What are psychedelics?
Psychedelics are substances that act on the central nervous system, mainly through serotonin receptors, causing altered states of consciousness. These include, in addition to possible hallucinations, “mystical experiences, ego dissolution, synesthesia, increased emotional charge, giving meaning to present or past experiences, softening points of view, and changing patterns and behaviors,” lists SMC Spain Rosa Mª Dueñas, psychiatrist, therapist, and researcher at the Parc Sanitari Sant Joan de Déu and Institut de Recerca Sant Joan de Déu, ANIMA group. These are profound and transient changes in perception, cognition, and emotion, with physiological alterations such as increased heart rate. Their effects depend on the substance, dose, person, and context.
The best-known psychedelics include psilocybin, which comes from certain mushrooms; artificially synthesized LSD; mescaline, extracted from peyote and San Pedro cacti; DMT, present in ayahuasca; and 5-MeO-DMT, which comes from a toad and some plants.
What substances are being researched and for what purpose?
In general, the study of these substances is in the clinical trial phase, some of them in Spain, with very few drugs authorized and only in some countries. Broadly speaking, the substances studied and their possible applications are:
- Psilocybin. The most studied and closest to approval, along with MDMA. It has low toxicity, its neurobiological mechanism of action is well understood, and the duration of its effect is compatible with structured clinical work. Research is focused on the treatment of depression, with clinical trials already in phase III. Psilocybin is also being studied for anxiety and depression associated with end of life or serious illness, addictions, or anorexia.
- MDMA. There are several phase III trials for post-traumatic stress disorder. MDMA is also being investigated for the treatment of anxiety, addictions, eating disorders, or emotional distress and existential angst in seriously ill and terminally ill patients.
- LSD. This psychedelic was extensively researched for the treatment of alcoholism beginning in the 1950s. It is currently being studied primarily for the treatment of depression and anxiety. For generalized anxiety, there are already phase III trials. Some other uses being explored include the treatment of pain and headaches or insomnia.
- DMT and 5-MeO-DMT. Both substances are similar in their rapid onset and short duration, and are being explored for depression and other conditions, such as anxiety, post-traumatic stress, alcoholism, and trauma, although there is still less solid scientific evidence.
- Ketamine and esketamine. The former consists of two enantiomers, mirror images of the same molecule, and the latter only one, which gives them different properties. Ketamine is in phase III trials for the treatment of alcoholism and, in less advanced phases, for depression. Esketamine has already been approved for treatment-resistant depression by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) and is also being studied for alcohol abuse.
- Ibogaine. Mainly in trials for the treatment of addictions.
Not all of these substances are psychedelic: strictly speaking, MDMA and ketamine belong to other groups. Antón Gómez Escolar, who has a master's degree in psychopharmacology and is a science communicator, points out that the term is sometimes used “more broadly to also include empathogens-entactogens such as MDMA, or dissociatives such as ketamine,” because “both substances are studied under the umbrella of psychedelic-assisted therapies and share some elements of the therapeutic model.” For his part, Eduard Vieta, head of the Psychiatry and Psychology Service at Hospital Clínic de Barcelona and researcher at the Center for Biomedical Research in Mental Health (CIBERSAM), explains to SMC Spain that the inclusion of MDMA and ketamine in the group of psychedelics is not correct: “True psychedelics are serotonergic agonists.”
Why are they being studied, and why now?
Psychotropic drugs—anxiolytics, antidepressants, or antipsychotics—cross the blood-brain barrier to act on the central nervous system, as psychedelics do. This is one of the reasons why these types of drugs are being explored as possible new pharmacological treatments for mental health. But the main reason is the body of evidence of their therapeutic value.
And why now? "The main reason is that there has been no innovation in psychopharmacology for more than 50 years, that the effectiveness of current treatments is limited, with side effects that are becoming increasingly apparent; and there is renewed interest in the medical properties of psychedelics, which show remarkable progress with low doses without chronic treatments," explains José Carlos Bouso, psychologist and doctor of pharmacology, scientific director of Clínica Synaptica, to SMC Spain.
“In recent years, it has been recognized that traditional psychotropic drugs are not always effective for everyone and in all contexts,” Elisabet Domínguez, psychologist and doctor of pharmacology at the Hospital de Sant Pau in Barcelona, president of the Spanish Society of Psychedelic Medicine (SEMPsi), and coordinator of the Psychedelicare initiative in Spain, tells SMC Spain. Dueñas points to the most serious and chronic mental disorders as those that pose the greatest pharmacological challenge.
In recent years, it has been recognized that traditional psychiatric drugs are not always effective for all people and in all contexts
Elisabet Domínguez
Part of the phenomenon has to do with the way these drugs were developed. “Many were based on fairly limited models of disease, such as chemical imbalance,” explains the expert. Although she acknowledges that psychotropic drugs have been useful, “disorders cannot be explained solely by low serotonin levels. Life experiences, trauma, and social and psychological context must also be taken into account.”
Added to this is a model of chronic use. “In most cases, current psychotropic drugs require daily doses and continued use to maintain their therapeutic effect, and discontinuation can lead to a recurrence of the symptoms for which they have been used,” explains Dueñas.
