This series explores the deep but underexamined connection between cannabis and psychedelics, two plant medicines that act on different yet overlapping systems in the brain and body.
Building on the foundation of cultural and biological context explored in Part 1, Part 2 dives deeper into the mechanics of how cannabis and psychedelics overlap in the brain. It explores shared signaling pathways, neuroplasticity effects, and cross-talk between the ECS and serotonin systems.
This section emphasizes how the “wiring” of these systems helps explain why co-use produces such variable results. Readers will begin to see how lab findings translate into subjective experiences.
The Serotonergic System and Psychedelics
If cannabis plugs into the body’s endocannabinoid system, classic psychedelics like psilocybin, LSD, DMT, and mescaline tune into the brain’s serotonergic system. Their favorite target: the 5-HT2A receptor, found in high density across cortical regions tied to perception, cognition, and sense of self (Nichols, 2016; Vollenweider & Kometer, 2010).
When psychedelics flip that switch, a cascade kicks off inside neurons: enzymes fire, calcium floods in, and pyramidal cells in the cortex change how they signal (Kometer & Vollenweider, 2016). The result isn’t just a louder signal — it’s a rewiring. Brain networks that usually keep information siloed begin cross-talking, while the default mode network (DMN) — the brain’s self-referential “chatter hub” — loosens its grip (Carhart-Harris et al., 2012).
That DMN disruption is strongly linked to ego dissolution — the feeling of boundaries between self and world breaking down (Lebedev et al., 2015). Far from just a trippy spectacle, this shift can loosen rigid self-narratives and boost psychological flexibility, key ingredients in how psychedelics support therapy for depression, anxiety, or addiction (Carhart-Harris & Friston, 2019).
The serotonergic system also drives longer-term change. Psychedelics have been shown to promote neuroplasticity — growth of dendritic spines, new synapse formation, and shifts in functional connectivity that outlast the acute trip (Ly et al., 2018; Dakic et al., 2017). Importantly, many of these same molecular pathways overlap with those influenced by the ECS, like BDNF signaling and stress resilience mechanisms (Bambico et al., 2010; Catlow et al., 2013).
But as with cannabis, context shapes outcome. Psychedelics amplify emotional salience — making both joy and fear feel more intense. Under the right set and setting, that can mean openness and empathy; under the wrong one, it can tip into anxiety or panic (Kometer et al., 2012). Adding cannabis into the mix has the potential to nudge those scales either way, depending on dose and mindset (Harris et al., 2019).
In short: psychedelics shake up the serotonin system to reorganize perception, self, and connection. They don’t just alter consciousness in the moment — they leave footprints in the brain’s wiring.
With cannabis working through the ECS and psychedelics through serotonin, what happens when these systems start talking to each other? Their downstream overlap shapes not only brain activity but also the connective tissues of the body and mind.
ECS–Serotonin System Interactions and Co-Use Effects
Cannabis and psychedelics may start from different launchpads — ECS vs. serotonin — but their systems cross-talk more than most people realize. This interaction isn’t just theoretical: many people already mix them in ceremonies, therapy circles, or casual use, often without guidance (Parker et al., 2021).
Neurochemical Crosstalk
THC, working through CB1 receptors, can influence serotonergic neurons in the dorsal raphe nucleus, a brainstem hub that regulates mood and sensory filtering (Häring et al., 2007). On the flip side, activating 5-HT2A receptors with psychedelics can alter endocannabinoid release — anandamide and 2-AG — in regions tied to emotional processing (Best & Regehr, 2008).
In practice, this means cannabis can “prime” cortical networks for a trip, either amplifying or muting the intensity depending on dose and timing (Busquets-Garcia et al., 2018).
Synergistic Potential
Phenomenologically, cannabis sometimes heightens psychedelic features like visual textures, music-driven synesthesia, or emotional recall (Mason et al., 2021; Carhart-Harris et al., 2014).
ECS activation may also lower prefrontal overactivity, which can deepen the surrender that helps therapeutic breakthroughs land. And it’s not entirely new: traditions from Rastafarian rites to Hindu tantric practices have long combined cannabis with other psychoactive plants (Clarke & Merlin, 2013).
Risks and Adverse Effects of Cannabis and Psychedelics
Synergy cuts both ways. THC increases heart rate and can dial up anxiety — which, layered on a psychedelic, risks spiraling into paranoia or panic (Solowij et al., 2019). Heavy cannabis use during or right after a trip may also muddy memory consolidation, making it harder to integrate insights (Morgan et al., 2010). Preclinical work even hints that CB1 activation could dampen some psychedelic-induced neuroplasticity by reducing glutamate release (Kano et al., 2009).
Translation: the wrong strain or dose might blunt the very rewiring that makes psychedelics therapeutic.
Clinical and Policy Implications
Clinical trials usually keep cannabis out of psychedelic protocols to avoid confounds. Yet it remains an open question whether small, intentional doses might actually help with emotional processing during therapy. For now, the absence of standardized guidelines is striking, especially as legalization expands on both fronts. Regulators will eventually need to decide whether cannabis–psychedelic co-use should be restricted, permitted, or systematically studied in licensed settings.
ECS–serotonin crosstalk is a frontier. It’s not just an academic curiosity, but a live factor shaping how two of the century’s most visible psychoactive categories may converge in practice.
The Overlap of Cannabis & Psychedelics
Part 2 shows that cannabis and psychedelics don’t just act in parallel—they intersect at key neural junctions that shape thought, emotion, and sensory processing. These intersections reveal why co-use can sometimes be synergistic and at other times destabilizing. By zooming in on the neurobiology, this section equips readers with a clearer map of the territory. The next installment moves from wiring diagrams to lived experience: how users actually report these combinations playing out.
Stay tuned for part 3, next week!
Additional References
- Clarke, R. C., & Merlin, M. D. (2013). Cannabis: Evolution and ethnobotany. University of California Press.
- L. A., Limebeer, C. L., & Rock, E. M. (2021). Regulation of nausea and vomiting by cannabinoids and the endocannabinoid system. European Journal of Pharmacology, 886, 173546. https://doi.org/10.1016/j.ejphar.2020.173546
About the Author
RN Collins is a 1L at Northeastern University School of Law and a neuroscientist exploring how brain health and the environment intersect. Through her writing, she bridges academic research and science communication to reframe how psychoactive plants and other traditional and alternative medicines are understood. She’s building a career that connects law, technology, and creativity—and welcomes conversations and opportunities across fields that share that vision. Connect with her on LinkedIn!
