate, or by producing unpleasant effects when alcohol is consumed, as with disulfiram. These drugs can be effective if treatment is maintained, but compliance can be an issue as patients with disordered alcohol use may forget to take their medication, or discontinue use because of excessive side effects. [19] [20] The opioid antagonist naltrexone has been shown to be an effective treatment for alcoholism, with the effects lasting three to twelve months after the end of treatment. [21]

Behavioral addictions

Behavioral addiction is a treatable condition. [22] Treatment options include psychotherapy and psychopharmacotherapy (i.e., medications) or a combination of both. Cognitive behavioral therapy (CBT) is the most common form of psychotherapy used in treating behavioral addictions; it focuses on identifying patterns that trigger compulsive behavior and making lifestyle changes to promote healthier behaviors. Because cognitive behavioral therapy is considered a short-term therapy, the number of sessions for treatment normally ranges from five to twenty. [23] During the session, therapists will lead patients through the topics of identifying the issue, becoming aware of one's thoughts surrounding the issue, identifying any negative or false thinking, and reshaping said negative and false thinking. While CBT does not cure behavioral addiction, it does help with coping with the condition in a healthy way. Currently, there are no medications approved for treatment of behavioral addictions in general, but some medications used for treatment of drug addiction may also be beneficial with specific behavioral addictions. [24] [25]

Cannabinoid addiction

The development of CB1 receptor agonists that have reduced interaction with β-arrestin 2 signaling might be therapeutically useful. [26] As of 2019, there has been some evidence of effective pharmacological interventions for cannabinoid addiction, but none have been approved. [27]

Nicotine addiction

Transdermal patch used in nicotine replacement therapy Nicoderm.JPG
Transdermal patch used in nicotine replacement therapy

Another area in which drug treatment has been widely used is in the treatment of nicotine addiction, which usually involves the use of nicotine replacement therapy, nicotinic receptor antagonists, and/or nicotinic receptor partial agonists. [28] [29] Examples of drugs that act on nicotinic receptors and have been used for treating nicotine addiction include antagonists like bupropion and the partial agonist varenicline. [28] [29] Cytisine, a partial agonist, is an effective, and affordable cessation treatment for smokers. [30] When access to varenicline and nicotine replacement therapy is limited (due to availability or cost), cytisine is considered the first line of treatment for smoking cessation. [30]

Opioid addiction

Opioids cause physical dependence and treatment typically addresses both dependence and addiction. Physical dependence is treated using replacement drugs such as buprenorphine (the active ingredient in products such as Suboxone and Subutex) and methadone. [31] [32] Although these drugs perpetuate physical dependence, the goal of opiate maintenance is to provide a measure of control over both pain and cravings. Use of replacement drugs increases the addicted individual's ability to function normally and eliminates the negative consequences of obtaining controlled substances illicitly. Once a prescribed dosage is stabilized, treatment enters maintenance or tapering phases. In the United States, opiate replacement therapy is tightly regulated in methadone clinics and under the DATA 2000 legislation. In some countries, other opioid derivatives such as dihydrocodeine, [33] dihydroetorphine [34] and even heroin [35] [36] are used as substitute drugs for illegal street opiates, with different prescriptions being given depending on the needs of the individual patient. Baclofen has led to successful reductions of cravings for stimulants, alcohol, and opioids and alleviates alcohol withdrawal syndrome. Many patients have stated they "became indifferent to alcohol" or "indifferent to cocaine" overnight after starting baclofen therapy. [37] Some studies show the interconnection between opioid drug detoxification and overdose mortality. [38]

Psychostimulant addiction

There is no effective and FDA- or EMA-approved pharmacotherapy for any form of psychostimulant addiction. [39] Experimental TAAR1-selective agonists have significant therapeutic potential as a treatment for psychostimulant addictions. [40]

Research

Anti-drug vaccines (active immunizations) for treatment of cocaine and nicotine addictions were successful in animal studies. Vaccines tested on humans have been shown as safe with mild to moderate side effects, though did not have firm results confirming efficacy despite producing expected antibodies. [41] Vaccines which use anti-drug monoclonal antibodies (passive immunization) can mitigate drug-induced positive reinforcement by preventing the drug from moving across the blood–brain barrier. [42] Current[ as of? ] vaccine-based therapies are only effective in a relatively small subset of individuals. [42] [43] As of November 2015, vaccine-based therapies are being tested in human clinical trials as a treatment for addiction and preventive measure against drug overdoses involving nicotine, cocaine, and methamphetamine. [42] The study shows that the vaccine may save lives during a drug overdose. In this instance, the idea is that the body will respond to the vaccine by quickly producing antibodies to prevent the opioids from accessing the brain. [44]

