Have a Good Trip: The Evolution and Benefits of Psychedelic Therapy

Introduction

When pondering the concept of psychedelics, most people will likely think of dangerous substances that can be harmful to physical and mental health. For decades, commonly known hallucinogens like MDMA, LSD, psilocybin, and ketamine have undergone immense shifts in popularity, legality, and overall stigma. What if these powerful substances can benefit mental health rather than harm it? Scientists have begun working on answering this question, and the results have proven to be rather interesting. In recent years, there has been a resurging focus on the therapeutic potential of psychedelics, showing promise for the treatment of major depressive disorders and other mental illnesses [1].

The origins of psychedelic-assisted treatment date back to the 1940s, when lysergic acid diethylamide (LSD) was first discovered and administered to mentally ill patients. This kickstarted the beginnings of clinical research with the substance. LSD treatments were provided to patients in doses deemed safe and appropriate by licensed professionals, showing immense promise for treating several mental health conditions including anxiety, depression, schizophrenia, war-time stress reactions, and substance abuse disorders. Beginning in the 1960s, LSD was eventually recreationally used, putting clinical research to a halt [2]. The stigmatization and laws placed around LSD and other hallucinogens prevented scientists from further understanding the numerous potential benefits of psychedelics from a therapeutic standpoint. Nevertheless, psychedelic therapy has once again been receiving substantially more attention in the clinical field, with research highlighting structural and behavioral improvements in patients undergoing this contemporary treatment method. With the accumulated research to date, it is very likely that we will soon witness an incredible breakthrough in the treatment of various mental illnesses, including mood disorders, post-traumatic stress disorder (PTSD), substance abuse, etc., through psychedelic-assisted therapy [3]. 

Structural Benefits

To better understand the possible benefits of psychedelic therapy on mental health, it is important to examine the positive impacts they can have on the underlying circuitry of the brain. Individuals who take psychedelics usually report long-term emotional alterations, like improved overall mood and motivation, that greatly enhance their general outlook on life. This suggests chemical and structural changes may take place in areas of the limbic system – a system of brain structures that are vital for the regulation of emotion – and are commonly impacted by certain psychotropic drugs [4]. One study in which rats were given different doses of psilocybin (magic mushrooms) and ketamine showed a significant increase in dopamine levels in the nucleus accumbens, a structure that is important for reward and motivation. Psilocybin intake also resulted in the inhibition of a neurotransmitter known as glutamate, which could indirectly allow for decreases in depression and chronic stress caused by excess glutamate [5]. Typically described as an otherworldly and spiritual experience, those who use certain psychedelics are capable of undergoing an “emotional breakthrough,” which can have long-lasting and positive psychological implications [6]. Evidence around this cognitive transformation suggests that when the drug is ingested, neurological processes occur and cause these long-term changes, and scientists have been taking a closer look at this aspect [7].

When long-term behavioral and cognitive alterations are reported, most neuroscientists’ minds turn to the possibility of neural plasticity – the brain’s ability to fundamentally rewire itself by forming new connections with neurons that can alter a person’s cognitive processes, behavior, overall mood, and personality. Neural plasticity is a process that is strongly associated with the act of learning and development in the human brain [8]. Studies have been conducted in an attempt to examine possible enhanced neural plasticity from ingesting psychedelics. Plasticity can be difficult to quantify in the human brain, but the use of cultured neuronal cells helps to provide insight into what may occur when they interact with certain substances. These techniques, along with several other preclinical animal studies, have been performed to determine whether psychedelics like LSD, psilocybin, and ketamine can be considered psychoplastogens – substances that can aid in neural plasticity. Such studies have shown that some common hallucinogens are capable of increasing synaptic transmission, encouraging dendritic growth, and altering gene expression within neurons that promote cell growth [9]. Synapses are convergent spaces between neurons, where they communicate with neurons nearby, signaling the dendrites of neighboring cells that process the information. When gene expression is altered by psychedelics, it causes an upregulation of growth factors that form new cells and connections throughout the brain. This is similar to the actions of antidepressants, except hallucinogens seem to act quicker for a prolonged period [10].

Behavioral Benefits

The subjective experiences of patients during and after sessions of psychedelic therapy provide evidence of psychedelics benefitting mental health. Most of the long-term effects are also heavily influenced by the quality of the patient’s overall experience. When a certain psychedelic is administered to a patient, the session may start as a very intense and frightening experience, as most individuals report facing themes of learned avoidance [11]. These themes can vary from person to person, but learned avoidance can refer to physical experiences or concepts that a person has developed a psychological aversion to in their lifetime, like a phobia or an anxiety-inducing event. However, the psychedelic experience allows patients to accept these aversive experiences and let go of their negative attachments to them. This has been known to persist after the session is over and also improve the patient’s overall quality of life that the negative experience prevented from occurring [12].

