Mechanisms of Action (MoA) in Substance Use Disorders (SUDs) Research (Past 3 Years):

Recent PubMed publications highlight several key MoAs being investigated in SUDs research. These span pharmacological, behavioral, and neuromodulatory approaches, reflecting the complex nature of addiction:

1. Pharmacological Interventions:

• Targeting Neurotransmitter Systems: Research continues to explore medications that modulate neurotransmitter systems implicated in SUDs, such as the dopamine, opioid, and serotonin systems. Studies investigate medications for opioid use disorder (e.g., methadone, buprenorphine), alcohol use disorder (e.g., naltrexone, acamprosate), and nicotine use disorder (e.g., nicotine replacement therapies). Novel agents targeting other neurotransmitter systems are also under investigation.
• PROteolysis Targeting Chimeras (PROTACs): This emerging technology utilizes small molecule-based heterobifunctional PROTACs to modulate protein target levels by hijacking the ubiquitin-proteasome system to induce degradation of the target. This event-driven MoA offers potential for targeting previously "undruggable" proteins involved in SUDs.

2. Behavioral Therapies:

• Cognitive Behavioral Therapy (CBT): CBT remains a cornerstone of SUD treatment. It focuses on identifying and modifying maladaptive thoughts and behaviors related to substance use, developing coping skills, and preventing relapse. Research explores adaptations of CBT for specific SUDs and populations.
• Motivational Interviewing (MI) and Motivational Enhancement Therapy (MET): MI and MET aim to enhance motivation for change and strengthen commitment to treatment. Studies investigate their effectiveness as standalone interventions and in combination with other therapies.
• Mindfulness-Based Interventions: Mindfulness-based relapse prevention (MBRP) and other mindfulness interventions focus on cultivating awareness of present-moment experiences, reducing craving, and promoting self-regulation. Research examines their efficacy in preventing relapse and improving overall well-being.
• Contingency Management: This approach uses positive reinforcement to encourage abstinence and treatment adherence. Studies investigate its effectiveness in various SUDs.

3. Neuromodulation:

• Transcranial Magnetic Stimulation (TMS): TMS uses magnetic pulses to stimulate specific brain regions implicated in SUDs, such as the dorsolateral prefrontal cortex. Research investigates its potential to reduce craving, improve cognitive function, and promote abstinence.
• Transcranial Direct Current Stimulation (tDCS): tDCS applies a weak electrical current to the scalp to modulate brain activity. Studies explore its effects on craving, impulsivity, and other SUD-related symptoms.
• Deep Brain Stimulation (DBS): DBS involves implanting electrodes in specific brain regions. While more invasive, it shows promise in treating severe, treatment-resistant SUDs. Research investigates its long-term efficacy and safety.

4. Other Emerging Approaches:

• Telehealth: The use of technology to deliver SUD treatment, including counseling, medication management, and recovery support, is expanding. Research examines its effectiveness in increasing access to care and improving outcomes.
• Social Support and Recovery Models: Emphasis on social support, peer recovery, and community-based interventions is growing. Research investigates their role in sustaining recovery and reducing stigma.

Quantitative Analysis:

While many studies report positive findings, effect sizes vary across interventions and SUDs. For example, a meta-analysis of MBRP for SUDs found small effects on withdrawal/craving and negative consequences. Remission rates for SUDs vary widely (35-54%) depending on the study methodology and follow-up period. Further research with larger samples, longer follow-up periods, and standardized outcome measures is needed to better quantify the effectiveness of different MoAs.

Future Directions:

Research continues to explore personalized medicine approaches, tailoring interventions to individual patient characteristics and needs. The development of reliable biomarkers for SUDs is also a priority, as these could aid in diagnosis, treatment selection, and monitoring of treatment response. Integrating multiple MoAs into comprehensive treatment plans is likely to be most effective in addressing the complex biopsychosocial factors contributing to SUDs.

GABA_B positive allosteric modulators (PAMs) are being investigated for several conditions beyond substance use disorders. Preclinical and clinical trials have explored their potential in various therapeutic areas, employing different intervention models:

1. Chronic Pain:

2. ADX71441: Tested in mouse and guinea pig models of overactive bladder (OAB), showing increased urinary latencies and reduced urinary events in mice, and increased intercontraction interval and bladder capacity in guinea pigs. Also tested in the monosodium iodoacetate model of chronic osteoarthritis pain in rats, showing increased pain thresholds. ADX71943, a peripherally restricted PAM, also showed efficacy in this model, particularly in the early inflammatory phase. ADX71441 was further investigated for its analgesic effect on urinary bladder and colon pain in rats, showing a dose-dependent decrease in visceromotor response.

3. ASP8062: Investigated for fibromyalgia treatment in a rat model, showing significant reversal of decreased muscle pressure threshold.

4. rac-BHFF: Tested in mice with chronic constriction injury-induced neuropathic pain, showing no analgesic activity alone but potentiating the analgesic effect of baclofen.

5. NS11394: Showed efficacy in rodent models of inflammatory and neuropathic pain, attenuating spontaneous nociceptive behaviors and reversing mechanical allodynia.

6. BHF177: Evaluated in a rat model of visceral pain, showing reduced visceromotor response to colorectal distension.

7. Anxiety Disorders:

8. ADX71441: Showed anxiolytic-like effects in mouse marble burying and elevated plus maze tests.

9. BHF177: Tested in rat models of anxiety, showing anxiolytic-like effects in high-anxiety rats in the light-enhanced startle test and blocking stress-induced hyperthermia.

10. KRM-II-81: Produced anxiolytic-like effects with minimal sedation in preclinical studies.

11. GS39783: Showed anxiolytic-like effects in rodent models without affecting locomotion, cognition, temperature, or narcosis.

12. Epilepsy:

13. ADX71441: Not directly tested in epilepsy models, but its general effects on GABA transmission suggest potential.

14. KRM-II-81: Showed broad-based anticonvulsant efficacy in rodent models, including blocking the development of seizure sensitivity in kindling models.

15. Ganaxolone: Approved for seizures associated with CDKL5 deficiency disorder and undergoing trials for tuberous sclerosis complex-related epilepsy.

16. Other Conditions:

17. ADX71441: Tested in a rat model of spasticity, showing reduced muscle tone.

18. ASP8062: Investigated for its effects on sleep in rats, showing decreased REM sleep time and increased delta wave power during non-REM sleep.

19. JNJ-40068782: Influenced rat sleep-wake organization by decreasing rapid eye movement sleep.

20. PF-06372865: Showed analgesic potential in healthy subjects in a pain study.

21. SAGE-217 (Zuranolone): Investigated for tremor in Parkinson's disease, showing improvement in tremor scores. Approved for postpartum depression.

These intervention models range from in vitro studies on receptor function to in vivo behavioral and physiological assessments in animal models and human clinical trials. The specific models used vary depending on the indication being investigated, but generally involve inducing the disease state or symptom and then assessing the effect of the GABAB PAM on relevant outcome measures.