Spain was a pioneer in the second wave of research with psychedelics. Bouso was one of the first groups to do so, with a trial authorized by the Ministry of Health in 1999, which sought to administer MDMA to treat trauma in women who had been raped. However, the clinical trial was eventually canceled after its impact in the press, and now Australia and the United States are the countries developing this type of research.
What are the risks and contraindications of psychedelics?
Psychedelics have shown low organic toxicity and few side effects in trials, or mild and transient ones, according to experts; although their effects “depend greatly on the context of use, dosage, frequency, or vulnerability of the person,” Domínguez clarifies.
“In other settings, such as recreational use or retreats with non-professional or untrained individuals, their administration can lead to complications due to the conditions in which they are administered,” says Dueñas.
In other settings, such as recreational use or retreats with non-professional or untrained individuals, its administration may lead to complications
Rosa Mª Dueñas
Classic psychedelics can cause intense experiences such as acute anxiety, panic, or disorientation. According to Gómez Escolar, this can trigger psychotic or manic episodes in vulnerable individuals. MDMA has more significant physiological effects, such as increased temperature, blood pressure, or dehydration, and the potential to interact with other drugs, such as antidepressants.
The main exclusion criteria are cardiovascular disease or a history of psychotic spectrum disorders or severe personality disorders.
What is behind the therapeutic effect?
The protocol for trials involves preparatory sessions beforehand, a calm environment, and follow-up sessions to integrate the experience. “A psychedelic would be a useful tool in psychotherapy for working with mental content,” says Bouso. “It's about facilitating a mental state at specific moments that allows rigid patterns or thoughts to be unblocked,” adds Domínguez.
Vieta explains that there is also another school of thought that considers alterations in consciousness and hallucinations to be an undesirable effect; thus, the therapeutic effect would reside in the neurobiological effects on the brain. A kind of brain reset.
“These substances increase the brain's neuroplasticity and generate new neural connections that can cause changes in patterns and behaviors, or create emotional ruptures that lead the affected person to face key events instead of avoiding them,” says Dueñas.
What regulations exist?
“In recent years, there has been gradual—albeit limited—progress toward regulating clinical research with psychedelics. Some countries have developed specific frameworks that allow for their study under controlled conditions and, in certain cases, their regulated therapeutic use,” says Domínguez.
Germany has approved compassionate use of psilocybin, allowing exceptional access for adults with treatment-resistant depression. In the Czech Republic, the Senate ratified a law authorizing the medical use of psilocybin for depression, post-traumatic stress disorder, and substance use disorders.
Outside the European Union, Switzerland has had a limited medical use program since 2014 that allows authorized physicians to treat patients with MDMA, LSD, and psilocybin under strict supervision, with an emphasis on training and the role of scientific societies. Australia has also allowed its clinical application in very limited contexts. The United States and Canada have joined this list.
Alongside these advances, political and social initiatives have emerged to generate informed debate. In 2024, the European Citizens' Initiative PsychedeliCare was launched to open a reflection on the regulation of these therapies and their possible integration into public health systems. In parallel, PsychedelicsEurope is working to promote a common regulatory framework that facilitates research and safe access, always based on scientific evidence.
Who can offer these therapies?
As these are medications, only psychiatrists in countries where they are authorized can prescribe these psychotropic drugs. Specific training is also required to accompany the patient during the experience and integrate it, the latter being fundamental to clinical improvement, with an ever-increasing range of training courses available.
What is the situation in Spain?
The only one of these substances approved internationally is esketamine for treatment-resistant depression, which is already administered in the public health system in Spain, although others are in the clinical trial phase, such as psilocybin.
The law regulating psychedelics in Spain is the Convention on Psychotropic Substances, established by the United Nations (UN) in 1971, which classifies psychedelics as substances with no medical interest and a high potential for abuse, placing them in the same category as heroin. This law regulates the active ingredients, but not the plants that contain them.
The Spanish Society for Psychedelic Medicine (SEMPsi), a scientific entity dedicated to promoting research and training, is working to design public policies based on health and safety. In collaboration with the Inawe Foundation, on February 13 it promoted a parliamentary conference in the Congress of Deputies where researchers, clinicians, regulatory experts, and patients gathered to discuss the state of the issue in our country.
Are expectations inflated?
The experts interviewed agree that there is a certain amount of optimism, “especially in the media and commercial discourse,” says Domínguez. "Psychedelic-assisted therapies are not a panacea; they do not work for everyone, nor do they replace other treatments. They are a powerful tool, but they are complex, costly, and demanding. The challenge now is to turn down the volume on the marketing and turn up the volume on the rigor of the scientific evidence," he adds.
In some cases, the number of participants in the trials is very small, or the evidence comes only from observational studies, explains Dueñas. For his part, Vieta points to the need to place more emphasis on long-term effects, both desired and undesired. For him, the greatest risk facing the scientific community is that, in practice, these substances “may be less effective than they currently appear” due to methodological problems when designing trials: “It is very difficult to conduct a double-blind trial, one of the standards for demonstrating that a drug works.”
