Many drugs derived from a simple chemical structure called phenethylamine can strongly influence the brain’s serotonin system, which plays a central role in mood, perception, and cognition. Some of these compounds are being studied for their therapeutic potential, while others have appeared on the recreational drug market because of their psychedelic and euphoric effects.
Most psychedelic phenethylamines act on a specific serotonin receptor called 5-HT2A, which is also the main target of classic psychedelics such as LSD. When this receptor is activated, it triggers distinctive behavioral and psychological effects, such as the “head-twitch response” in mice, which scientists use as an indicator of psychedelic activity.
Recent studies suggest that the intensity of this response depends on how strongly a drug activates certain signaling pathways within cells, particularly the one known as 5-HT2A–Gq signaling. Drugs that activate this pathway strongly tend to produce psychedelic-like effects, whereas those that bias signaling toward a different pathway involving β-arrestin 2 may reduce or block these effects.
In addition to acting on 5-HT2A receptors, most psychedelic phenethylamines also stimulate related receptors(such as 5-HT2B and 5-HT2C, which can influence both safety and effects. Long-term activation of 5-HT2B receptors has been linked to potential heart valve problems, suggesting caution with frequent use. Meanwhile, 5-HT2C receptor activity can either dampen or support psychedelic effects, depending on the dose. This contributes to complex dose–response patterns seen in animal studies.
Many of these compounds also interact, to varying degrees, with other brain receptors such as 5-HT1A, which can modulate their effects. For example, activation of 5-HT1A receptors can soften or reduce psychedelic intensity. Phenethylamines tend to be more selective for 5-HT2A than 5-HT1A, but the interplay between these receptors still shapes their overall effects.
Beyond serotonin receptors, psychedelic phenethylamines may influence dopamine, norepinephrine, histamine, or opioid receptors, as well as monoamine transporters and enzymes, though the importance of these interactions varies. One major question in the field is how small structural changes in these molecules alter their receptor-binding profiles, subjective effects, and potential medical uses.
To explore this, we examined 4-alkylated derivatives of 2,5-dimethoxyamphetamine (2,5-DMA), a family of compounds first synthesized by the chemist Alexander Shulgin. Shulgin modified the natural psychedelic mescaline to create more potent analogs. Adding an alpha-methyl group and rearranging the position of the methoxy groups led to TMA-2, which is distinctively more potent than mescaline. Replacing one methoxy group with a methyl group created DOM (also known as “STP”), which is even more potent and became a well-known recreational drug in the late 1960s.
Interestingly, while 2,5-DMA itself is not strongly psychoactive, adding small carbon chains at one specific position on the molecule (the 4-position) greatly increases potency. Derivatives with a two- or three-carbon chain (known as DOET and DOPR) produce strong psychedelic effects, whereas those with a four- or five-carbon chain (DOBU and DOAM) show much weaker activity.
In the present study, we examined how these small structural differences in the alkyl chain affect receptor signaling and behavior. Each compound was tested for its ability to activate various serotonin-linked signaling pathways, to interact with other receptors, and to induce the head-twitch response in mice. It was also measured how the drugs were distributed in the plasma and brain. Furthermore, microdialysis was used to track concentrations in the brain extracellular fluid. The findings showed that compounds with shorter 4-alkyl chains (methyl, ethyl, or propyl) are the most potent psychedelics, primarily due to their strong affinity and activation of the 5-HT2A receptor. As the carbon chain lengthened, potency decreased, not because of weaker receptor activity, but likely due to pharmacokinetic factors. Specifically, the longer-chain compounds entered the brain less efficiently and reached lower concentrations in brain tissue.
In summary, this study suggests that small structural changes in psychedelic phenethylamines strongly influence their potency and brain activity. Shorter-chain derivatives cross the blood–brain barrier more effectively and produce stronger psychedelic effects, while longer-chain versions are less active due to reduced brain penetration. These insights deepen our understanding of how molecular structure determines the biological activity of psychedelic compounds.