Weed and LSD: Brain Activity and Neurotransmitters

Psychoactive substances like LSD and cannabis alter perception, mood, and cognition by interacting with key neurotransmitter systems in the brain. While both drugs produce distinct effects, their influence on neural activity provides insight into how different chemical pathways shape consciousness.

LSD And Serotonergic Pathways

Lysergic acid diethylamide (LSD) exerts its effects primarily through the serotonergic system. It is a potent partial agonist at the 5-HT2A receptor, a serotonin receptor densely expressed in the prefrontal cortex and other brain regions involved in sensory processing and higher-order cognition. By binding to these receptors, LSD disrupts normal serotonergic signaling, leading to altered perception, time distortion, and changes in self-awareness. Neuroimaging studies using fMRI and PET scans have shown that LSD induces hyperconnectivity between brain regions that typically do not communicate extensively, contributing to its hallucinogenic effects.

The 5-HT2A receptor plays a key role in modulating cortical excitability and synaptic plasticity. Under normal conditions, serotonin regulates mood, cognition, and perception by fine-tuning neural activity. LSD prolongs receptor activation by preventing serotonin reuptake and degradation, leading to sustained excitatory signaling. This results in increased glutamate release in the cortex, amplifying sensory input and disrupting predictive coding mechanisms. As a result, individuals under LSD experience intensified colors, enhanced pattern recognition, and a breakdown of the usual boundaries between self and environment. Studies published in Cell Reports and Neuropsychopharmacology indicate that this dysregulation of predictive processing contributes to LSD’s profound alterations in consciousness.

Beyond perception, LSD affects mood and cognition by modulating activity in the default mode network (DMN), a collection of brain regions involved in self-referential thought and introspection. Research has shown that LSD significantly reduces DMN activity, leading to a temporary dissolution of the ego and a sense of interconnectedness with the external world. This effect has been linked to its potential therapeutic applications, particularly in treating depression, anxiety, and post-traumatic stress disorder (PTSD). Clinical trials conducted by the Multidisciplinary Association for Psychedelic Studies (MAPS) suggest that LSD-assisted psychotherapy can produce lasting reductions in mental health symptoms, likely due to its ability to promote neuroplasticity and emotional processing.

Cannabis And The Endocannabinoid Network

Cannabis affects the brain by interacting with the endocannabinoid system (ECS), a network of receptors, endogenous ligands, and enzymes that regulate neurological and physiological processes. The primary psychoactive compound in cannabis, delta-9-tetrahydrocannabinol (THC), mimics endogenous cannabinoids by binding to cannabinoid receptors, particularly CB1 receptors, which are densely distributed in areas involved in memory, motor coordination, and sensory integration. When THC activates CB1 receptors, it disrupts neurotransmission by modulating excitatory and inhibitory neurotransmitter release, leading to altered perception, impaired short-term memory, and changes in motor control.

The ECS functions as a neuromodulatory system, fine-tuning synaptic activity to maintain homeostasis. Endogenous cannabinoids such as anandamide and 2-arachidonoylglycerol (2-AG) act as retrograde messengers, traveling backward across synapses to regulate neurotransmitter release. This mechanism suppresses excessive excitatory signaling, preventing neuronal overstimulation. When THC binds to CB1 receptors, it mimics this process but with prolonged effects, dampening glutamatergic and GABAergic signaling. This disruption contributes to cannabis’s characteristic effects, such as relaxation, euphoria, and altered sensory perception. Studies published in Nature Neuroscience and The Journal of Neuroscience indicate that chronic THC exposure can desensitize CB1 receptors, reducing their responsiveness and potentially contributing to cognitive impairments and tolerance development.

Cannabis also contains cannabidiol (CBD), a non-intoxicating cannabinoid that interacts with the ECS in a more indirect manner. Unlike THC, CBD has low affinity for CB1 receptors and instead modulates their activity by inhibiting the enzyme fatty acid amide hydrolase (FAAH), which degrades anandamide. By increasing anandamide levels, CBD enhances endogenous cannabinoid signaling without directly inducing the psychoactive effects associated with THC. Additionally, CBD influences serotonin (5-HT1A) and transient receptor potential vanilloid (TRPV1) receptors, contributing to its anxiolytic and anti-inflammatory properties. Clinical trials published in JAMA Psychiatry and The New England Journal of Medicine suggest CBD’s potential in treating epilepsy, anxiety disorders, and chronic pain by modulating ECS activity without intoxication.

Combined Neurotransmitter Dynamics

The interplay between neurotransmitter systems reveals how different psychoactive compounds influence cognition and perception through overlapping yet distinct mechanisms. While receptor interactions shape immediate effects, broader neural connectivity shifts highlight the complexity of altered states of consciousness. Cross-talk between neurotransmitter systems occurs through secondary signaling pathways, where receptor activation in one system modulates another. This dynamic interplay explains why substances with different primary targets can produce overlapping psychological and physiological responses.

Excitatory and inhibitory balance is a primary factor in how these substances reshape neural activity. Dysregulation of excitatory neurotransmitters such as glutamate exaggerates sensory processing, heightening awareness of external and internal stimuli. Simultaneously, disruptions in inhibitory control, particularly through GABAergic pathways, reduce the brain’s ability to filter irrelevant information. This dual effect contributes to the intense perceptual distortions and cognitive shifts reported in altered states. Functional neuroimaging studies show that these changes involve large-scale network reconfigurations. Increased connectivity between regions that normally function independently results in novel associations and fluid cognitive processing, which may underlie both creative insights and disorganized thought patterns.

Neuroplasticity also plays a role in the lasting effects of neurotransmitter modulation. Changes in synaptic strength and receptor density can persist beyond the acute effects of a substance, influencing mood, cognition, and behavior over time. This phenomenon is particularly relevant in therapeutic contexts, where repeated modulation of neurotransmitter systems can lead to sustained mental health improvements. Electrophysiological studies show that synaptic remodeling occurs in response to altered neurotransmission, reinforcing the idea that these substances do not merely induce temporary shifts in perception but can also drive long-term adaptations in brain function.