Summary: Researchers examine how psychedelic compounds influence brain function and explore their therapeutic potential for a variety of psychiatric conditions.
Source: Stanford
Interest in psychedelic substances—compounds that alter perception, emotion, thought, and behavior—has resurged in both the scientific community and the public sphere. Robert Malenka, MD, Ph.D., the Nancy Friend Pritzker Professor in Psychiatry and Behavioral Sciences at Stanford, has made foundational contributions to our understanding of how individual neurons respond to experience, how those neurons interact within the brain’s reward circuitry, and how those interactions shape social motivation, mood disorders, and addiction.
In recent years, Malenka has been investigating the therapeutic possibilities of psychedelics across several psychiatric disorders. Awarded the Peter Seeburg Integrated Neuroscience Prize by the Society for Neuroscience and the Federation of European Neuroscience Societies, he traces a line from basic discoveries about neural plasticity to new ideas about treating mental illness.
What is synaptic plasticity, and how does it relate to learning, memory, behavior, and habit formation?
Neurons communicate via electrical signals that travel along axons to synaptic terminals, where they trigger release of chemical messengers—most commonly glutamate. Glutamate crosses the tiny gap between neurons and binds to receptor proteins on the receiving cell. Those receptors open ion channels, allowing charged particles to flow and altering the electrical state of the downstream neuron.
These synapses—the connection points between neurons—are the basis for every brain function, from perception to complex thought. Crucially, synaptic connections are not fixed. They change in strength in response to experience. This dynamic ability is called synaptic plasticity.
Synaptic plasticity appears in two main forms: long-term potentiation (LTP), where synaptic communication becomes stronger, and long-term depression (LTD), where it becomes weaker. Malenka’s earlier work showed that experiences such as stress or drug exposure can induce LTP and LTD across thousands or millions of synapses in multiple brain regions.
Plasticity is also essential for brain development as infants mature into adults. Without the capacity to reshape synaptic connections, we could not learn, adapt our behavior, or update how we feel and think.
What is the brain’s reward system, why did it evolve, and how can it malfunction?
The reward system centers on dopamine-producing neurons located deep in the brain. These neurons signal important or rewarding events by releasing dopamine into target regions such as the nucleus accumbens. That chemical signal helps reinforce behaviors that support survival—eating when hungry, seeking social contact, or reproducing—by making those actions feel rewarding and worth repeating.
Addictive drugs hijack this natural circuitry. Substances like cocaine, heroin, nicotine, and alcohol produce dopamine release in the nucleus accumbens at levels that exceed natural rewards. With repeated use, these drugs drive maladaptive changes in synaptic plasticity within dopamine circuits and the nucleus accumbens, contributing to compulsive drug-seeking and addiction. Malenka’s lab helped demonstrate that addiction can be viewed as a pathological form of learning that co-opts the same synaptic mechanisms the brain normally uses to learn and remember.
Current experimental therapies for addiction aim to reverse or normalize these pathological plasticity changes.
Are other psychiatric disorders linked to dysfunction in the reward system?
Yes. An inability to experience pleasure is a core feature of depression, and research in mice indicates that altered synaptic plasticity in the nucleus accumbens and dopaminergic circuits contributes to depressive behaviors. Social interactions are typically rewarding for most people, and synaptic plasticity helps generate those positive effects.
Interestingly, while dopamine is released during social interaction, Malenka’s research highlights an important role for serotonin in promoting positive, non-aggressive social behavior. In mouse models of autism spectrum disorder, serotonin release in the nucleus accumbens is disrupted. The lab tested a compound that mimics certain serotonin actions in this region and found it could restore more typical social behavior in mice. A biotechnology company co-founded by Malenka and Stanford colleague Karl Deisseroth is pursuing these findings and plans clinical testing of related compounds for autism spectrum disorder. Comparable social deficits can also be present in schizophrenia and depression.
What is the clinical potential of psychedelic drugs that have been historically banned?
Malenka and his colleague Boris Heifets, MD, Ph.D., have focused substantial effort on MDMA (commonly known as ecstasy or molly). MDMA enhances prosocial feelings and interactions in humans and is known to trigger substantial serotonin release. In mice, their work links MDMA’s prosocial effects specifically to serotonin release in the nucleus accumbens. Because these effects appear similar across mice and humans, findings in animal models can directly inform how these drugs act in people.
MDMA is under clinical investigation for conditions such as post-traumatic stress disorder, and trials have reported promising results when the drug is combined with psychotherapy. Because MDMA is an amphetamine derivative, it also provokes dopamine release and carries abuse potential. Developing MDMA-like compounds that preserve prosocial and therapeutic benefits while minimizing addictive liability could broaden treatment options for disorders characterized by social withdrawal.
Do other psychedelics show therapeutic promise?
Yes. Heifets and Malenka are also studying psilocybin, which small clinical trials suggest may be effective for severe depression and other conditions. Psychedelics like MDMA and psilocybin are powerful tools for probing brain function: animal studies can reveal which specific synapses and circuits are modified, while carefully controlled human studies with brain imaging can test whether the same pathways are engaged in people.
These substances are potent and can produce both beneficial and harmful effects. Much more research is needed to understand their mechanisms, ensure safety, and develop improved, targeted therapies.
About this psychopharmacology research news
Author: Bruce Goldman
Source: Stanford
Contact: Bruce Goldman – Stanford
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