Since addiction involves abnormalities in glutamate and GABAergic neurotransmission, [45] [46] receptors associated with these neurotransmitters (e.g., AMPA receptors, NMDA receptors, and GABAB receptors) are potential therapeutic targets for addictions. [45] [46] [47] [48] N-acetylcysteine, which affects metabotropic glutamate receptors and NMDA receptors, has shown some benefit involving addictions to cocaine, heroin, and cannabinoids. [45] It may be useful as an adjunct therapy for addictions to amphetamine-type stimulants, but more clinical research is required. [45]

Current medical reviews of research involving lab animals have identified a drug class – class I histone deacetylase inhibitors [note 1] – that indirectly inhibits the function and further increases in the expression of accumbal ΔFosB by inducing G9a expression in the nucleus accumbens after prolonged use. [51] [52] [49] [50] These reviews and subsequent preliminary evidence which used oral administration or intraperitoneal administration of the sodium salt of butyric acid or other class I HDAC inhibitors for an extended period indicate that these drugs have efficacy in reducing addictive behavior in lab animals [note 2] that have developed addictions to ethanol, psychostimulants (i.e., amphetamine and cocaine), nicotine, and opiates. [52] [50] [53] [54] Few clinical trials involving humans with addictions and any HDAC class I inhibitors have been conducted to test for treatment efficacy in humans or identify an optimal dosing regimen. [note 3]

Gene therapy for addiction is an active area of research. One line of gene therapy research involves the use of viral vectors to increase the expression of dopamine D2 receptor proteins in the brain. [56] [57] [58] [59] [60]

See also

Notes

  1. ↑ Inhibitors of class I histone deacetylase (HDAC) enzymes are drugs that inhibit four specific histone-modifying enzymes: HDAC1, HDAC2, HDAC3, and HDAC8. Most of the animal research with HDAC inhibitors has been conducted with four drugs: butyrate salts (mainly sodium butyrate), trichostatin A, valproic acid, and SAHA; [49] [50] butyric acid is a naturally occurring short-chain fatty acid in humans, while the latter two compounds are FDA-approved drugs with medical indications unrelated to addiction.
  2. ↑ Specifically, prolonged administration of a class I HDAC inhibitor appears to reduce an animal's motivation to acquire and use an addictive drug without affecting an animals motivation to attain other rewards (i.e., it does not appear to cause motivational anhedonia) and reduce the amount of the drug that is self-administered when it is readily available. [52] [50] [53]
  3. ↑ Among the few clinical trials that employed a class I HDAC inhibitor, one used valproate for methamphetamine addiction. [55]
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    References

