Intravenous self-administration – Valid experimental designs to evaluate the abuse potential of psychedelics, entactogens and drugs with novel mechanisms

Abstract

Intravenous self-administration (IVSA) evaluates whether a CNS drug-candidate produces rewarding effects that could cause psychological dependence in patients and lead to its diversion for abuse. The model was originally developed to investigate powerful reinforcers like opiates and stimulants. For that reason, IVSA is not well adapted to detect the abuse potential of a new generation of drugs with moderate/low abuse potential. Using experience gained from conducting IVSA experiments with many types of drugs of abuse and novel drug-candidates, we offer insights on obtaining translationally predictive results from IVSA experiments, and technical refinements to increase the sensitivity and granularity of the findings. All experiments were conducted in mildly food-restricted, male, Sprague-Dawley rats with implanted with intravenous catheters. Standard IVSA tests were conducted on low fixed ratio (FR) schedules (FR3 or FR5), not FR10 as recommended in CDER/FDA guidance (CDER/FDA, 2017). As a technical refinement, the relative reinforcing effect was assessed by break-point determination on a progressive ratio (PR) schedule of reinforcement. All break-points were determined across a range of reinforcing drug doses to ensure the maximum reinforcing effect was identified. Moderate reinforcers, MDMA (entactogen), butorphanol (κ-agonist/μ-partial agonist), and (−)pentazocine (κ-agonist/μ-antagonist) produced break-points between 25 and 33 lever-presses/infusion. Weak reinforcers, WIN55,212 (CB1/CB2 agonist), diazepam, midazolam and methohexital (all GABA-A receptor positive allosteric modulators [PAMs]) produced mean break-points of 17–22 lever-presses/infusion. In contrast, powerful reinforcers like the opioids, eg heroin, remifentanil, oxycodone, and stimulants, eg cocaine, methylphenidate, supported mean break-points ranging between 41 and 98 lever‑presses/infusion. The break-point for saline (non-reinforcing control) was 10.4 ± 0.8 lever-presses/infusion. The results were used to design and conduct successful IVSA evaluations on cannabidiol (CBD), ulotaront and samidorphan on a FR3 schedule, difelikefalin, dasotraline, centanafadine, and soticlestat on a FR5 schedule, and PR/break-point determinations on samidorphan and naloxone. CNS drug development is in an era where new entactogens, psychedelics and drugs with novel mechanisms are undergoing clinical evaluation. Refinements to IVSA testing that we advocate have proven value based on experiments with known substances of abuse and novel drug-candidates.