<div> <p>Historically, natural products from plants, fungi, bacteria and animals have played an important role in the discovery of new drugs. In fact, it has been found that 34% of new FDA-approved drugs over the last 30 years were derived from natural products or their derivatives. Because of the chemical and structural diversity of natural products, they continue to be one of the best options for discovering novel compounds and scaffolds; this is especially true for compounds targeting the µ-, δ-, and κ- opioid receptors. However, traditional opioids such as morphine cause many therapeutically limiting side effects. Therefore, there have been immense efforts to develop opioids that avoid these side effects, with “signal-biased” compounds being an intense area of interest. The research presented here investigates of the biased mechanisms of compounds found in and derived from <i>Mitragyna speciosa</i>, also known as kratom, and <i>Picralima nitida</i>, also known as akuamma. Kratom and akuamma compounds are examined for their therapeutic potential in treating alcohol abuse and pain, respectively, two prevalent conditions with extreme societal and economic costs.</p> </div> <br>