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