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    10. ↑ Maxwell AL, Gardiner E, Loxton NJ (9 February 2020). "Investigating the relationship between reward sensitivity, impulsivity, and food addiction: A systematic review". European Eating Disorders Review. 28 (4): 368–384. doi:10.1002/erv.2732. ISSN   1099-0968. PMID   32142199. S2CID   212565361 . Retrieved 9 March 2023.
    11. 1 2 3 4 Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC   3139704 . PMID   21459101. Functional neuroimaging studies in humans have shown that gambling (Breiter et al, 2001), shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004), playing video games (Koepp et al, 1998; Hoeft et al, 2008) and the sight of appetizing food (Wang et al, 2004a) activate many of the same brain regions (i.e., the mesocorticolimbic system and extended amygdala) as drugs of abuse (Volkow et al, 2004). ... Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some people taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)."
      Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers"
    12. ↑ Carroll ME, Smethells JR (February 2016). "Sex Differences in Behavioral Dyscontrol: Role in Drug Addiction and Novel Treatments". Front. Psychiatry. 6: 175. doi: 10.3389/fpsyt.2015.00175 . PMC   4745113 . PMID   26903885. Environmental Enrichment ...
      In humans, non-drug rewards delivered in a contingency management (CM) format successfully reduced drug dependence ... In general, CM programs promote drug abstinence through a combination of positive reinforcement for drug-free urine samples. For instance, voucher-based reinforcement therapy in which medication compliance, therapy session attendance, and negative drug screenings reinforced with vouchers to local business (e.g., movie theater, restaurants, etc.) directly reinforces drug abstinence, provides competing reinforcers, enriches the environment, and it is a robust treatment across a broad range of abused drugs (189). ...
      Physical Exercise
      There is accelerating evidence that physical exercise is a useful treatment for preventing and reducing drug addiction ... In some individuals, exercise has its own rewarding effects, and a behavioral economic interaction may occur, such that physical and social rewards of exercise can substitute for the rewarding effects of drug abuse. ... The value of this form of treatment for drug addiction in laboratory animals and humans is that exercise, if it can substitute for the rewarding effects of drugs, could be self-maintained over an extended period of time. Work to date in [laboratory animals and humans] regarding exercise as a treatment for drug addiction supports this hypothesis. ... However, a RTC study was recently reported by Rawson et al. (226), whereby they used 8 weeks of exercise as a post-residential treatment for METH addiction, showed a significant reduction in use (confirmed by urine screens) in participants who had been using meth 18 days or less a month. ... Animal and human research on physical exercise as a treatment for stimulant addiction indicates that this is one of the most promising treatments on the horizon. [(emphasis added)]
    13. 1 2 3 4 Lynch WJ, Peterson AB, Sanchez V, Abel J, Smith MA (September 2013). "Exercise as a novel treatment for drug addiction: a neurobiological and stage-dependent hypothesis". Neurosci Biobehav Rev. 37 (8): 1622–44. doi:10.1016/j.neubiorev.2013.06.011. PMC   3788047 . PMID   23806439. [exercise] efficacy may be related to its ability to normalize glutamatergic and dopaminergic signaling and reverse drug-induced changes in chromatin via epigenetic interactions with brain-derived neurotrophic factor (BDNF) in the reward pathway. ... these data show that exercise can affect dopaminergic signaling at many different levels, which may underlie its ability to modify vulnerability during drug use initiation. Exercise also produces neuroadaptations that may influence an individual's vulnerability to initiate drug use. Consistent with this idea, chronic moderate levels of forced treadmill running blocks not only subsequent methamphetamine-induced conditioned place preference, but also stimulant-induced increases in dopamine release in the NAc (Chen et al., 2008) and striatum (Marques et al., 2008). ... [These] findings indicate the efficacy of exercise at reducing drug intake in drug-dependent individuals ... wheel running [reduces] methamphetamine self-administration under extended access conditions (Engelmann et al., 2013) ... These findings suggest that exercise may "magnitude"-dependently prevent the development of an addicted phenotype possibly by blocking/reversing behavioral and neuro-adaptive changes that develop during and following extended access to the drug. ... Exercise has been proposed as a treatment for drug addiction that may reduce drug craving and risk of relapse. Although few clinical studies have investigated the efficacy of exercise for preventing relapse, the few studies that have been conducted generally report a reduction in drug craving and better treatment outcomes (see Table 4). ... Taken together, these data suggest that the potential benefits of exercise during relapse, particularly for relapse to psychostimulants, may be mediated via chromatin remodeling and possibly lead to greater treatment outcomes.