Techniques Involving MDMA

MDMA, known recreationally as ecstasy, stands for 3,4-methylenedioxymethamphetamine. This drug usually produces effects similar to those of other amphetamine derivatives, like Adderall and other stimulants. These types of drugs tend to act on serotonergic neurons, which initially generate very desirable effects. These effects include feelings of empathy, the urge to be close to others, and interpersonalization [13]. MDMA is a reuptake inhibitor for several neurotransmitters such as serotonin, dopamine, and norepinephrine. Reuptake inhibitors cause neurotransmitters to build up within the synapse, allowing for the opportunity for increased binding and prolonged action at postsynaptic receptors. Also, enhanced mood and euphoric feelings due to MDMA manipulation of these three neurotransmitter systems are reported often [14].

While any drug like MDMA can be dangerous if taken in large doses, a number of benefits can ensue in a therapeutic setting where doses are heavily regulated by the researchers. One study conducted in 2022 across 15 different study sites involved participants who met the DSM-5 criteria for PTSD and mild to moderate alcohol and drug use disorders. The participants underwent three 8-hour psychotherapy sessions, in which they received a divided dose of MDMA. Also, a control group received the same doses of a placebo at the same time intervals for each session. Following an evaluation after the sessions, study results demonstrated that the group receiving MDMA treatment showed significantly decreased potential for alcohol and drug abuse disorders compared to the placebo group [15]. This was a very important study that showcased not only the therapeutic efficacy of MDMA-assisted psychotherapy, but also its safety.

Techniques Involving LSD

LSD stands for lysergic acid diethylamide, more commonly known as acid recreationally. The most memorable side effect of ingesting LSD is the hallucinations that accompany it, which typically are incredibly intense and can last several hours depending on the side of the dose. While there are several different studies investigating what exactly is occurring in the brain to induce these hallucinations, one observation that appears to be universally agreed upon is that the serotonin neurotransmitter pathway is especially impacted by LSD. One study, in particular, found that ingestion and serotonin pathway activation of the drug leads to inhibition of the hippocampal-prefrontal cortex, areas of the brain that are crucial for sensory perception and cognition. This is likely the cause of the visual, auditory, and thought distortion that is typically associated with LSD [16].

Despite the somewhat anxiety-inducing experiences that can occur when using LSD recreationally, it has shown immense efficacy in controlled doses within a clinical setting. Most of the benefits associated with LSD-assisted therapy involve effective treatments for depression and anxiety, specifically involving patients with life-threatening or terminal illnesses. A 2014 study showcases the safety and efficacy of controlled doses of LSD paired with psychotherapy sessions; patients with anxiety from life-threatening illnesses were either administered LSD treatment or a placebo. The treatment group yielded a significant decrease in anxiety symptoms, with no chronic adverse effects persisting after one day of treatment [17]. There have also been several studies conducted dating all the way back to the 1930s involving the administration of LSD to terminal cancer patients, resulting in reduced depression, better sleep, and less anxiety about mortality [18]. Being somewhat of a pioneer psychedelic, a lot of scientific research has been conducted and continues to be conducted in hopes of discovering even more positive effects LSD can have in clinical settings.

Techniques Involving Psilocybin 

Psilocybin is the active hallucinogenic ingredient found in what is recreationally known as magic mushrooms. It is a naturally-occurring psychedelic that has been used ritualistically and therapeutically for centuries; therefore, its efficacy is more apparent than any other hallucinogen. Psilocybin has agonistic effects on two of the major serotonin pathways in the brain which, similarly to LSD, is the leading cause of the sensory alterations that come with consumption of this drug [19]. There has also been immense research conducted surrounding psilocybin’s acute ability to increase neural connectivity in certain brain regions such as the claustrum, a structure that aids in cognition, learning, and memory. These benefits, however, still need to be further studied through the use of clinical trials and alternative brain-imaging techniques [20].

Many psilocybin-assisted therapy studies that have been conducted in clinical settings focused on the very noticeable personality shifts that come with it. One study conducted in 2018 took a closer look at specific aspects of personality that tend to shift following any kind of antidepressant treatment, including neuroticism, extraversion, insightfulness, openness, conscientiousness, and agreeableness. The subjects all suffered from treatment-resistant depression, and they were given controlled doses of psilocybin weekly. After a three-month follow-up evaluation, the results were strikingly similar to other antidepressant treatments with a key difference of heightened extraversion and openness, two changes that are considered to be specific to psychedelic therapy [21]. There is no doubt that psilocybin has the most evidence for therapeutic efficacy, proving that it is arguably one of the most promising psychedelic therapy techniques. 

