Role of neurochemistry of substance use on treatment considerations

 

Invited Review Article 

Role of Neurochemistry of Substance Use on Treatment Considerations 


Amrita Pain,1 Rajinder K. Dhamija2 

1Assistant Professor, Human Behavior Department, IHBAS, Delhi 2Director, IHBAS, Delhi 

Address for Correspondence: Email: a.pain.psyd@gmail.com 


ABSTRACT 

Understanding the neurochemical mechanism in substance use disorders have a two- fold role  in  identifying  and understanding brain circuits,  neural  connections  and neuroplasticity following substance use that aids tolerance, dependence, relapse and difficulties with abstinence along with possible implications on pharmacotherapy. Key neurotransmitters that  are  implicated in  these  neuroadaptations include  dopamine, enkephalins, glutamate, ã-aminobutyric acid, norepinephrine, corticotropin-releasing factor (CRF), dynorphin, neuropeptide Y and endocannabinoids. This review aims to explore neurochemistry in substance use disorders along with factors that may contribute to treatment considerations in dependence disorders. 

Keywords: neurochemistry, neuroadaptations, intervention challenges in substance use disorder  


INTRODUCTION 

There is a disparity between the prevalence and  incidence  rates  of  substance  use  across varying  socio-demographic  communities  and those  with  substance  use  disorders  (SUD) approaching  treatment.  The  possibility  of substance-related  concerns such as behaviour problems or academic decline among juveniles and crimes under the influence of a substance and socio-occupational distress in adults may be the  primary  reason  for  referrals  to  a detoxification/rehabilitation clinic. For instance, there are more than 1 million incarcerated adults who are serving  time for  offences  committed under the influence of substances (van Wormer and Davis, 2017); India has seen an 11% increase in conviction rates for crimes committed under the influence of substances in 2020 in comparison to  the  last  4  years according  to  the  National Crime Records Bureau, 2020 (Rai, 2021); nearly 86%  of  a  sample  of  detained  juveniles  in  a shortstay observation home in Delhi had a history of  substance  use  (Sharma,  Sharma  and Barkataki, 2016). Alcohol is a common substance of use in India with a 1:17 ratio of women to men with reported alcohol use (Ambekar et al., 2019). A report issued by the Ministry of Social Justice  and  Empowerment; India (PIB,  2021) suggested  approximately 700  deaths owing to substance  overdose  across  all  ages  in  2019. Factors  determining  substance  use  and developing dependence are an interplay of genetic  factors, developmental factors (e.g.: adolescents are at greater risk for developing substance use) and environmental (e.g.: peer pressure, genders are  prone  to  developing  use  (NIDA,  2022). Studies on the metabolism of substances between genders have highlighted that women are more susceptible to feelings of craving (Robbins et al., 1999; Hitschfeld et al., 2015; Fox, Morgan and Sinha, 2014), developing dependence quickly and experiencing substance-related health concerns more rapidly and frequently than men (CASA, 2006) as well as higher relapse (NIDA, 2022). Ethnicity  has  been  associated  with  specific patterns of use and outcomes (McCabe et al., 2007).  Those  who  are  homeless  have  been reported to have higher rates of substance abuse than those who are not experiencing homelessness (Shearer et al., 2022). 

Neurochemical mechanisms in substance use As  a  biopsychosocial  disorder,  SUD  is understood as a chronic disorder of brain reward, motivations,  memory  and  related  circuitry reflected  in  specific biological, psychological, social  and  even  spiritual  manifestations. Individuals with substance use disorders show characteristic  patterns of  seeking rewards or relief  through  substance  use  and  related behaviours (e.g.: truancy  from  school  to  use, engaging  with  peers  who  use  substances, choosing  time  in  isolation  to  avoid  aversive consequences  of  long-term substance  use and continuing to  use). Definitions  and  diagnostic clarifications help  in  the accuracy of medical communication. An  understanding  of  the neurochemistry of addiction can help enhance patient education to understand the process of use  as  an  influence  of  biological  and environmental factors to help engage both the patient and their primary caregiver in treatment. 

