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Surprising new research links LSD-induced brain entropy to seizure protection
Two recent studies conducted by scientists at the University Health Network and the University of Toronto provide new evidence regarding the effects of lysergic acid diethylamide (LSD) on the brain. The findings suggest that this psychedelic compound may have unexpected neuroprotective properties against severe seizures in mice.
Additionally, the research indicates that LSD significantly alters the electrical stability of brain networks. These papers, published in Next Research and Brain Research, challenge conventional assumptions about psychedelics and safety in the context of epilepsy.
Lysergic acid diethylamide is a potent psychoactive substance known for its ability to alter perception, mood, and cognitive processes. It functions primarily by binding to serotonin receptors in the brain. These receptors are proteins that receive chemical signals to regulate various biological functions. While LSD is famous for its recreational use and its ability to induce hallucinations, medical researchers are increasingly examining its potential therapeutic benefits. Past studies suggest it may help treat conditions such as depression and anxiety.
The rationale for investigating LSD in the context of seizures stemmed from a need to improve treatments for epilepsy. Epilepsy is a neurological disorder characterized by recurrent seizures. It affects roughly 50 to 60 million people globally. Current medications fail to control seizures in about one-third of patients. This drug resistance creates an urgent need for alternative therapeutic approaches.
“This work started in a completely different direction than it ended up going in,” said study author Brenden Rabinovitch, a PhD student affiliated with the University of Toronto and the Krembil Brain Institute.
The researchers initially designed the study to test the safety of LSD rather than its efficacy as a treatment. They were interested in using psychedelics to treat functional seizures. Functional seizures are behavioral events that resemble epileptic seizures but are psychological in origin. They do not involve the abnormal electrical discharges seen in epilepsy. Because some patients suffer from both epilepsy and functional seizures, the scientists needed to verify that LSD would not worsen epileptic seizures before proposing it as a treatment.
“We thought this was a fascinating phenomenon that psychedelics could potentially treat due to their therapeutic promise in functional neurological disorder and other psychiatric disorders,” Rabinovitch said. “However, we knew this was very non-traditional, since psychedelics are often treated as potential seizure-inducing drugs, although there is no evidence to suggest this is true in the context stated (we also wrote a review on this recently).”
“Now, it is also important to consider that between 9–11% of epilepsy patients have some functional seizures. If a drug we think may treat functional seizures also has a risk of inducing seizures, that is a clear conflict. Thus, we initially set out to do a ‘safety’ experiment, and we viewed a ‘positive’ result as one in which LSD had no effect on epileptic seizures at all. When we saw that certain behavioural characteristics of seizures actually improved in these mice, we were shocked to say the least.”
The first study, published in Next Research, utilized a mouse model to observe the effects of LSD on acute seizures. The researchers worked with adolescent male and female C57BL/6J mice. They divided the animals into groups and administered either a saline solution or LSD. The LSD was given at doses of 17 or 30 micrograms per kilogram. Forty minutes after this pre-treatment, the researchers injected the mice with kainic acid. Kainic acid is a chemical that mimics the neurotransmitter glutamate. It overstimulates neurons and reliably induces seizures in rodents.
The researchers recorded the behavior of the mice for eighty minutes following the injection. They used a modified version of the Racine scale to measure seizure severity. This scale rates behaviors from mild stages, such as facial movements and freezing, to severe stages, such as full-body convulsions and continuous seizing. The team analyzed the video footage to determine how the pre-treatment influenced the onset, severity, and outcome of the seizures.
The results revealed a distinct difference between the treated mice and the control group, particularly among the males. In the control group, nearly 40 percent of the male mice progressed to status epilepticus. Status epilepticus is a medical emergency where a seizure lasts longer than five minutes or seizures occur close together without recovery. This state is life-threatening. In the control group, roughly 23 percent of the male mice died as a result.
The mice treated with the higher dose of LSD showed a complete absence of status epilepticus. None of the male mice in the 30-microgram group entered this dangerous state, and none of them died. The lower dose of LSD also provided protection, reducing the incidence of severe seizures and death compared to the controls. The drug appeared to alter the early stages of the seizure as well. The treated mice spent more time in a “freezing” state and less time performing repetitive involuntary movements known as automatisms.
“We thought that the best-case scenario was LSD would have no effect on the behavioural seizure characteristics,” Rabinovitch told PsyPost. “At worst, we thought the mice might go into status epilepticus—a prolonged, life-threatening seizure state—and we would urgently need to treat them with an anti-epileptic drug and provide fluids and other supportive treatments until the LSD was fully out of their system.”
“I almost did not believe it when I did the seizure-induction injections and some of the mice did not progress past stage 1 or 2 on the Racine scale, which is a standard measure of seizure severity ranging from mild facial movements at stage 1 up to full convulsive seizures at stage 5.”
The results for the female mice were less dramatic. The female control group was naturally more resistant to the kainic acid and did not experience status epilepticus or death even without the drug. However, the researchers noted that LSD increased the variability of the behavioral responses in both sexes. This suggests that the drug affects individuals differently, leading to a wider range of reactions.