    14. 1 2 Linke SE, Ussher M (2015). "Exercise-based treatments for substance use disorders: evidence, theory, and practicality". Am J Drug Alcohol Abuse. 41 (1): 7–15. doi:10.3109/00952990.2014.976708. PMC   4831948 . PMID   25397661. The limited research conducted suggests that exercise may be an effective adjunctive treatment for SUDs. In contrast to the scarce intervention trials to date, a relative abundance of literature on the theoretical and practical reasons supporting the investigation of this topic has been published. ... numerous theoretical and practical reasons support exercise-based treatments for SUDs, including psychological, behavioral, neurobiological, nearly universal safety profile, and overall positive health effects.
    15. 1 2 Zhou Y, Zhao M, Zhou C, Li R (July 2015). "Sex differences in drug addiction and response to exercise intervention: From human to animal studies". Front. Neuroendocrinol. 40: 24–41. doi:10.1016/j.yfrne.2015.07.001. PMC   4712120 . PMID   26182835. Collectively, these findings demonstrate that exercise may serve as a substitute or competition for drug abuse by changing ΔFosB or cFos immunoreactivity in the reward system to protect against later or previous drug use. ... As briefly reviewed above, a large number of human and rodent studies clearly show that there are sex differences in drug addiction and exercise. The sex differences are also found in the effectiveness of exercise on drug addiction prevention and treatment, as well as underlying neurobiological mechanisms. The postulate that exercise serves as an ideal intervention for drug addiction has been widely recognized and used in human and animal rehabilitation. ... In particular, more studies on the neurobiological mechanism of exercise and its roles in preventing and treating drug addiction are needed.
    16. ↑ Sachdeva A, Choudhary M, Chandra M (September 2015). "Alcohol Withdrawal Syndrome: Benzodiazepines and Beyond". Journal of Clinical and Diagnostic Research. 9 (9): VE01–VE07. doi:10.7860/JCDR/2015/13407.6538. PMC   4606320 . PMID   26500991.
    17. ↑ Soyka M, Roesner S (December 2006). "New pharmacological approaches for the treatment of alcoholism". Expert Opinion on Pharmacotherapy. 7 (17): 2341–53. doi:10.1517/14656566.7.17.2341. PMID   17109610. S2CID   2587029.
    18. ↑ Pettinati HM, Rabinowitz AR (October 2006). "Choosing the right medication for the treatment of alcoholism". Current Psychiatry Reports. 8 (5): 383–88. doi:10.1007/s11920-006-0040-0. PMID   16968619. S2CID   39826013.
    19. ↑ Bouza C, Angeles M, Magro A, Muñoz A, Amate JM (July 2004). "Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review". Addiction. 99 (7): 811–28. doi:10.1111/j.1360-0443.2004.00763.x. PMID   15200577.
    20. ↑ Williams SH (November 2005). "Medications for treating alcohol dependence". American Family Physician. 72 (9): 1775–80. PMID   16300039.
    21. ↑ Rösner S, Hackl-Herrwerth A, Leucht S, Vecchi S, Srisurapanont M, Soyka M (December 2010). Srisurapanont M (ed.). "Opioid antagonists for alcohol dependence". The Cochrane Database of Systematic Reviews (12): CD001867. doi:10.1002/14651858.CD001867.pub2. PMID   21154349.
    22. ↑ Rosenberg, Kenneth Paul; Feder, Laura Curtiss (2014), "An Introduction to Behavioral Addictions", Behavioral Addictions, Elsevier, pp. 1–17, doi:10.1016/b978-0-12-407724-9.00001-x, ISBN   9780124077249 , retrieved 2023-11-03
    23. ↑ Bannink, F. P. (2013-06-26). "Positive CBT: From Reducing Distress to Building Success". Journal of Contemporary Psychotherapy. 44 (1): 1–8. doi:10.1007/s10879-013-9239-7. ISSN   0022-0116. S2CID   24029889.