Neuroadaptations  occurring  in  the basal ganglia, extended amygdala and prefrontal cortex over time with substance use play a role in the development and maintenance of substance use disorders (Substance Abuse and Mental Health Services Administration; Office of the Surgeon General (US), 2016). Disruptions in these centres with  use  lead  to  increased  sensitivity  to substance-related  paraphernalia,  heighten  the brain’s  stress  systems  and  disturb  the mechanisms  involved  in  self  and  emotional regulation (Substance Abuse and Mental Health Services Administration; Office of the Surgeon General (US), 2016). 

One of the major reward pathways in the brain  consists  of  the  ventral  tegmental  area (VTA), The  nucleus accumbens  and the  pre- frontal cortex. Dopamine is released by the VTA in the nucleus accumbens on taking a substance. ‘Feelings’ of reward are activated here, and the prefrontal cortex recognizes and remembers the reward  and  what  was  rewarded. The  reward system is activated by any perceivable reward stimulus;  the  reward  is  measured either  as  a necessity for survival or pleasure (van Wormer and Davis, 2017). In adolescents, the prefrontal cortex,  also  associated  with  judgement  and decision-making, continues to develop well into the mid-20s, leaving them with a vulnerability for pursuing rewards and reinforcing pleasure. A critical ‘at-risk-period’ with ongoing develop- ment across all domains, early introduction to substances and the challenges in postponing or preventing future exposure to substances related to  feelings of rewards/pleasure may  increase vulnerability  to  use  if  adequate  skills  of socialization, communication, assertiveness, age- appropriate  sense  of  mastery,  feelings  of autonomy in identity and the protective factors of  secure emotional  affiliations have not been achieved (NIDA, 2014). 

Dopamine deficit  following long-term use and  associated highs and euphoria  may cause changes in the brain that may help maintain levels of substance  used  or cause  relapse. Hyman’s (2005)  ‘extreme  memory’  theory  posits  that overlearned  behaviours  associated  with  the reward of a dopamine release may condition a person  to attend to cues in the form of these pleasant memories that helps repeat substance- seeking  behaviours.  Dopamine  depletion following substance use such as with nicotine use may account for reinforcing tolerance and craving. As  the  brain  cuts  back  dopamine oversupply, there is a behavioural effort to search and refill the surge; taking the substance of choice regenerates a surge in dopamine. The substance is a mediator in generating the ‘high’. Chronic substance use can  lead to  changes in  genetic expressions;  accumulation  of  gene  molecule ÄFos-B (implicated in making the reward circuit sensitive to the effect of substances that in turn impacts craving and euphoria associated with use paraphernalia) and corticotropin-releasing factor activate  the  endogenous  stress  response  as overuse suppresses the reward circuitry, leading to a state of emotional dysregulation (MacNicol, 2017). ‘Feeling memories’ (Whitten, 2005) cued with  the  paraphernalia  of  substance  use  can involve a severe risk of relapse (Johnson, 2004). The mere anticipation of receiving a substance leads to  a  surge in  dopamine,  activating  the pathways that can maintain substance use. fMRI studies have evidence for cue-induced craving, even for those who may have stopped using but have hidden memories of use being triggered by these cues (Linden 2011). 

Dopamine has been associated with effort- based behaviours (Kurniaan, Guitart-Masip and Dolan, 2011) especially ascending dopaminergic pathways, in mediating general addiction pheno- types (Sey, 2022). Baez—Mendoza et al. (2021) reviewed the possible role of dopaminergic and related neural activity on decision-making in the probability  of  rewards  and  factors  such  as conformity,  attitudes  and  social  perception. Controlled  laboratory  studies  manipulating serotonin  and  dopamine  have  suggested  that dopamine receptor  systems  influence learning out-comes  that support value-based decision- making. Serotonin may play a role in learning about decision  outcomes  (especially  the non- rewarding, aversive outcomes), atypical aspects of  risk-seeking behaviour  and  social  choices involving  affiliation  and  fairness,  supporting decision-making  through selective  attention to reinforcers,  processing  information  about aversive out-comes and social choices. Impair- ment in deciding between possible outcomes in individuals with chronic substance use disorders may reflect disturbances in dopaminergic and serotonergic  modulations  of  fronto-striatal systems (van Wormer and Davis, 2017; Ersche et al., 2012; Paulus et al., 2005; Rogers et al., 1999). These pre-existing disturbances, such as an increase in dopamine 2 receptor expression within the nucleus accumbens, may be associated with  impulsivity,  seeking  substances  and variability  in  functional  decision-making (Rogers, 2011). 

