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. While cannabis primarily tunes the endocannabinoid system (ECS) and psychedelics activate the serotonergic system, both influence mood, perception, and neuroplasticity in striking ways.
Part 1 lays the foundation by tracing cultural histories, mapping basic brain pathways, and setting the stage for how these substances interact when used together. It offers readers a starting framework to understand why the cannabis–psychedelic relationship matters.
Cannabis and Psychedelics
Cannabis and psychedelics usually get treated like they live in separate silos — each with its own research papers, cultural baggage, and policy debates. But in real life, the lines blur. People who explore one often bump into the other, whether that’s at a festival, in a therapist’s office, in ceremony, or just experimenting with friends (Harris et al., 2019).
On paper, the two drugs are tied to different “main” systems: cannabis with the endocannabinoid system (ECS) and psychedelics with the serotonin 5-HT2A receptor. But the story is messier.
The ECS, discovered only in the late 20th century, helps regulate almost everything — mood, memory, pain, immunity (Zou & Kumar, 2018). Cannabis taps into it through compounds like THC and CBD, which slot into CB1 and CB2 receptors like keys into locks (Pertwee, 2008).
Psychedelics like psilocybin, LSD, and DMT, on the other hand, hit serotonin’s 5-HT2A receptor hard, sparking the shifts in perception and sense of self they’re famous for (Vollenweider & Preller, 2020).
And yet, the overlap is striking. Both cannabis and psychedelics ripple outward to affect brain plasticity, how networks connect, and how emotions are regulated (Ly et al., 2018; Volkow et al., 2014). That raises real-world questions: What happens when people use them together? Does cannabis smooth a trip, sharpen it, or dull it? Could it change safety risks, therapy outcomes, or just the feel of the experience itself? These aren’t fringe curiosities — legalization and easier access mean more people are experimenting without much science-based guidance (Johnson et al., 2019).
The research gap is obvious. We’ve got shelves of studies on cannabis, and a rapidly expanding field around psychedelics, but almost nothing peer-reviewed on their co-use (Mason et al., 2021). Right now, most knowledge comes from anecdotes, Reddit threads, and underground communities. This article is an attempt to change that. By pulling from neuroscience, psychopharmacology, and clinical research, we’ll map the intersections between these two worlds and build a baseline for better conversation.
If cannabis and psychedelics are usually filed in different drawers, the ECS might be the hidden hinge connecting them. That’s where we’ll start — unpacking the biology of this system and how it sets the stage for their overlap.
The Endocannabinoid System and Cannabis
The endocannabinoid system (ECS) is your body’s built-in cannabis-like network. It keeps things in balance — mood, memory, stress recovery, pain control, even immunity (Zou & Kumar, 2018).
At its core are three pieces:
- Endocannabinoids like anandamide and 2-AG (the “keys”)
- CB1 and CB2 receptors that sit on nerve and immune cells (the “locks”)
- Enzymes that flip the signal on or off (Pertwee, 2008)
When you consume cannabis, THC acts as a partial agonist at CB1 receptors — which are especially dense in the brain — altering neurotransmitter release in ways that produce the plant’s
classic psychoactive effects (Volkow et al., 2014). CBD doesn’t directly “fit” into CB1 or CB2, but it influences the system indirectly and cross-talks with others, like the serotonin 5-HT1A receptor. That’s why CBD often shows up in research on anxiety relief, inflammation control, and neuroprotection (Maldonado et al., 2020).
The ECS isn’t just about relaxation or pain. It’s also deeply tied to how we process fear and stress. CB1 activation in the amygdala helps quiet hyperactive fear circuits and supports extinction of aversive memories — a process that mirrors what psychedelic-assisted therapy often calls an “emotional reset” (Vollenweider & Preller, 2020).
Both cannabis and psychedelics also promote neuroplasticity — the brain’s ability to rewire itself — which raises an open question: could using them together enhance therapy outcomes, or might overlapping “plasticity windows” make the brain more vulnerable to negative learning?
On the cellular level, cannabis also changes glutamate signaling and inflammation, two levers that can prime circuits for perceptual and emotional shifts. THC has been shown to boost brain-derived neurotrophic factor (BDNF), the same growth factor psychedelics upregulate to promote synaptic remodeling (Ly et al., 2018). This overlap suggests the ECS and serotonergic system don’t just run in parallel — they sometimes converge on the same downstream targets.
But the effects aren’t always additive. Because CB1 activation can suppress glutamatergic transmission, heavy THC could theoretically dampen the cortical excitation psychedelics rely on for their “opening up” effects (Nichols & Grob, 2018). And anyone who’s overdone high-potency THC knows the other risks: anxiety spikes, paranoia, even psychosis-like symptoms (Volkow et al., 2014). Combine that with a destabilizing trip, and you may end up amplifying the wrong aspects of the experience.
What makes this even trickier is that legalization has expanded cannabis access without offering much in the way of guidance on polydrug use. Surveys show cannabis–psychedelic co-use is already common in both recreational and ceremonial settings (Harris et al., 2019), yet harm reduction protocols lag behind.
The ECS isn’t just background noise in psychedelic contexts. It’s a powerful, sometimes complementary and sometimes antagonistic system that shapes how these journeys unfold. To build evidence-based guidelines for co-use, we first need to understand cannabis not just as “weed,” but as a neurochemical modulator that can tilt psychedelic experiences in surprising directions.
The Overlap of Cannabis and Psychedelics
Cannabis and psychedelics, though distinct, share common biological ground that makes their interaction both intriguing and important. By outlining cultural, historical, and scientific contexts, it opens the door for readers to think about co-use beyond stereotypes. This groundwork is essential for the practical, lived-experience focus of the next installment. The journey ahead will move from theory to real-world patterns of overlap.
Stay tuned for part 2, next week!
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!