Techniques Involving Ketamine

Ketamine and similar substances are often used in clinical settings as an anesthetic, first introduced into the medical field in the 1950s. The psychological effects of it, however, put its medical use on hold for a while before its recent resurgence through less potent variants. Ketamine acts on NMDA receptors when administered, blocking these channels as well as diminishing the presynaptic release of glutamate. Both of these effects appear to be the primary mechanism for the drug’s anesthetic and analgesic properties, including temporary loss of consciousness, memory loss, and impaired movement or immobility. Ketamine also seems to increase metabolism in various areas of the brain, which in turn can not only cause several effects to occur in other systems of the body but can also lead to a dissociative psychic state in the user. This can include dream-like hallucinations and sensations, such as feeling as if you are out of your body or floating [22].

Most of the clinical ketamine-assisted treatments tend to target symptoms of depression as well as pain management. Much like psilocybin, it appears to have positive effects on those who suffer from treatment-resistant depression, and it even produces more rapid effects than traditional antidepressant techniques. This was proven in a 2019 study in which patients who suffered from depression were administered a subanesthetic dose intravenously, producing almost instant effects on their symptoms that persisted after a one-month follow-up. It is worth mentioning, however, that ketamine has effects that occur all throughout the body, including the cardiovascular and respiratory systems. This means that patients typically must pass health screenings before undergoing any type of ketamine-involved treatment to ensure their safety [23].

Conclusions (What’s Next for Psychedelic Therapy?)

There are many more hallucinogens that exist in the world to be explored, all with different short and long-term effects on the brain and body. Based on the research that has already been conducted on a few of them, it is important that the stigmatization surrounding them be rejected in order to allow more opportunities to better understand their therapeutic potential. It is easy to forget that any drug taken recreationally in unsupervised doses can be dangerous- not just psychedelics. When used in a clinical setting that is regulated by licensed professionals, so many doors can be opened for discovering advanced psychiatric treatments and improving the lives of many. 

Psychedelic therapy research is still very limited in many locations, with only a select few research centers around the world currently specializing in it. There have also recently been discussions about funding for these types of clinical studies, raising questions about cost-effectiveness and health insurance implications. However, based on what has already been discovered from these research centers, it is safe to suggest that psychedelic therapy may be implemented into traditional medical practices in the years to come. The more these fascinating substances are studied and understood, the more health benefits will be discovered, and therefore, the more lives will be improved everywhere [24]. 

References

1. Ko, K., Kopra, E. I., Cleare, A. J., & Rucker, J. J. (2022, October 7). Psychedelic therapy for depressive symptoms: A systematic review and meta-analysis. Journal of Affective Disorders. https://doi.org/10.1016/j.jad.2022.09.168 

2. Belouin, S. J. (2018, February 21). Psychedelics: Where we are now, why we got here, what we must do. Neuropharmacology. https://doi.org/10.1016/j.neuropharm.2018.02.018 

3. Chi, T., & Gold, J. A. (2020, January 30). A review of emerging therapeutic potential of psychedelic drugs in the treatment of psychiatric illnesses - journal of the neurological sciences. Journal of the Neurological Sciences. https://doi.org/10.1016/j.jns.2020.116715 

4. Bartholini, G. (2011, April 12). Differential effect of neuroleptic drugs on dopamine turnover in the extrapyramidal and Limbic System. OUP Academic. https://doi.org/10.1111/j.2042-7158.1976.tb04648.x 

5. Wojtas, A., Bysiek, A., Wawrzczak-Bargiela, A., Maćkowiak, M., & Gołembiowska, K. (2023, December 20). Limbic system response to psilocybin and ketamine administration in rats: A Neurochemical and behavioral study. MDPI. https://doi.org/10.3390/ijms25010100 

6. Roseman, L., Haijen, E., Idialu-Ikato, K., Kaelen, M., Watts, R., & Carhart-Harris, R. (2019, July 11). Emotional breakthrough and psychedelics: Validation of the emotional breakthrough inventory. Journal of Psychopharmacology. https://doi.org/10.1177/0269881119855974 

7. Knudsen, G. M. (2022, June 21). Sustained effects of single doses of classical psychedelics in humans. Neuropsychopharmacology. https://doi.org/10.1038/s41386-022-01361-x 

8. Galván, A. (2010, May 14). Neural plasticity of development and learning. Wiley Online Library. https://doi.org/10.1002/hbm.21029 

9. Bouso, José Carlos, et al. “Long-term use of psychedelic drugs is associated with differences in brain structure and personality in humans.” European Neuropsychopharmacology, vol. 25, no. 4, Apr. 2015, pp. 483–492, https://doi.org/10.1016/j.euroneuro.2015.01.008. 

10. Grieco, S. F., Castrén, E., Knudsen, G. M., Kwan, A. C., Olson, D. E., Zuo, Y., Holmes, T. C., & Xu, X. (2022, November 9). Psychedelics and neural plasticity: Therapeutic implications. Journal of Neuroscience. https://www.jneurosci.org/content/42/45/8439 

11. Behar, Isaac. “Learned avoidance of nonreward.” Psychological Reports, vol. 9, no. 1, Aug. 1961, pp. 43–52, https://doi.org/10.2466/pr0.1961.9.1.43. 