Neurologic adaptations can be strengthened or put at risk via diseases, substances or environ- mental hazards.  Neuronal  damage  caused by extensive substance use may reduce responses to  pleasurable  activities  without  substance. Neurologic  changes  following  long-term substance use may become irreversible without pharmacotherapy  especially  for those  with  a history of increased tolerance and frequency of relapse if attempting to abstain (van Wormer and Davis, 2017). 

Serotonin,  involved  in  sleep  and  sensory experiences,  is  influenced  by  substance  use. Decreased levels of serotonin are associated with depression,  anxiety,  poor  impulse  control, aggression and suicidal ideation (van Wormer and Davis, 2017). Middle-aged and older men are  at  greater  risk  for  suicide  when  alcohol dependence co-exists with a mood disorder (Sher, 2006).  Laboratory  research  (on  monkeys) suggests that those with lower levels of dopamine receptors were especially responsive to cocaine’s  reinforcing  effects,  serotonin  was  possibly involved as well (Whitten, 2009). Substances like cocaine and alcohol increase dopamine, serotonin (linked with a sense of well-being) and gamma- amino-butyric  acid  (GABA)  (linked  with regulating anxiety)  availability  leading  to the feeling of ‘high’ or euphoria. Alcohol enhances GABA activity (Hasin, Hatzenbuehler and Waxman, 2006) and a genetic predisposition to alcoholism may increase dependence risk. 

Development  of substance  use related to feelings of  pleasure along with the  release  of dopamine  that  helps  process  the  reward reinforces  this  triad of  substance  use-neural activation and feelings of pleasure that becomes an associated rewarding experience resulting in the  search  to  feel  the  rush  rather  than  the substance  primarily.  fMRI  studies  indicated impairment in the serotonin-dopamine pathways following substance use that may be reflected in decision-making that can interfere with behaviour control. The excessive spike in dopamine follow- ing substance use triggers memories of rewards leading to a search and the reinforcing through taking  may reflect in the  attentional bias and compulsive seeking behaviour that develops in individuals   using substances   (Valkow, Michaelides and Baler, 2019; van Wormer and Davis, 2017; Valkow et al., 2011). Medicines that increase  serotonin levels may help  in the recovery  process  to  minimize and eventually unlearn  the  searching  behaviour  by  helping experience  the  ‘Nicotine  Dependence  Test (FTND).11  rush’  without  the  substance. The addiction cycle (Substance Abuse and Mental Health  Services Administration;  Office of the Surgeon  General  (US),  2016)  of  binge/ intoxication,  withdrawal/negative  affect  and preoccupation/anticipation  correlates  with impulsivity, positive and negative reinforcement that  increases  the  probability  of  using  and compulsivity in the repetitive substance seeking behaviours. 

 Treatment considerations 

Treatment  considerations  will  require keeping the  neurochemistry  of  substance  use affecting the age of onset, duration and severity of  use  or  dependence  apart  from  socio- demographics of cultural contributions in the risk or prevention of substance use by an individual. The following are some factors to consider for intervention: 

Socio-cultural factors: There  has  been a qualitative change towards approaching mental health professionals for substance use, as may be  seen  in  the  rise  of  government  aided deaddiction  centres  adhering  to  the laws  and policies laid down for treating and rehabilitating individuals with substance use disorders such as the  Community  based  Peerled  Intervention (CPLI) as a prevention programme that trains children between 10-18 years to become peer- educators, training them in life-skills and raising awareness for delayed initiation from substances among others in the community (PIB, 2021). The sense  of  responsibility,  autonomy  (personal skills), teaching boundaries and involvement of responsible adults (social factors) may form the basis of protective factors of the critical ‘at-risk’ stage of development (physical factors) in adoles- cents that in turn lends to positive neural adapta- tions that eventually  buffer  against  impulsive substance related rewards and pleasure-seeking compulsions. Schools could become a ground for early  identification  of  risk  factors  for  their students  (e.g.:  identifying  bullies,  those  with intellectual  disabilities,  academic  concerns, parental   discord   leading   to   emotional disturbances in the child) and addressing them at school through teachers/school counsellors. A referral system in schools/colleges to the nearest treatment centres such as a Hospital/Clinic that eases accessibility to treatment may have the two- fold  benefit  of  intervention  and reduction  in stigma.  The  Nasha  Mukt  Bharat Abhiyaan, launched  in August  2020  by  the  Ministry of  Social Justice and Empowerment, India, aims at the promotion of awareness about substance use and its negative effects and the prevention of use, across all levels of educational institutions. The Ministry of Social Justice and Empowerment’s National  Action  Plan  for  Drug  Demand Reduction  (NAPDDR)  scheme funds projects such  as The  Outreach  and  Drop  In  Centres (ODICs)  aims  to  provide  a  safe  place  for individuals  with substance  use  for screening, treatment and rehabilitation services (PIB, 2021). 

