It is tempting to speculate that the increase in connectivity between brain regions induced by LSD could ultimately be due to the increase in the number of connections between neurons in two or more brain regions, carried out by a boost in the number of synapses.
Depression is a staple of modern times, with approximately 350 million people from all ages across the world suffering from the disease. It is the most common mental health condition, with patients displaying a range of symptoms like prolonged sadness, apathy or anhedonia, feelings of guilt or low self-worth, among others. Severe depression can lead to suicide and an overall increased risk of mortality. According to the World Health Organization, depression will rank second in global disease burdens in 20201. In fighting the high societal costs associated with it, medical research on depression is currently facing two key challenges. On the one hand, from a neurobiological perspective, we still do not fully understand the mechanisms underlying depression. On the other hand, many of the available treatments are either ineffective or only partially effective2.
Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed class of antidepressant drugs. However, only 56% to 60% of patients respond to this type of therapy3. Moreover, their antidepressant effects only start to show with a delay of about two to four weeks, and many patients report side effects like dry mouth, weight gain, headaches, and loss of sexual desire4. The lack of effective therapies for depression can also be attributed to the fact that, even after decades of research, there is no consensus on what causes depression, and which neurobiological mechanisms are affected. Yet, one important insight from basic research has been the association of the development of depressive-like states with chronic stress exposure, driving research for effective therapies5,6.
It is well known that stressful life events can induce a depressive episode. Hence, while minding the difficulties in transferring this knowledge to living humans, in animal and laboratory experiments one can study how stress impacts the brain and individual neurons. Such research has shown that exposure to stress can profoundly affect structural plasticity, which is the capacity of neurons to alter their morphology upon stimulation. In most neurons, stress exposure leads to reductions in the number of dendritic spines, the main place where neurons connect and communicate (for a brief explanation of the neuronal morphology and the synapse see Figure 1). The issue increases in complexity with the observation that stress impacts the brain in a region-specific manner7,8. In the amygdala, an important center for emotional processing, stress leads to increased complexity of the neuronal morphology, due to an increase in the number of synapses9. In contrast, in other brain regions like the hippocampus and the pre-frontal cortex, important brain centers for the processing of declarative memories and decision-making, stress leads to reductions in complexity, due to a decrease of synaptic contacts, a phenomenon known as “synaptic stripping”6.
Cornered by the limited success of currently available treatments for depression, medical and scientific communities are now reaching out to psychedelic compounds, which seem to herald a new era in the treatment of psychiatric diseases. In a first clinical trial, psilocybin and MDMA have been shown to alleviate symptoms of depression for at least two months10,11. Remarkably, these studies involved patients with treatment-resistant depression. Moreover, ketamine has a fast-acting profile and received approval from the US Food and Drug Administration, designating it “breakthrough therapy” for depression in 2018. In light of the aforementioned stress-induced changes to neural morphology, this poses the question of whether psychedelic compounds have the capacity to revoke such changes in neuronal morphology and whether this may be linked with their therapeutic effects. Recently, a study from the lab of David Olson at the University of California, Davis, tackled this question by investigating the effect of psychedelic compounds on neuronal morphology, in terms of dendritic length and branching, as well as spine number and morphology. Like tree branches, dendrites are cellular specializations that increase the reach of a given neuron and, thereby, their connectivity (See figure 1). Therein, they have shown that psychedelic compounds from distinct classes have the property to increase the number of synaptic contacts, inaugurating a new classification for psychedelic compounds: the psychoplastogens12.
The term psychoplastogens refers to compounds that have profound psychedelic effects plus the capacity to alter the morphology of neurons. In the study of David Olson’s lab12, the authors asked the question of whether psychedelic compounds from different classes (and therefore with distinct pharmacological targets) have the capacity to alter the morphology of neurons, therefore altering the probability of contact between neurons. To do that, the group used in-vitro methods, that is they took living neuronal cell cultures from rat brains and incubated them with different concentrations of psychedelic compounds. They described that LSD-25, MDMA, DMT, ketamine, psilocin (the active form of psilocybin), and other psychedelic compounds have the potential to induce changes in the number of synaptic contacts, as well as in the structure of neurons, by increasing the number and length of their dendritic branches. Moreover, based on the results obtained with the in-vitro experiments, the authors tested whether DMT could also induce alterations on neuronal morphology when injected in a living animal. Similar to the in-vitro data, they found that injected DMT also promoted an increase in the number of spines in the prefrontal cortex of rats. This effect was accompanied by changes in neuronal activity, demonstrated by electrophysiological recordings of brain slices of rats that received DMT.