12. Wolff, M., Evens, R., Mertens, L. J., Koslowski, M., Betzler, F., Gründer, G., & Jungaberle, H. (2020, January 3). Learning to let go: A cognitive-behavioral model of how psychedelic therapy promotes acceptance. Frontiers in Psychiatry. https://doi.org/10.3389/fpsyt.2020.00005 

13. McCann, U., Szabo, Z., Scheffel, U., Dannals, R., & Ricaurte, G. (1998, October 31). Positron emission tomographic evidence of toxic effect of MDMA (“Ecstasy”) on brain serotonin neurons in human beings. The Lancet. https://doi.org/10.1016/S0140-6736(98)04329-3 

14. de la Torre, R., Farré, M., Roset, P. N., Pizarro, N., Abanades, S., Segura, M., Segura, J., & Camí, J. (2004, April). Human Pharmacology of MDMA Pharmacokinetics, Metabolism, and Disposition. LWW. https://journals.lww.com/drug-monitoring/abstract/2004/04000/human_pharmacology_of_mdma__pharmacokinetics,.9.aspx 

15. Nicholas, C. R., Wang, J. B., Coker, A., Mitchell, J. M., Klaire, S. S., Yazar-Klosinski, B., Emerson, A., Brown, R. T., & Doblin, R. (2022, February 11). The effects of MDMA-assisted therapy on alcohol and substance use in a phase 3 trial for treatment of severe PTSD. Drug and Alcohol Dependence. https://doi.org/10.1016/j.drugalcdep.2022.109356 

16. Schmidt, A., Müller, F., Lenz, C., Dolder, P. C., Schmid, Y., Zanchi, D., Lang, U. E., Liechti, M. E., & Borgwardt, S. (2017, October 2). Acute LSD effects on response inhibition neural networks: Psychological medicine. Cambridge Core. https://doi.org/10.1017/S0033291717002914 

17. Gasser, P., Holstein, D., Michel, Y., Doblin, R., Yazar-Klosinski, B., Passie, T., & Brenneisen, R. (2014, July). Safety and Efficacy of Lysergic Acid Diethylamide-Assisted Psychotherapy for Anxiety Associated With Life-threatening Diseases. LWW. https://journals.lww.com/jonmd/FullText/2014/07000/Safety_and_Efficacy_of_Lysergic_Acid.1.aspx 

18. Richards, W., Grof, S., Goodman, L., & Kurland, A. (1972, January 1). LSD-Assisted psychotherapy and the human encounter with death. ProQuest. https://www.proquest.com/scholarly-journals/lsd-assisted-psychotherapy-human-encounter-with/docview/1312135990/se-2?accountid=14270 

19. Tylš, F., Páleníček, T., & Horáček, J. (2013, December 17). Psilocybin – summary of knowledge and new perspectives. European Neuropsychopharmacology. https://doi.org/10.1016/j.euroneuro.2013.12.006 

20. Barrett, F. S., Krimmel, S. R., Griffiths, R. R., Seminowicz, D. A., & Mathur, B. N. (2020, May 23). Psilocybin acutely alters the functional connectivity of the claustrum with brain networks that support perception, memory, and attention. NeuroImage. https://doi.org/10.1016/j.neuroimage.2020.116980 

21. Erritzoe, D., Roseman, L., Nour, M. M., MacLean, K., Kaelen, M., Nutt, D. J., & Carhart-Harris, R. L. (2018, June 19). Effects of psilocybin therapy on personality structure. Wiley Online Library. https://doi.org/10.1111/acps.12904 

22. Anirudda, P., & Mark, H. (2007, April 1). Ketamine. Continuing Education in Anaesthesia Critical Care & Pain. https://doi.org/10.1093/bjaceaccp/mkm008 

23. Mandal, S., Sinha, V. K., & Goyal, N. (2019). Efficacy of ketamine therapy in the treatment of depression. LWW. https://journals.lww.com/indianjpsychiatry/fulltext/2019/61050/Efficacy_of_ketamine_therapy_in_the_treatment_of.9.aspx 

24. Gründer, G., & Jungaberle, H. (2021, May 12). The potential role of psychedelic drugs in mental health care of the future. Pharmacopsychiatry. https://www.thieme-connect.com/products/ejournals/abstract/10.1055/a-1486-7386?casa_token=mHwiXMsI-asAAAAA%3AXTAX8ZiGMYUS0MycpYque-DXNAe_UnpoRowEe0L0-6K6qSowoD8fymtcZRbh2R4XcDXwD3rv5iv2n9g#N1139F