The treating team: Interventions may require multi-disciplinary communication with a treating team comprising but not limited to, physicians, psychiatrists, psychologists, nurses and social workers. Ethnicity and gender of the patients can predict risk factors for co-morbidities as well as social  vulnerabilities. Women  reporting  with symptoms  of  depression,  anxiety  or  related distress following divorce, loss of child custody or death of a loved one may be more prone to developing substance use disorders, especially prescription drugs (SAMHSA, 2011). There are more  men  in  the  treatment  of  substance  use disorders than women. Minority stress may also be correlated  to  substance  use  (Parent  et a., 2018).  For instance:  an  8-year-old  with  a 6- month history of inhalant use may be screened for  dental  health,  deficiency  disorders/ developmental  concerns  by  a  pediatrician,  a psychiatrist if there is a need for medication for detoxification  or  use-related  emotional  or behavioural disturbances, a psychologist for an assessment of current levels of functioning and providing individual and family counselling, a special educator to assess for and train the child for scholastic and related difficulties in executive functioning and a psychiatric social worker (for family  visits  in their  community). Treatment plans may be different when elderly are brought in; ruling out age-related physical degeneration (physical health), loneliness and social isolation (environmental factors) and loss of meaningful engagement in life (personal factors) may require specialists in the respective  fields of concern. Multilevel interventions that treat symptoms via medication and include socio-cultural considera- tions of the individual in the community (e.g.: single parent with a financial burden, experiences with stigma during substance use and treatment, might  have  better  outcomes  in  engaging  the individual in treatment. Regular updation with the latest scientific findings for medicine, therapy, laws and policies related to substance use on part of  professionals  would  help  identify  any resistance or treatment blind spots in intervention to promote the delivery of regulated standards of care. 

The Patient:  As  current  research  stands, gender  and  age  have  a  strong  influence  on developing  susceptibility  to  substance  use. Explaining the contribution of neurochemistry in exploring substances with eventual or expected dependence may empower patients to understand that  brain functioning,  and behaviours simul- taneously  maintain  use.  Each  component  is equally  compelling  as  maintaining  use  or abstinence.  Explaining  the role of  the reward circuits in the first phase of the addiction cycle, strengthening  these  circuits  through  seeking behaviours that further impact stress regulation and increasing socio-occupational dysfunction through interferences in decision-making over time may help patients understand the importance of changes in behaviour, albeit challenging, work at the biological level to support  reduced use. Hidden memories that spark craving are not a sign  of  lapse  but neural responses  to  neutral stimuli that recall an association with use. Social skills, self-regulation and resilience training may help over time to undergo the change of absti- nence and protect against sudden, unexplained cravings for substances. 

Family: Educating family members about the changes that take place in the brain centres and  the neuronal networks with use may  help address feelings of helplessness,  shame, guilt, anger/resentment  and  enabling  behaviours; information  focused  on  understanding  the structural changes affected by short or long-term substance use may help compartmentalize factors of  change  within  control  and  those  without. Myths associated with substance use, such as associating  weakness  of  character  and  self- control with individuals with substance use, may help  raise  awareness  of  the  critical  need  for medical treatment instead of willing change to occur. Training family members such as parents, spouses or children to elderly parents to manage their  own  stress  responses  to  the  patient, understanding the latter in the backdrop of the interaction  of  physical,  social  and  personal factors may engage them in treatment follow- ups. 