    24. ↑ Grant JE, Potenza MN, Weinstein A, Gorelick DA (September 2010). "Introduction to behavioral addictions". Am. J. Drug Alcohol Abuse. 36 (5): 233–241. doi:10.3109/00952990.2010.491884. PMC   3164585 . PMID   20560821. Naltrexone, a mu-opioid receptor antagonist approved by the US Food and Drug Administration for the treatment of alcoholism and opioid dependence, has shown efficacy in controlled clinical trials for the treatment of pathological gambling and kleptomania (76–79), and promise in uncontrolled studies of compulsive buying (80), compulsive sexual behavior (81), internet addiction (82), and pathologic skin picking (83). ... Topiramate, an anti-convulsant which blocks the AMPA subtype of glutamate receptor (among other actions), has shown promise in open-label studies of pathological gambling, compulsive buying, and compulsive skin picking (85), as well as efficacy in reducing alcohol (86), cigarette (87), and cocaine (88) use. N-acetyl cysteine, an amino acid that restores extracellular glutamate concentration in the nucleus accumbens, reduced gambling urges and behavior in one study of pathological gamblers (89), and reduces cocaine craving (90) and cocaine use (91) in cocaine addicts. These studies suggest that glutamatergic modulation of dopaminergic tone in the nucleus accumbens may be a mechanism common to behavioral addiction and substance use disorders (92).
    25. ↑ Better Life Recovery
    26. ↑ Fratta W, Fattore L (August 2013). "Molecular mechanisms of cannabinoid addiction". Curr. Opin. Neurobiol. 23 (4): 487–92. doi:10.1016/j.conb.2013.02.002. PMID   23490548. S2CID   40849553. 14. Nguyen PT, Schmid CL, Raehal KM, Selley DE, Bohn LM, Sim-Selley LJ: b-Arrestin2 regulates cannabinoid CB1 receptor signaling and adaptation in a central nervous system region dependent manner. Biol Psychiatry 2012, 71:714–24.
      A pioneering study revealing both positive and negative modulatory effects of beta-arrestin2 on THC tolerance. By demonstrating that tolerance to antinociception is reduced whereas tolerance to catalepsy is enhanced in beta-arrestin2 knockout mice, authors suggest that development of cannabinoid agonists that minimize interactions between CB1Rs and beta-arrestin2 might produce improved cannabinoid analgesics with reduced motor suppression, and be therapeutically beneficial.
    27. ↑ Sabioni P, Le Foll B (April 2019). "Psychosocial and Pharmacological Interventions for the Treatment of Cannabis Use Disorder". Focus. 17 (2): 163–168. doi:10.1176/appi.focus.17202. PMC   6527000 . PMID   32021586.
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    29. 1 2 Crooks PA, Bardo MT, Dwoskin LP (2014). "Nicotinic Receptor Antagonists as Treatments for Nicotine Abuse". Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse. Advances in Pharmacology. Vol. 69. pp. 513–551. doi:10.1016/B978-0-12-420118-7.00013-5. ISBN   978-0-12-420118-7. PMC   4110698 . PMID   24484986.
    30. 1 2 Tutka P, Vinnikov D, Courtney RJ, Benowitz NL (November 2019). "Cytisine for nicotine addiction treatment: a review of pharmacology, therapeutics and an update of clinical trial evidence for smoking cessation". Addiction. 114 (11): 1951–1969. doi:10.1111/add.14721. PMID   31240783. S2CID   195660208.
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    32. ↑ Connock M, Juarez-Garcia A, Jowett S, Frew E, Liu Z, Taylor RJ, Fry-Smith A, Day E, Lintzeris N, Roberts T, Burls A, Taylor RS (March 2007). "Methadone and buprenorphine for the management of opioid dependence: a systematic review and economic evaluation". Health Technology Assessment. 11 (9): 1–171, iii–iv. doi: 10.3310/hta11090 . PMID   17313907.
    33. ↑ Robertson JR, Raab GM, Bruce M, McKenzie JS, Storkey HR, Salter A (December 2006). "Addressing the efficacy of dihydrocodeine versus methadone as an alternative maintenance treatment for opiate dependence: A randomized controlled trial". Addiction. 101 (12): 1752–9. doi:10.1111/j.1360-0443.2006.01603.x. PMID   17156174.
    34. ↑ Qin BY (1998). "Advances in dihydroetorphine: From analgesia to detoxification". Drug Development Research. 39 (2): 131–34. doi:10.1002/(SICI)1098-2299(199610)39:2<131::AID-DDR3>3.0.CO;2-Q. S2CID   201878290.
    35. ↑ Metrebian N, Shanahan W, Wells B, Stimson GV (June 1998). "Feasibility of prescribing injectable heroin and methadone to opiate-dependent drug users: associated health gains and harm reductions". The Medical Journal of Australia. 168 (12): 596–600. doi:10.5694/j.1326-5377.1998.tb141444.x. PMID   9673620. S2CID   43302721.
    36. ↑ Metrebian N, Mott J, Carnwath Z, Carnwath T, Stimson GV, Sell L (2007). "Pathways into receiving a prescription for diamorphine (heroin) for the treatment of opiate dependence in the United kingdom". European Addiction Research. 13 (3): 144–7. doi:10.1159/000101550. PMID   17570910. S2CID   7397513.
    37. ↑ Kenna GA, Nielsen DM, Mello P, Schiesl A, Swift RM (2007). "Pharmacotherapy of dual substance abuse and dependence". CNS Drugs. 21 (3): 213–37. doi:10.2165/00023210-200721030-00003. PMID   17338593. S2CID   25979050.
