Despite decades of research on amphetamine derivatives, a class of compounds sharing a structural foundation with amphetamine, crucial gaps remain in our understanding of these drugs in a variety of animal species and humans. This dissertation addresses three of these gaps through a multi-level approach involving studies in both humans and mice. Specifically, it focuses on investigating the lack of information regarding: 1) repeated dosing of 3,4-methylenedioxymethamphetamine in humans, 2) methamphetamine/alcohol combinations in humans and 3) methamphetamine/oxycodone combinations in mice. Study 1 involved administering three consecutive doses of 3,4 methylenedioxymethamphetamine to human volunteers at 12- and 24-hour intervals while physiological, behavioral, and subjective measures were collected. Study 2 reanalyzed Kirkpatrick and colleagues (2012a) data to evaluate repeated administrations of methamphetamine and alcohol. The reanalysis focused on quantifying the physiological and subjective effect differences between the first and second administrations, which occurred at a 12-hour interval on the same day, an aspect not previously analyzed or reported by the original authors. Study 3 utilized well-established animal models such as Conditioned Place Preference, Open Field Test, and Novel Object Recognition to evaluate the reward-like and aversive effects of methamphetamine and oxycodone combinations in mice. Study 1 was the first to quantify the effects of multiple 3,4-methylenedioxymethamphetamine doses administered over a 36-hour period of time. Initially, acute 3,4-methylenedioxymethamphetamine produced dose-dependent increases in peak heart rate, blood pressure, and more positive than negative subjective effects. However, by the third dose, many of these effects dissipated, heart rate was no longer elevated, and residual mood effects were minor. Overall, the data do not support the general perception that 3,4-methylenedioxymethamphetamine produces dangerous cardiovascular and residual mood effects in humans following repeated administration. The results of Study 2, again a first in the field, discovered that contrary to expectations, heart rate increases produced by the methamphetamine/alcohol combination were not further increased with repeated dosing, but rather attenuated. In fact, methamphetamine offset alcohol-induced intoxication, even after repeated administration. Study 3 revealed that combining methamphetamine and oxycodone in mice increased reward as measured by Conditioned Place Preference, but not more than either drug alone. However, methamphetamine lengthened the duration of Conditioned Place Preference for the lower oxycodone dose and offset the oxycodone-induced disruptions in novel object recognition performance. One crucial cross-species observation was that methamphetamine mitigated adverse effects such as alcohol-related intoxication and oxycodone cognitive disruption, even after repeated administration. While seemingly beneficial, this observation raises concerns that individuals who combine these drugs may be at risk of underestimating their overall degree of impairment, potentially leading to hazardous activities like driving while intoxicated or engaging in risky behaviors. Sharing this insight is crucial to encourage informed, responsible behavior and safeguard public safety. In conclusion, these studies have significantly enhanced our understanding of two frequently used amphetamine derivatives and their interactions with two commonly used psychoactive drugs—oxycodone and alcohol. Most importantly, we strongly advocate for robust empirical experimentation to counteract misinformation related to 3,4-methylenedioxymethamphetamine and methamphetamine. These endeavors are crucial for developing more precise assessments of the risks and benefits associated with these substances, and for improving drug policies and optimizing public health interventions.