The therapeutic potential of psychedelics in the treatment of psychiatric or substance use disorders has been known for decades. However, the reasons why psychedelics show striking results are not so obvious. This publication focuses on examining the neuroplasticity induced by psychedelics as a major factor in their effectiveness.
Psychedelics, matter and spirit
As Dr. Nora Volkow writes in her research comments: "The dominant view of drug addiction views it as a disease of the brain". In this model addiction is characterized by a loss of free will and is explained by neurobiological reasons - drug use turns normal cognitive processes as well as those associated with the reward system into pathological ones (Figure 2). This model is supposed to destigmatize substance use: after all, the cause is not a natural weakness of character, but a disease. Unfortunately, in reality, going to the narcologist is also labeled and, as a result, stigma is again created.
An alternative is the learning model, which, in turn, is repelled by societal and environmental factors: adverse experiences in childhood and adolescence, physical and psychological trauma, and poverty lead to substance use. In this paradigm, addiction is seen as a natural, context-dependent response to complex environmental circumstances, rather than an illness or character weakness.
Neurobiological changes are also present here, but they are seen as a consequence of normal brain functioning: behavioral habits develop according to the "stimulus-response" model, and their subsequent repetition is normal learning. Awareness as a patient, on the other hand, implies that one's first duty is to follow the instructions of those professionals who rely on the medication approach, which in some cases leads to shifting the responsibility for recovery to medical personnel. In terms of the learning model, exploring one's own motivations and beliefs is key.
Neurobiological changes are also present here, but they are seen as a consequence of normal brain functioning: behavioral habits develop according to the "stimulus-response" model, and their subsequent repetition is normal learning. Awareness as a patient, on the other hand, implies that one's first duty is to follow the instructions of those professionals who rely on the medication approach, which in some cases leads to shifting the responsibility for recovery to medical personnel. In terms of the learning model, exploring one's own motivations and beliefs is key.
In general, the term "(neuro)plasticity" refers to the ability of the brain to change the existing neuronal pathways at the structural and functional level during life.
Structural plasticity refers to morphological changes in neurons (in axons, dendrites, and dendritic spines - Figure 3) or neuronal pathways, the appearance and removal of synapses, and neurogenesis.
Synaptic plasticity refers to an increase or decrease in synaptic strength depending on an increase or decrease in activity between neurons. Changes in activity are affected by experience: learning, in which communication between certain neurons is increased; and forgetting, when communication is weakened.
A vivid example of plasticity associated with adaptive change is reorganization of the cerebral cortex due to changes in incoming information. For example, in blind people the visual cortex is activated during sound localization, tactile perception, and odor perception. Apparently, unoccupied by visual perception, this part of the brain begins to process sensory flows of other modalities. An equally striking example of maladaptive change is addiction, as it is based on plasticity of neural circuits involved in decision-making; mechanisms of reinforcement and reward; changes in neurotransmitter systems, neuronal morphology, etc. On a personal level, this manifests as a decreased ability to control use, and less motivation to enjoy natural sources such as sports, food, or sex.
But can plasticity be induced by cognitive processes, but by pills? - It seems that this question already has an answer!
Substances capable of significantly changing plasticity (affecting neurite growth, density of dendritic spines, number of synapses, etc.) after a single administration are called psychoplastogens. Their important distinguishing features are the manifestation of effects after a single application and their persistence for a long time.
But can plasticity be induced by cognitive processes, but by pills? - It seems that this question already has an answer!
Substances capable of significantly changing plasticity (affecting neurite growth, density of dendritic spines, number of synapses, etc.) after a single administration are called psychoplastogens. Their important distinguishing features are the manifestation of effects after a single application and their persistence for a long time.
It is worth emphasizing that both decreasing and increasing the number of spikes refer to plasticity. However, whether this is good or bad depends on the brain area and on the type of influence on plasticity (use of stimulants, psychoplastogens, sudoku solving, learning a new language, etc.). For example, more spikes can mean a neuron's ability to form more synapses with other neurons.
Let's dive into the ocean of psychoplastogens
Initially, research on psychedelics began with other goals and questions. In the 1950s, psychiatrists investigated the possibility of using psychedelics both to understand the nature of psychoses (by taking them themselves) and to accompany psychotherapy (in this case the psychoactive substances were already being taken by patients). However, after LSD leaked from laboratories to the streets, research was banned, first in the U.S. and then in numerous other countries. The prohibition in the U.S. and the outbreak of the war against drugs is attributed to the fact that in the 1960s America was at war with Vietnam, and among the participants in the antiwar movement were hippies, a counterculture partly linked to the use of psychedelics. The U.S. government demonized LSD by propagating myths, such as that LSD contained the poison strychnine.
Of course, this did not contribute to the flowering of scientific research, which blossomed decades later and was called the "psychedelic renaissance" - since then, psychedelics have been investigated as a treatment for depression, PTSD, substance addictions, reducing anxiety related to the fear of death in people with terminal cancer.
Today, the methodology used in the pilot and follow-up studies is beginning to be revised, as the psychedelic experience makes double-blind placebo-controlled trials (what scientists say instead of a mantra) extremely difficult, because, despite using an active placebo, both doctor and patient are able to distinguish high doses of psychedelics from placebo. Researchers are now more rigorous in setting up control experiments, asking new questions-and here we find ourselves at a point where, instead of describing an intangible mystical experience, scientists are counting the number of spikes or receptors to look at the phenomenon from a more materialistic perspective.