    38. ↑ Strang J, McCambridge J, Best D, Beswick T, Bearn J, Rees S, Gossop M (May 2003). "Loss of tolerance and overdose mortality after inpatient opiate detoxification: follow up study". BMJ (Clinical Research Ed.). 326 (7396): 959–60. doi:10.1136/bmj.326.7396.959. PMC   153851 . PMID   12727768.
    39. ↑ Chan B, Freeman M, Kondo K, Ayers C, Montgomery J, Paynter R, Kansagara D (December 2019). "Pharmacotherapy for methamphetamine/amphetamine use disorder-a systematic review and meta-analysis". Addiction. 114 (12): 2122–2136. doi:10.1111/add.14755. PMID   31328345. S2CID   198136436.
    40. ↑ Liu JF, Li JX (December 2018). "Drug addiction: a curable mental disorder?". Acta Pharmacologica Sinica. 39 (12): 1823–1829. doi:10.1038/s41401-018-0180-x. PMC   6289334 . PMID   30382181.
    41. ↑ Scendoni R, Bury E, Ribeiro IA, Cameriere R, Cingolani M (November 2022). "Vaccines as a preventive tool for substance use disorder: A systematic review including a meta-analysis on nicotine vaccines' immunogenicity". Human Vaccines & Immunotherapeutics. 18 (6). doi:10.1080/21645515.2022.2140552. PMC   9746524 . PMID   36351881.
    42. 1 2 3 Zalewska-Kaszubska J (November 2015). "Is immunotherapy an opportunity for effective treatment of drug addiction?". Vaccine. 33 (48): 6545–51. doi:10.1016/j.vaccine.2015.09.079. PMID   26432911.
    43. ↑ Laudenbach M, Baruffaldi F, Vervacke JS, Distefano MD, Titcombe PJ, Mueller DL, Tubo NJ, Griffith TS, Pravetoni M (June 2015). "The frequency of naive and early-activated hapten-specific B cell subsets dictates the efficacy of a therapeutic vaccine against prescription opioid abuse". J. Immunol. 194 (12): 5926–36. doi:10.4049/jimmunol.1500385. PMC   4458396 . PMID   25972483. Translation of therapeutic vaccines for addiction, cancer, or other chronic noncommunicable diseases has been slow because only a small subset of immunized subjects achieved effective Ab levels.
    44. ↑ Painter A. (2019) "Researchers working to develop vaccines to fight opioid addiction" Vtnews.vt.edu
    45. 1 2 3 4 Cao DN, Shi JJ, Hao W, Wu N, Li J (March 2016). "Advances and challenges in pharmacotherapeutics for amphetamine-type stimulants addiction". Eur. J. Pharmacol. 780: 129–35. doi:10.1016/j.ejphar.2016.03.040. PMID   27018393.
    46. 1 2 Moeller SJ, London ED, Northoff G (February 2016). "Neuroimaging markers of glutamatergic and GABAergic systems in drug addiction: Relationships to resting-state functional connectivity". Neurosci Biobehav Rev. 61: 35–52. doi:10.1016/j.neubiorev.2015.11.010. PMC   4731270 . PMID   26657968.
    47. ↑ Agabio R, Colombo G (April 2015). "[GABAB receptor as therapeutic target for drug addiction: from baclofen to positive allosteric modulators]". Psychiatr. Pol. (in Polish). 49 (2): 215–23. doi: 10.12740/PP/33911 . hdl: 11584/102912 . PMID   26093587.
    48. ↑ Filip M, Frankowska M, Sadakierska-Chudy A, Suder A, Szumiec L, Mierzejewski P, Bienkowski P, Przegaliński E, Cryan JF (January 2015). "GABAB receptors as a therapeutic strategy in substance use disorders: focus on positive allosteric modulators". Neuropharmacology. 88: 36–47. doi:10.1016/j.neuropharm.2014.06.016. PMID   24971600. S2CID   207229988.
    49. 1 2 McCowan TJ, Dhasarathy A, Carvelli L (February 2015). "The Epigenetic Mechanisms of Amphetamine". J. Addict. Prev. 2015 (Suppl 1). PMC   4955852 . PMID   27453897. Epigenetic modifications caused by addictive drugs play an important role in neuronal plasticity and in drug-induced behavioral responses. Although few studies have investigated the effects of AMPH on gene regulation (Table 1), current data suggest that AMPH acts at multiple levels to alter histone/DNA interaction and to recruit transcription factors which ultimately cause repression of some genes and activation of other genes. Importantly, some studies have also correlated the epigenetic regulation induced by AMPH with the behavioral outcomes caused by this drug, suggesting therefore that epigenetics remodeling underlies the behavioral changes induced by AMPH. If this proves to be true, the use of specific drugs that inhibit histone acetylation, methylation or DNA methylation might be an important therapeutic alternative to prevent and/or reverse AMPH addiction and mitigate the side effects generate by AMPH when used to treat ADHD.
    50. 1 2 3 4 Walker DM, Cates HM, Heller EA, Nestler EJ (February 2015). "Regulation of chromatin states by drugs of abuse". Curr. Opin. Neurobiol. 30: 112–21. doi:10.1016/j.conb.2014.11.002. PMC   4293340 . PMID   25486626. Studies investigating general HDAC inhibition on behavioral outcomes have produced varying results but it seems that the effects are specific to the timing of exposure (either before, during or after exposure to drugs of abuse) as well as the length of exposure
