Abstract:Substance use disorders (SUDs) affect over 36 million people worldwide, yet few receive effective care due to stigma, motivational barriers, and limited personalized support. Although large language models (LLMs) show promise for mental-health assistance, most systems lack tight integration with clinically validated strategies, reducing effectiveness in addiction recovery. We present ChatThero, a multi-agent conversational framework that couples dynamic patient modeling with context-sensitive therapeutic dialogue and adaptive persuasive strategies grounded in cognitive behavioral therapy (CBT) and motivational interviewing (MI). We build a high-fidelity synthetic benchmark spanning Easy, Medium, and Hard resistance levels, and train ChatThero with a two-stage pipeline comprising supervised fine-tuning (SFT) followed by direct preference optimization (DPO). In evaluation, ChatThero yields a 41.5\% average gain in patient motivation, a 0.49\% increase in treatment confidence, and resolves hard cases with 26\% fewer turns than GPT-4o, and both automated and human clinical assessments rate it higher in empathy, responsiveness, and behavioral realism. The framework supports rigorous, privacy-preserving study of therapeutic conversation and provides a robust, replicable basis for research and clinical translation.