Psychedelic Therapy and Mood Disorders: Where Are We with the Research?

Mood disorders are conditions that affect both the psychological and physical aspects of a person. The main disorders include major depression, characterized by persistent sadness, fatigue, and tiredness, and bipolar disorder, which is marked by irregular alternating periods of happiness and euphoria followed by mood dips.

“Mood disorders are multifactorial conditions. They can arise from biological, environmental, or genetic factors, or be triggered by chronic medication use or traumatic life events,” explains Professor De Gregorio.

According to the World Health Organization, approximately 280 million people worldwide suffer from major depression, while in Italy alone, approximately 6-7 million people are affected by mood disorders. Before the COVID-19 pandemic and the forced social isolation we all experienced, the numbers were around 4 million.

“These are certainly significant numbers that we need to reflect on. In particular, the incidence of mood disorders, whether depressive or bipolar, is higher in the female population,” continues the professor.

Demographic data shows that young adults, aged between 20 and 45-50, are most vulnerable to these conditions, although there are mood disorders that affect younger individuals or the elderly.

According to neurobiology (a branch of biology studying the nervous system), the cause of mood disorders is also multifactorial.

“Historically, the main cause attributed to the onset of these disorders is the alteration of certain neurotransmission mechanisms, such as those mediated by serotonin and norepinephrine. It has long been believed that a decrease in the production of these neurotransmitters is the cause of depressive symptoms. In major depression, for example, a reduced production of serotonin in certain brain areas is observed, which is involved in various functions, including mood regulation,” explains Professor De Gregorio.

However, beyond the alteration of serotonin pathways, it appears that mood disorders are also associated with dysfunction and a deficiency in glutamate-mediated transmission, another neurotransmitter.

“Finally, research has shown that mood disorders are associated with immune system dysfunction and a persistent inflammatory state throughout the body, as studied in our hospital by Professor Francesco Benedetti’s research unit,” adds De Gregorio.

Professor De Gregorio started his career as a neuropharmacologist and later shifted his focus to neuropsychopharmacology. Initially, his lab focused solely on psychiatric disorders, with particular attention to mood disorders. Today, he states, “We also deal with other psychiatric conditions, such as pathological addictions: we have projects concerning both major depression and the chronic impact of alcohol consumption.”

One of the primary goals of the pre-clinical research led by De Gregorio is to investigate the functioning of hallucinogens and psychedelics in the treatment of mood disorders and pathological addictions through neural, morphological, and behavioral analysis in various mood disorder models.

Hallucinogenic substances temporarily alter the sensations, perceptions, and consciousness of the individual who consumes them, and their potential therapeutic benefits are a subject of international debate.

“These substances have very complex pharmacology, which also depends on the type of condition they are used to treat. Although there are standardized clinical therapies for these conditions, such as the use of antidepressants like serotonin reuptake inhibitors, only 30% of patients respond positively and benefit from them.

For this reason, it’s essential to explore new therapies and pharmacological strategies to increase the percentage of responsive patients. Our interest is to understand how hallucinogens and psychedelics work, after thirty years in which research on them has remained stagnant,” says De Gregorio, highlighting some of the challenges of current treatments for mood disorders.

A long period indeed, since by the 1970s, psychedelics were classified as substances of abuse, with no potential therapeutic benefits. However, research on these substances dates back to 1938 when Swiss chemist Albert Hofmann, in an attempt to create a new antihypertensive, accidentally synthesized LSD (lysergic acid diethylamide), a hallucinogenic substance capable of altering perceptions and moods, which he tested on himself.

Talking about psychedelics means discussing a particular class of substances known as ‘hallucinogens.’ These substances produce visual hallucinations and other phenomena, such as synesthesia, where two or more senses are perceived together or in contrast. For example, synesthesia might occur when one perceives a color while listening to a sound or smelling it.

Another phenomenon associated with the use of hallucinogens is ego-dissolution, a form of delirium that induces an individual to detach from reality and create a deeper connection with themselves.

Among hallucinogens, we recognize two classes of substances:

• Psychedelics, such as LSD, mescaline, or psilocybin.
• Dissociative anesthetics, such as ketamine, which generate a sense of ‘detachment’ from reality.

“In our Neuropsychopharmacology Unit, directed by Professor Flavia Valtorta, we experimentally study the effect of ketamine and LSD on preclinical models of major depression and chronic alcohol consumption disorders,” says Professor De Gregorio.

From a neuropharmacological perspective, hallucinogens work by interacting with receptors, protein structures found on the cell membrane of neurons, to which specific neurotransmitters bind.

Psilocybin, derived from hallucinogenic mushrooms, is an example of a psychedelic currently undergoing experimental trials in some countries, such as the United States and Switzerland, for the treatment of major depression forms resistant to approved antidepressant treatments.

Psilocybin acts by activating the serotonin 5HT2A receptor. However, when an agonist substance like psilocybin binds to a receptor, it enhances serotonin’s action, inducing a stronger biological response.

Ketamine and its chemical derivative, esketamine, on the other hand, “represent a major breakthrough in psychiatry,” explains De Gregorio. Unlike psilocybin, ketamine, a dissociative anesthetic, was approved for therapeutic use in Italy in 2023, but only for patients with treatment-resistant depression.

From a neuropharmacological perspective, ketamine is an antagonist that blocks the NMDA receptor for glutamate. In addition to modulating the excitatory activity of glutamate, ketamine also affects the GABAergic system, which uses the neurotransmitter GABA. Unlike glutamate, GABA inhibits neuronal activity.

Ketamine works by blocking NMDA receptors on GABAergic neurons, thereby preventing GABA from blocking glutamate transmission.

“So, it’s as if ketamine removes the ‘inhibitory brake’ represented by GABA and enhances glutamatergic transmission,” says the professor.

Why use hallucinogens to treat mood disorders? One advantage of this therapeutic approach is the potential for rapid benefits, given the relatively quick action of these molecules.

“For example, ketamine or esketamine take effect after just one administration, within a few hours. On the other hand, a classic antidepressant therapy typically takes at least 3 or 4 weeks to show results: for a patient with severe depression, it is crucial that the therapeutic effect is timely,” continues De Gregorio.

Additionally, it is important to note that, aside from ketamine, these substances do not create dependence, contrary to previous beliefs. They do not engage the ‘reward and gratification system,’ which is typically involved in addiction behaviors.

The use of hallucinogen and psychedelic therapy has several advantages but requires carefully defined guidelines and tightly controlled protocols.

“Psychedelics, especially at high doses, can cause side effects such as hallucinations that need to be monitored. This means that this type of treatment must take place in a well-defined and controlled therapeutic environment,” emphasizes the professor.

Once the first dose of psychedelics is administered, the patient must be monitored for at least 12 hours in a relaxed environment where they feel protected, especially after experiencing something like a hallucination.

“There are specialized clinics for psychedelic therapy administration in the United States and Switzerland, where the patient is properly followed by specialized doctors and accompanied by a nurse and a psychotherapist,” explains De Gregorio.

Psychedelics could represent a possible alternative for treating mood disorders, particularly in cases of severe, treatment-resistant depression, which is why international research and debate around these substances are now very intense. However, mental health remains a particularly sensitive topic:

“There is still a stigma surrounding psychiatric disorders. It’s difficult to consider them as ‘serious’ diseases because they are seen as illnesses that impact less immediately compared to others. These diseases are also wrongly associated with a weakness of character, when in fact, there is a biological impairment underneath them,” says the professor.