    51. ↑ Biliński P, Wojtyła A, Kapka-Skrzypczak L, Chwedorowicz R, Cyranka M, Studziński T (2012). "Epigenetic regulation in drug addiction". Ann. Agric. Environ. Med. 19 (3): 491–96. PMID   23020045. [...]ΔFosB is considered a primary and causative transcription factor in creating new neural connections in the reward centre, prefrontal cortex, and other regions of the limbic system. This is reflected in the increased, stable and long-lasting level of sensitivity to cocaine and other drugs, and tendency to relapse even after long periods of abstinence.
    52. 1 2 3 Nestler EJ (January 2014). "Epigenetic mechanisms of drug addiction". Neuropharmacology. 76 (Pt B): 259–68. doi:10.1016/j.neuropharm.2013.04.004. PMC   3766384 . PMID   23643695. Short-term increases in histone acetylation generally promote behavioral responses to the drugs, while sustained increases oppose cocaine's effects, based on the actions of systemic or intra-NAc administration of HDAC inhibitors. ... Genetic or pharmacological blockade of G9a in the NAc potentiates behavioral responses to cocaine and opiates, whereas increasing G9a function exerts the opposite effect (Maze et al., 2010; Sun et al., 2012a). Such drug-induced downregulation of G9a and H3K9me2 also sensitizes animals to the deleterious effects of subsequent chronic stress (Covington et al., 2011). Downregulation of G9a increases the dendritic arborization of NAc neurons, and is associated with increased expression of numerous proteins implicated in synaptic function, which directly connects altered G9a/H3K9me2 in the synaptic plasticity associated with addiction (Maze et al., 2010).
      G9a appears to be a critical control point for epigenetic regulation in NAc, as we know it functions in two negative feedback loops. It opposes the induction of ΔFosB, a long-lasting transcription factor important for drug addiction (Robison and Nestler, 2011), while ΔFosB in turn suppresses G9a expression (Maze et al., 2010; Sun et al., 2012a). ... Also, G9a is induced in NAc upon prolonged HDAC inhibition, which explains the paradoxical attenuation of cocaine's behavioral effects seen under these conditions, as noted above (Kennedy et al., 2013). GABAA receptor subunit genes are among those that are controlled by this feedback loop. Thus, chronic cocaine, or prolonged HDAC inhibition, induces several GABAA receptor subunits in NAc, which is associated with increased frequency of inhibitory postsynaptic currents (IPSCs). In striking contrast, combined exposure to cocaine and HDAC inhibition, which triggers the induction of G9a and increased global levels of H3K9me2, leads to blockade of GABAA receptor and IPSC regulation.
    53. 1 2 Primary references involving sodium butyrate:
       •Kennedy PJ, Feng J, Robison AJ, Maze I, Badimon A, Mouzon E, Chaudhury D, Damez-Werno DM, Haggarty SJ, Han MH, Bassel-Duby R, Olson EN, Nestler EJ (April 2013). "Class I HDAC inhibition blocks cocaine-induced plasticity by targeted changes in histone methylation". Nat. Neurosci. 16 (4): 434–40. doi:10.1038/nn.3354. PMC   3609040 . PMID   23475113. While acute HDAC inhibition enhances the behavioral effects of cocaine or amphetamine1,3,4,13,14, studies suggest that more chronic regimens block psychostimulant-induced plasticity3,5,11,12. ... The effects of pharmacological inhibition of HDACs on psychostimulant-induced plasticity appear to depend on the timecourse of HDAC inhibition. Studies employing co-administration procedures in which inhibitors are given acutely, just prior to psychostimulant administration, report heightened behavioral responses to the drug1,3,4,13,14. In contrast, experimental paradigms like the one employed here, in which HDAC inhibitors are administered more chronically, for several days prior to psychostimulant exposure, show inhibited expression3 or decreased acquisition of behavioral adaptations to drug5,11,12. The clustering of seemingly discrepant results based on experimental methodologies is interesting in light of our present findings. Both HDAC inhibitors and psychostimulants increase global levels of histone acetylation in NAc. Thus, when co-administered acutely, these drugs may have synergistic effects, leading to heightened transcriptional activation of psychostimulant-regulated target genes. In contrast, when a psychostimulant is given in the context of prolonged, HDAC inhibitor-induced hyperacetylation, homeostatic processes may direct AcH3 binding to the promoters of genes (e.g., G9a) responsible for inducing chromatin condensation and gene repression (e.g., via H3K9me2) to dampen already heightened transcriptional activation. Our present findings thus demonstrate clear cross talk among histone PTMs and suggest that decreased behavioral sensitivity to psychostimulants following prolonged HDAC inhibition might be mediated through decreased activity of HDAC1 at H3K9 KMT promoters and subsequent increases in H3K9me2 and gene repression.