To understand the mechanism behind these behavioral changes, the scientists focused on how LSD modulates the electrical activity of the brain in freely moving mice. The researchers surgically implanted electrodes into the brains of male mice. They targeted two specific regions: the hippocampus and the cortex. The hippocampus is essential for memory and navigation, while the cortex is involved in sensory processing and decision-making.
After the mice recovered from surgery, the researchers recorded their baseline brain activity using intracranial electroencephalography (iEEG). They then administered the same 30-microgram dose of LSD used in the seizure study. They continued to record the electrical signals to observe changes in neural oscillations. Neural oscillations, or brain waves, are rhythmic patterns of electrical activity produced by the synchronized firing of neurons.
The analysis, published in Brain Research, showed that LSD caused a broad reduction in the power of these brain waves. The term “power” in this context refers to the strength or amplitude of the electrical signal. The researchers observed this decrease across all measured frequency bands, including delta, theta, alpha, and beta waves. This effect was most pronounced in the ventral hippocampus, a region associated with emotional memory.
In addition to reducing signal power, the drug increased the variance of the brain activity. Variance refers to the fluctuation or instability of the signal over time. The brain waves became less predictable and more heterogeneous after LSD administration. This finding aligns with the “entropic brain” theory. This hypothesis suggests that psychedelics work by increasing the entropy, or disorder, within the brain. They disintegrate rigid, organized networks and allow for a more flexible state of connectivity.
The scientists propose a theoretical link between the two studies. Seizures are characterized by hypersynchronization. This means that large groups of neurons fire together in an excessive and rigid pattern. By inducing a state of desynchronization and lowering the power of neural rhythms, LSD may make it difficult for this hypersynchronized seizure activity to organize and spread. The drug essentially introduces enough noise or “chaos” into the system to prevent the seizure from generalizing across the brain.
The researchers emphasize that these findings are preliminary. There are several limitations to consider. Both studies were conducted in mice, and human brain physiology is significantly more complex. The protective effects against status epilepticus were clear in male mice, but the differences were harder to assess in females due to their natural resistance to the seizure model used. Additionally, the variability in the responses suggests that the effects of LSD are highly individual-specific.
The scientists also caution against interpreting this as a recommendation for using LSD to treat epilepsy directly. The study used a specific timing for the dosage relative to the seizure induction. In a clinical setting, predicting when a seizure will occur is often impossible.
“The average person should not look at this and immediately think that we should start dosing people with LSD to cure their seizures,” Rabinovitch said. “I think people can take away the idea that epilepsy may be a condition which benefits from multi-target drugs rather than classical single-target anti-seizure medications (ASMs), which have focused on blocking excitatory and enhancing inhibitory transmission in the brain.”
“Epilepsy is complex, so maybe complex drugs could be of benefit to individuals who are ‘drug-resistant’—meaning their seizures persist after having tried two or more classical ASMs. More broadly, novel treatments in the future of epilepsy drug development may want to focus on drugs with broad, multi-mechanism pharmacology instead of focusing on single mechanisms that may differ from person to person.”
The primary long-term goal for the researchers is to explore the use of LSD for functional seizures. Since functional seizures are psychogenic, the psychological effects of psychedelics could address the root cause of the disorder. The fact that the drug appears safe—and potentially protective—regarding epileptic seizures removes a significant barrier to testing it in patient populations who may have both conditions.
“In the long term, we would love the opportunity to run a clinical trial with patients who have functional seizures but do NOT have epilepsy,” Rabinovitch explanined. “This would be the ideal population since we think they would stand to benefit the most from treatment due to the psychological nature of their seizures, absent other neurological pathologies.”
“Looking ahead, we would love to follow up by examining how the electrical (EEG) signal of mice undergoing seizures may be altered with LSD. We are also interested in more translational questions around the framing of treatment. For example, does it make sense to ‘treat’ seizures with LSD directly, or is LSD something that may augment concomitant anti-seizure medications? It is also not clear that LSD would work like a traditional rescue medication such as diazepam, because when and how often it is given likely has a substantial effect on outcomes. This was a preliminary investigation, so we naturally have many ideas for how this could play out.”
The scientists urge the medical research community to remain open to ideas that might initially seem counterintuitive. They note that epilepsy is still a surprisingly misunderstood condition given how many people it affects globally.
“This has resulted in nearly all anti-seizure medications being different flavors of the same idea for over 50 years,” Rabinovitch said. “This is likely a contributing factor to 1/3 of epilepsy patients being treatment-resistant with uncontrollable seizures. When we look at the blossoming of psychedelic research in recent years, it is quite clear that these drugs—when used appropriately in controlled clinical settings with physician supervision—have potential ameliorative effects for many more conditions than we had previously thought.”
The study, “Lysergic acid diethylamide inhibits status epilepticus and mortality in a mouse model of acute kainic acid-induced motor seizures,” was authored by BS Rabinovitch, W Hu, C Tang, N Silverman, EC Lewis, and PL Carlen.
The study, “Lysergic acid diethylamide modulates hippocampal and cortical local field potential oscillatory rhythms in male mice,” was authored by B.S. Rabinovitch, N. Silverman, D. Ji, D. Shizgal, E.C. Lewis, and P.L. Carlen.