What is so surprising about this study is that all the tested psychedelic compounds displayed similar psychoplastogenic effects, despite them targeting different classes of pharmacological receptors. Therefore, the research group went on to investigate the underlying mechanisms promoting the psychoplastogenic effects. It is well known that certain messenger molecules, like so-called ‘brain factors’, can induce changes in neuronal morphology. Of those, brain-derived neurotrophic factor (BDNF) is one of the most studied molecules. BDNF is a member of the neurotrophin family of growth factors, playing a key role in neuronal survival, growth, and differentiation of new neurons and synapses. It is highly abundant in brain regions involved in learning and higher cognition, such as the hippocampus and different cortical areas13. Interestingly, BDNF production can be induced by exercise and, conversely, disrupted by stress14,15. In the present study, the authors found that inhibiting BDNF function, through blockade of its membrane receptors called TrkB receptors, completely abolished the psychoplastogenic effects of compounds like LSD, DMT, and MDMA, suggesting that BDNF signaling might be a common mechanism underlying the effects of different psychedelic compounds on structural plasticity.
The effects described by the group of David Olson are indeed compelling, but the question of whether the same psychoplastogenic effect is also observed when psychedelic compounds are given to animals that were subjected to stress remained. Recently, a seminal study has shed light on this question by using advanced technology to image real-time changes in synaptic contacts induced both by stress and by ketamine in the brain of living mice16. The authors used a chronic stress exposure protocol, which is known to induce depressive-like behavior accompanied by a reduction of dendritic spines in neurons of the prefrontal cortex. Employing two-photon imaging, they tracked the fate of a subset of dendritic spines in the prefrontal cortex and showed that some of them disappeared after chronic stress. Interestingly, a single antidepressant dose of ketamine was able to rescue the spines that were lost due to chronic stress. Moreover, the authors went on to show that the ketamine-induced restoration of lost spines is, in fact, crucial for the behavioral effects of the drug. Overall, ketamine treatment restores lost spines and normalizes microcircuit activity in the prefrontal cortex, leading to the remission of depression-like behavior in mice. Figure 1 provides a graphical representation of the main findings from both studies12,16.
The results discussed above warrant further questions: Is the effect of ketamine region-specific? If yes, does ketamine also induce structural plasticity changes in brain regions like the hippocampus and the amygdala? And, given that other psychedelic compounds, like psilocybin and MDMA, also display a similar fast-acting and long-lasting therapeutic profile as ketamine, do they also have the ability to rescue dendritic spines that were lost due to chronic stress?
Figure 1: A brief explanation of relevant cellular neuroanatomical structures. Graphical representation of the major findings from A) Ly and coworkers12 and B) Moda-Sava and coworkers16 – adapted from Beyeler17.
Could Structural Plasticity be the Underlying Mechanism of the Psychedelic Experience?
The studies discussed above pose a further question, regarding the acute effect of the psychedelic experience. Namely, could structural plasticity be the cellular effector of the psychedelic experience? To date, neuroimaging methods employed in human brain research do not confer enough resolution for the visualization of dendritic spines. Nevertheless, several studies have looked at the effect of psychedelic substances on the brain, using a variety of neuroimaging methods. From the seminal work of Carhart-Harris and coworkers in 201618, we have learned that LSD alters brain blood flow, electrical activity, and network communication and that this correlated with the subjective effects of the drug. It is tempting to speculate that the increase in connectivity between brain regions induced by LSD could ultimately be due to the increase in the number of connections between neurons in two or more brain regions, carried out by the boost in the number of synapses. A potential involvement of structural plasticity in the psychedelic experience again raises many questions, such as: Do psychedelic compounds impact structural plasticity in a timeframe that correlates with the psychedelic experience? And, could structural plasticity be responsible for the long-term effects of the psychedelic experience?
The basic research on the psychoplastogenic effects of psychedelic drugs, which has been introduced above, greatly contributes to our understanding of the effects of psychedelic compounds on the brain. Ly and coworkers12 published the first study to systematically show the effect of different chemical classes of psychedelics on the growth of both dendrites and dendritic spines, and Moda-Sava and collaborators16 were able to show that the ketamine-induced restoration of dendritic spines in neurons of the prefrontal cortex is pivotal for its long-term effects in mice. As the current psychedelic renaissance evolves, and interest and funding increase19, some of the key questions outlined above will hopefully be addressed by taking advantage of more powerful neuroimaging techniques and analysis algorithms. The basic research community will also be able to produce important insights into the molecular mechanisms of psychedelics, using a wide range of new technologies, combining genetic engineering and neuroscience, in order to better understand how psychedelics impact neuronal morphology and synaptic connectivity and, thereby affect overall brain activity and bring about their therapeutic effects. Engaging in this endeavor can bring insights not only to the quest for new treatments for psychiatry disorders but also for the understanding of the neurobiological basis of consciousness and self.