       •Simon-O'Brien E, Alaux-Cantin S, Warnault V, Buttolo R, Naassila M, Vilpoux C (July 2015). "The histone deacetylase inhibitor sodium butyrate decreases excessive ethanol intake in dependent animals". Addict Biol. 20 (4): 676–89. doi:10.1111/adb.12161. PMID   25041570. S2CID   28667144. Altogether, our results clearly demonstrated the efficacy of NaB in preventing excessive ethanol intake and relapse and support the hypothesis that HDACi may have a potential use in alcohol addiction treatment.
       •Castino MR, Cornish JL, Clemens KJ (April 2015). "Inhibition of histone deacetylases facilitates extinction and attenuates reinstatement of nicotine self-administration in rats". PLOS ONE. 10 (4): e0124796. Bibcode:2015PLoSO..1024796C. doi: 10.1371/journal.pone.0124796 . PMC   4399837 . PMID   25880762. treatment with NaB significantly attenuated nicotine and nicotine + cue reinstatement when administered immediately ... These results provide the first demonstration that HDAC inhibition facilitates the extinction of responding for an intravenously self-administered drug of abuse and further highlight the potential of HDAC inhibitors in the treatment of drug addiction.
    54. ↑ Kyzar EJ, Pandey SC (August 2015). "Molecular mechanisms of synaptic remodeling in alcoholism". Neurosci. Lett. 601: 11–19. doi:10.1016/j.neulet.2015.01.051. PMC   4506731 . PMID   25623036. Increased HDAC2 expression decreases the expression of genes important for the maintenance of dendritic spine density such as BDNF, Arc, and NPY, leading to increased anxiety and alcohol-seeking behavior. Decreasing HDAC2 reverses both the molecular and behavioral consequences of alcohol addiction, thus implicating this enzyme as a potential treatment target (Fig. 3). HDAC2 is also crucial for the induction and maintenance of structural synaptic plasticity in other neurological domains such as memory formation [115]. Taken together, these findings underscore the potential usefulness of HDAC inhibition in treating alcohol use disorders ... Given the ability of HDAC inhibitors to potently modulate the synaptic plasticity of learning and memory [118], these drugs hold potential as treatment for substance abuse-related disorders. ... Our lab and others have published extensively on the ability of HDAC inhibitors to reverse the gene expression deficits caused by multiple models of alcoholism and alcohol abuse, the results of which were discussed above [25,112,113]. This data supports further examination of histone modifying agents as potential therapeutic drugs in the treatment of alcohol addiction ... Future studies should continue to elucidate the specific epigenetic mechanisms underlying compulsive alcohol use and alcoholism, as this is likely to provide new molecular targets for clinical intervention.
    55. ↑ Kheirabadi GR, Ghavami M, Maracy MR, Salehi M, Sharbafchi MR (2016). "Effect of add-on valproate on craving in methamphetamine depended patients: A randomized trial". Advanced Biomedical Research. 5: 149. doi: 10.4103/2277-9175.187404 . PMC   5025910 . PMID   27656618.
    56. ↑ "Gene Therapy For Addiction: Flooding Brain With 'Pleasure Chemical' Receptors Works On Cocaine, As On Alcohol". Sciencedaily.
    57. ↑ "Gene Transfer Therapy for Cocaine Addiction Passes Tests in Animals". National Institute on Drug Abuse. 14 January 2016. Archived from the original on 27 November 2020. Retrieved 25 June 2017.
    58. ↑ Murthy V, Gao Y, Geng L, LeBrasseur NK, White TA, Parks RJ, Brimijoin S (2014). "Physiologic and metabolic safety of butyrylcholinesterase gene therapy in mice". Vaccine. 32 (33): 4155–62. doi:10.1016/j.vaccine.2014.05.067. PMC   4077905 . PMID   24892251.
    59. ↑ "Using Adeno-Associated Virus (AAV) Mediated Sustained Expression of an Anti-methamphetamine Antibody Fragment to Alter Methamphetamine Disposition in Mice" (PDF). Archived from the original (PDF) on 3 March 2018. Retrieved 25 June 2017.
    60. ↑ "ATTC – Addiction Science Made Easy". www.attcnetwork.org. Archived from the original on 27 September 2018. Retrieved 25 June 2017.
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