CONCLUSION 

Neural changes, individual behaviours and social reinforcements highlight the importance of long-term intensive treatment for success in abstinence. Medication and counseling patients and their  caregivers are  equally important in understanding the interplay of nature-nurture in substance use and in the treatment approach. 

Conflicting Interests: The authors declared no potential conflicts of interest. 

Funding: Nil. 

REFERENCES 

Ambekar, A., Agrawal, A., Rao, R., Mishra, A.K., Khandelwal S.K., & Chadda, R.K. on behalf of the group of investigators for the National Survey on Extent and Pattern of Sub-stance Use in India (2019). Magnitude of  Substance  Use  in  India.  New  Delhi: Ministry  of Social Justice and Empower- ment, Government of India. 

Báez-Mendoza, R., Vázquez, Y., Mastrobattista, E. P., & Williams, Z. M. (2021). Neuronal circuits for social decision-making and their clinical implications. Frontiers in Neuros- cience, 15. 

Ersche,  K.D.,  Jones,  P.S.,  Williams,  G.B., Turton, A.J., Robbins, T.W., & Bullmore, E.T.  (2012). Abnormal  brain  structure implicated  in  stimulant  drug  addiction. Science, 335(6068), 601-604. 

Fox, H.C., Morgan, P.T., & Sinha, R. (2014). Sex differences in guanfacine effects on drug craving  and  stress  arousal  in  cocaine- dependent individuals. Neuropsychopharma- cology, 2014, 39(6), 1527-1537. 

Hasin, D., Hatzenbuehler, M., & Waxman, R. (2006). Genetics of substance use disorders. In Miller W & Carroll K (eds). Rethinking Sub-stance Abuse. NY: Guilford Press. 

Hitschfeld, M.J., Schneekloth, T.D., Ebbert, J.O., Hall-Flavin,   D.K.,   Karpyak,  V.M., Abulseoud, O.A., Patten, C.A., Geske, J.R., & Frye, M.A. (2015). Female smokers have the highest alcohol craving in a residential alcoholism  treatment  cohort.  Drug  and alcohol dependence, 150, 179–182. 

Hyman, S.E.  (2005). Addiction: A disease of learning and memory. American Journal of Psychology, 162, 1414-1422. 

Johnson,  H.C.  (2004).  Psyche  and  synapse expanding worlds: the role of neurobiology in  emotions,  behavior,  thinking,  and addiction  for  non-scientists  (2nd  ed.). Greenfield, MA: Deer-field Valley. 

Kurniawan, I.T., Guitart-Masip, M., & Dolan, R.J. (2011). Dopamine and effort-based deci- sion making. Frontiers in Neuroscience, 5. https://doi.org/10.3389/fnins.2011.00081 

MacNicol, B. (2017). The biology of addiction. Canadian Journal of Anesthesia, 64, 141– 148. McCabe, S.E., Morales, M., Cranford, J.A., Delva, J., McPherson, M.D., & Boyd, C.J.  (2007).  Race/ethnicity  and  gender differences in  drug  use  and  abuse among college  students.  Journal  of  ethnicity  in substance abuse, 6(2), 75–95.  

Ministry  of Social  Justice and  Empowerment (2021, August  11).  Deaths  due  to  drug abuse.  Press  Information  Bureau,  Delhi. https://www. pib.gov.in/PressReleasePage. aspx?PRID=1744800 

National Centre on Addiction  and Substance Abuse (CASA). (2006). Women under the influence.  Baltimore:  Johns  Hopkins University Press. 

National Institute on Drug Abuse (2022). Sex and Gender Differences in Substance Use. Advancing Addiction  Science,  National Institutes of Health. 

National  Institute  on  Drug Abuse.  (2014). Principles  of  adolescent  substance  use disorder treatment: A research-based guide. U.S.  Department  of  Health  and  Human Services, National Institutes of Health. 

Paulus, M.P., Tapert, S.F., & Schuckit,  M.A. (2005).  Neural  activation  patterns  of metham-  phetamine-dependent  subjects during  decision  making  predict  relapse. Archives of general psychiatry, 62(7), 761- 768. 

