For more than 50 years, studies have investigated the potential therapeutic aspects of LSD. Researchers are also approaching LSD as a mechanism through which to understand aspects of cognition and human experience, including mysticism, emotionality, creativity, perception, and the way the brain works.
Currently, LSD is being investigated by researchers1 for the possible treatment of depression, treatment-resistant depression (TDR), anxiety, substance misuse, headache disorders, OCD, inflammation and Alzheimer’s, among other medical conditions. Other research looks at LSD’s role in perception, creativity, spirituality, and more.
LSD Science and Research
Things to Know
- LSD is in a class of substances known as tryptamines that act upon the serotonin receptors in the brain; more specifically, LSD is a lysergamide.
- Initial LSD research was carried out in the 1950s and 60s before the compound was made illegal.
- In recent years, North American and European researchers have received government permission to do clinical studies
- The current research looking into LSD focuses on anxiety, depression, Alzheimer’s, microdosing, cluster headaches, and alcoholism.
- LSD disrupts the local connectivity within the brain’s default mode network (DMN) and task-positive networks like the Central Executive Network (CEN), promoting increased global functional connectivity
LSD Chemistry and Neuroscience
Lysergic acid diethylamide (LSD, or LSD-25) is one of the classical psychedelics (which act as serotonergic agonists), also known as tryptamines, which binds primarily to the brain’s serotonin (5-HT) 2a receptors as an agonist. LSD is also known as a lysergamide. In recent literature, the compound has begun to be reclassified as a lysergamide rather than a tryptamine. LSD also binds with dopamine receptors.
LSD makes the relationship between the brain’s default mode network (DMN) and task-positive networks (like the Central Executive Network – CEN) less antagonistic. It increases global functional connectivity and decreases local connectivity. Essentially, the DMN loses its integrity of local connectivity and begins to communicate with other areas like the CEN. Also while under LSD, the energy required to communicate with these areas is reduced, which allows DMN to connect with more areas at a faster rate.2 In effect, an individual might experience what’s called ego dissolution (also referred to as “oceanic boundlessness”).
Research also shows that LSD increases activity in the visual cortex. This increase of activity is due to the density of serotonin receptors within the visual cortex. Hallucinations and visual disturbances associated with LSD are the result of a disruption of communication between the visual cortex and subcortical regions like the thalamus and the claustrum.
LSD was widely studied in the 1960s and generated over 1000 scientific papers. These studies showed positive developments in reducing anxiety during “end-of-life” care, depression3 and alcoholism.
Recent research has explored the mechanism of action of LSD in the brain using modern brain imaging techniques, including arterial spin labeling, blood oxygen level-dependent measures, fMRI, EEG, and magnetoencephalography. These studies have confirmed that changes in brain activity are correlated with the subjective effects of the LSD experience.
One notable study was conducted by Carhart-Harris et al. in 2016. This showed that increases in activity in the visual cortex are associated with hallucinations, but not necessarily with changes in perception associated with treatment benefits. Additionally, decreased brain activity in other areas was connected to the experiential qualities that are presumed to affect positive shifts in mental health and substance use disorders. Both of these findings have implications for future research on LSD’s treatment potential in behavioral health.
The study reports: “LSD’s marked effects on the visual cortex did not significantly correlate with the drug’s other characteristic effects on consciousness, however. Rather, decreased connectivity between the parahippocampus and retrosplenial cortex (RSC) correlated strongly with ratings of “ego-dissolution” and “altered meaning,” implying the importance of this particular circuit for the maintenance of “self” or “ego” and its processing of “meaning”…
The results of this study contribute new insights into the characteristic hallucinatory and consciousness-altering properties of psychedelics that inform on how they can model certain pathological states and potentially treat others.
A 2017 review of prior research referenced in this report evaluated all LSD clinical studies conducted in the past 25 years related to pharmacology, effects, experience, tolerability, and efficacious treatment outcomes4. The overview looked at clinical studies over the past quarter century involving LSD with both healthy populations (five studies) and with patients (one study).
The author’s findings, summarized in the study’s abstract, offer promising information. “In a controlled setting, LSD acutely induced bliss, audiovisual synesthesia, altered meaning of perceptions, derealization, depersonalization, and mystical experiences,” reads the study. “Resting-state functional magnetic resonance studies showed that LSD acutely reduced the integrity of functional brain networks and increased connectivity between networks that normally are more dissociated… LSD acutely induced global increases in brain entropy that were associated with greater trait openness 14 days later.
In patients with anxiety associated with life-threatening disease5 (with research dating back to 1969), anxiety was reduced for [two] months after two doses of LSD. In medical settings, no complications of LSD administration were observed.”
This is important because, when resting-state functional connectivity (RSFC) operates at equilibrium when we’re mostly in the default mode network. When we do something, this RSFC gets disrupted and energy is used to complete a task (task-positive network/CEN). So the decreased integrity of the DMN correlates with the decreased integrity of RSFC.
Research continues to investigate the possibility that LSD could contribute to a healthier brain, which could also support its potential in mental and behavioral health treatments. A 2021 pharmacological study from Maastricht University found that healthy people who microdose with LSD show increases in brain-derived neurotrophic factor (BDNF) levels6. BDNF stimulates the growth of new brain cells and assists in healthy synaptic connections, improving learning and memory. Conversely, a drop in BDNF7 is correlated with cognitive decline and depression.
Recently, a groundbreaking study8 emerged from Finland that shows the therapeutic effects of LSD (and other psychedelics) may not necessarily be because of serotonin activation, but another receptor entirely called TrkB.
LSD Clinical Trials
In the current era of research, some two dozen clinical trials have been conducted with LSD, including investigations into the effects of microdosing LSD. Unlike psilocybin, MDMA, and ketamine, LSD has been used in few rigorous Phase 2 trials. The duration of an LSD trip and historical stigma makes it a less likely candidate to be developed as a medicine.
The trials with LSD focus not only on mental health disorders, but also serve a purpose for better understanding how our brains work. For instance, one study investigated the role of dopamine and serotonin after LSD administration and how this affected emotional processing. Studies like this can then inform those which more directly study mental health disorders in which emotional processing is disturbed.
Some current clinical trials are studying:
- LSD for cluster headaches
- LSD treatment for alcoholism
- Comparative effects of LSD, psilocybin, and mescaline
- LSD therapy for major depression
- LSD treatment for people with illness-related anxiety