Initially, research on psychedelics began with other goals and questions. In the 1950s, psychiatrists investigated the possibility of using psychedelics both to understand the nature of psychoses (by taking them themselves) and to accompany psychotherapy (in this case the psychoactive substances were already being taken by patients). However, after LSD leaked from laboratories to the streets, research was banned, first in the U.S. and then in numerous other countries. The prohibition in the U.S. and the outbreak of the war against drugs is attributed to the fact that in the 1960s America was at war with Vietnam, and among the participants in the antiwar movement were hippies, a counterculture partly linked to the use of psychedelics. The U.S. government demonized LSD by propagating myths, such as that LSD contained the poison strychnine.
Of course, this did not contribute to the flowering of scientific research, which blossomed decades later and was called the "psychedelic renaissance" - since then, psychedelics have been investigated as a treatment for depression, PTSD, substance addictions, reducing anxiety related to the fear of death in people with terminal cancer.
Today, the methodology used in the pilot and follow-up studies is beginning to be revised, as the psychedelic experience makes double-blind placebo-controlled trials (what scientists say instead of a mantra) extremely difficult, because, despite using an active placebo, both doctor and patient are able to distinguish high doses of psychedelics from placebo. Researchers are now more rigorous in setting up control experiments, asking new questions-and here we find ourselves at a point where, instead of describing an intangible mystical experience, scientists are counting the number of spikes or receptors to look at the phenomenon from a more materialistic perspective.
Speaking of psychoplastogens, we cannot but mention the most well-known one - ketamine, which causes rapid changes in the prefrontal cortex through an increase in the number of spines. Perhaps, the antidepressant effect of ketamine is related to this (Figure 5), as it is assumed that in depression the number of dendritic spines decreases, so increasing their number can be the basis for recovery.
Regarding medical use, there are studies that report no serious side effects when ketamine is used for severe pain relief in emergency departments, while others report the same frequency of adverse events as benzodiazepines. In randomized clinical trials focusing on postoperative pain, ketamine has demonstrated no adverse events--and yet effective pain relief in the short term, as well as reduced opioid use when ketamine is added as an adjuvant in general anesthesia. All this occurs at low doses, since more than 1 mg/kg already causes not only sedation, but also a dissociative state.
And in the U.S. in 2019, the S-enantiomer of ketamine, which is more potent than the R-enantiomer, was approved by the FDA (Food and Drug Administration) for the treatment of resistant depression. However, scientists are concerned that ketamine is addictive, so this research needs a thorough, large-scale follow-up.
However, it should also be considered that the therapeutic potential of psychedelics may be limited by the following factors:
Regarding medical use, there are studies that report no serious side effects when ketamine is used for severe pain relief in emergency departments, while others report the same frequency of adverse events as benzodiazepines. In randomized clinical trials focusing on postoperative pain, ketamine has demonstrated no adverse events--and yet effective pain relief in the short term, as well as reduced opioid use when ketamine is added as an adjuvant in general anesthesia. All this occurs at low doses, since more than 1 mg/kg already causes not only sedation, but also a dissociative state.
And in the U.S. in 2019, the S-enantiomer of ketamine, which is more potent than the R-enantiomer, was approved by the FDA (Food and Drug Administration) for the treatment of resistant depression. However, scientists are concerned that ketamine is addictive, so this research needs a thorough, large-scale follow-up.
However, it should also be considered that the therapeutic potential of psychedelics may be limited by the following factors:
- Probability of short-term anxiety or psychological discomfort;
- Contraindications to use due to a history of psychiatric disorders;
- High price of psychedelic-associated therapy (because of the need to involve specialists who will accompany the patient throughout the duration of the psychedelic effect).
In countries where this research is developing, there is already a Center for the Study of Psychedelics and Consciousness (USA) and a Center for the Study of Psychedelics (UK). Separately, it is worth mentioning the fact that since psychoactive substances are outside the law, a special license is required to obtain permission to work with them.
The book by Stanislav Grof, the pioneer of LSD-associated therapy, has information about the scientific paradigm: how rigid it is when it is accepted by the academic community; how constrained it is by the scientist who becomes merely a "problem solver" rather than a questioning subject, and who explores only that field of the unexplained which is considered valuable within the paradigm. Under such conditions, revolutionary knowledge is not born, new concepts are not considered, and there is stagnation for decades.
Today, on the contrary, the ambassadors of the psychedelic renaissance go beyond the paradigms of the past and ask themselves: can the structure of psychedelics be changed so as to retain their therapeutic effects but remove their hallucinatory ones? And is it possible that the therapeutic effects of psychedelics are due specifically to their effects on neuroplasticity rather than to deep mystical experiences?
Today, on the contrary, the ambassadors of the psychedelic renaissance go beyond the paradigms of the past and ask themselves: can the structure of psychedelics be changed so as to retain their therapeutic effects but remove their hallucinatory ones? And is it possible that the therapeutic effects of psychedelics are due specifically to their effects on neuroplasticity rather than to deep mystical experiences?