Rai, D. (2021, October 4). All you need to know about drugs, substance abuse in India. India Today. https://www.indiatoday.in/diu/story/ all-you-need-to-know-about-drugs-sub- stance-abuse-in-india-1860644-2021-10-04 

Robbins, S.J., Ehrman, R.N., Childress, A.R., & O’Brien, C.P. (1999). Comparing levels of cocaine cue reactivity in male and female outpatients. Drug and alcohol dependence, 53(3), 223-230. 

Rogers R.D. (2011). The roles of dopamine and serotonin in decision making: evidence from pharmacological  experiments  in  humans. Neuropsychopharmacology: official  pub- lication  of  the  American  College  of Neuropsychopharmacology,  36(1),  114– 132. 

Rogers,  R.D.,  Everitt,  B.J., Baldacchino, A., Blackshaw, A.J.,  Swainson,  R.,  Wynne-Jones, K., Baker, N.B., Hunter, J., Carthy, T.,  Booker, E., London,  M., Deakin, J.F., Sahakian,  B.J., &  Robbins, T.W.  (1999). Dissociable deficits in the decision-making cognition of chronic amphetamine abusers, opiate abusers, patients with focal damage to prefrontal cortex, and tryptophan-depleted normal  volunteers:  evidence  for  mono- aminergic  mechanisms.  Neuropsycho- pharmacology: official publication of the American College of Neuropsychopharma- cology, 20(4), 322-339. 

Sey, N.Y.A., Hu, B., Iskhakova, Lee, S., Sun, H., Shokrian, N., Hutta, G.B., Marks, J.A., Quach, B.C., Johnson, E.O., Hancock, D.B., Akbarian,  S.,  & Won,  H.  (2022).  Chro- matin  architecture  in  addiction  circuitry identifies risk genes and potential biological mechanisms underlying  cigarette  smoking and alcohol use traits. Molecular Psychiatry, 27, 3085–3094. 

Sharma, S., Sharma, G., & Barkataki, B. (2016). Substance  use  and  criminality  among juveniles-under-enquiry  in  New  Delhi. Indian journal of psychiatry, 58(2), 178– 182. 

Shearer, R.D.,  Shippee, N.D., Vickery,  K.D., Stevens,  M.A.,  &  Winkelman,  T.N.A. (2022). A  longitudinal  cross-sectional analysis of substance use treatment trends for individuals experiencing homelessness, criminal justice involvement, both, or neither - United States, 2006-2018. Lancet regional health. Americas, 7, 100174. 

Sher,  L.  (2006). Alcohol  consumption  and suicide.  QJM:  Monthly  Journal  of  the Association of Physicians, 99(1), 57-62. 

Substance Abuse and Mental Health Services Administration  (2011).  Addressing  the Needs of  Women  and  Girls: Developing Core Competencies for Mental Health and Substance  Abuse  Service  Professionals. HHS Pub. No. (SMA) 11-4657. Rockville,  MD: Substance Abuse and Mental Health Services Administration. 

Substance Abuse and Mental Health Services Administration (US); Office of the Surgeon General (US). Facing Addiction in America: The Surgeon General’s Report on Alcohol, Drugs,  and Health [Internet]. Washington (DC): US Department of Health and Human Services; 2016 Nov. Chapter 2, the neuro- biology  of  substance  use,  misuse,  and addiction. Available from: https://www.ncbi. nlm.nih.gov/books/NBK424849/ 

Van Wormer,  K.S.,  &  Davis,  D.R.  (2017). Addiction treatment: a strengths perspective (Fourth edition.). Cengage Learning. 

Volkow,  N.D.,  Michaelides,  M.,  &  Baler, R. (2019). The neuroscience of drug reward and addiction.  Physiological  Reviews,  99(4), 2115–2140. 

Volkow, N.D., Wang, G.J., Fowler, J.S., Tomasi, D., & Telang, F. (2011). Addiction: Beyond dopamine reward circuitry. Proceedings of the National Academy of Sciences, 108(37), 15037–15042. 

Whitten, L. (2005). A single cocaine ‘binge’ can establish long-term cue-induced drug seeking in rats. NIDA Notes, 19(6). 

Whitten,  L.  (2009).  Low  dopamine  receptor availability may promote cocaine addiction. NIDA Research Findings, 22(3), 5-7.  


Journal of Society for Addiction Psychology | Volume 1 | Issue 1 | March 2024 Page 12 - 19