By Reshma Kolala
Abstract
Psychedelic drugs are far from what is considered to be conventional medicine. An infamous history of misuse has stigmatized psychedelics, making it difficult to garner support for its use as a potential therapeutic tool. However, among working adults, taking low doses of psychedelics has recently gained popularity in its ability to boost productivity, reduce anxiety and depression, and enhance overall well-being. Only a few studies have investigated these benefits in a controlled, randomized setting, all of which produced promising results. However, the data is far from sufficient, and significant further study is warranted before psychedelics may become a mainstream nootropic supplement.
Introduction
Psychedelic drugs such as lysergic acid diethylamide (LSD), psilocybin, and N, N-dimethyltryptamine (DMT) are notorious for their ability to induce a hallucinogenic episode or an altered state of consciousness. These effects are brought about by visual, psychological, and auditory changes following the intake of a recreational dose. In recent years, however, the profile of psychedelic drug usage has shifted to microdosing. Psychedelic microdosing is the use of low doses of hallucinogenic drugs on a chronic, relatively regular schedule. On average, users take about one-tenth to one-twentieth of a typical, recreational dosage every two to three days [1]. Anecdotal reports have shown that users experience enhanced creativity and productivity as well as improved cognitive function [2]. In an online questionnaire, Hutten et al. (2019) observed that the primary motivation for microdosing is performance and mood enhancement, symptom relief, and curiosity [3]. Despite encouraging reviews from users, there is minimal empirical evidence to support the commercialization of psychedelics for clinical purposes. The following review evaluates the practice of microdosing by examining its efficacy, application, safety, and relevance to the social and health challenges faced by individuals presently.
Microdosing as a therapeutic tool
History of clinical psychedelic drug use
The clinical use of psychedelics to treat mood disorders is not an unfamiliar avenue for hallucinogenic drugs. The discovery of LSD in the 1940s, and its wider distribution in the 1950s, began a new era of research into psychoactive compounds. Psychedelics were considered useful as a supplemental treatment to facilitate successful therapies. This prompted further research, leading to nearly 1,000 clinical studies being published by 1965 [4]. These studies reported positive therapeutic outcomes in patients suffering from various mood and substance abuse disorders. However, a cultural shift in recreational psychedelic drug usage during the 1960s and 1970s led to a relabeling of psychedelic drugs. These hallucinogens became synonymous with rebellious and dangerous behavior, leading to the criminalization of psychedelics in the United States. This severely restricted research into psychedelics as a therapeutic, causing interest and funding to diminish and ultimately stalling further advancement.
The demand for an alternative approach
Microdosing is portrayed as an alternative to traditional antidepressant or anti-anxiety medications. The prescription rates of medications treating behavioral and mood disorders remain alarmingly high, most notably in the United States. Despite this, there has been minimal improvement in the efficacy of these medications in the last few decades. These medications are slow to act, have several adverse effects, and only show improvement in ⅔ of patients [2]. This has encouraged patients to seek alternative methods of treatment, such as microdosing. Despite known unwanted effects, standard antidepressants, or SSRIs (selective serotonin reuptake inhibitors), continue to be prescribed because of the large volume of controlled, clinical trials that demonstrate their safety and efficacy. The same cannot be said for psychedelic use however, due to the controversial nature of funding research into illicit drugs, particularly those that cannot be patented by pharmaceutical companies. Therefore, the substantial anecdotal support for microdosing, notably their reported lack of relative side effects, cannot be reliably concluded. However, amidst logistical challenges, the increasing prevalence of microdosing unveils a new niche of therapeutics that target individuals who may be unreceptive to traditional modes of treatment for mood and anxiety disorders.
Chronic, low-dosage psychedelic treatment (microdosing)
Few studies have investigated the effects of microdosing in ameliorating depression and anxiety symptoms in controlled, randomized trials. One of these is a UC Davis study where DMT was administered at sub-hallucinogenic levels (1 mg/kg) on a chronic, intermittent schedule to rats (Cameron et al. 2019). This was opposed to a standard high dose (10 mg/kg) which is known to induce symptoms of anxiety. These rats were subjected to tests that quantified their anxiety levels and behavioral responses. DMT was specifically chosen for this study because of its chemical architecture, as it possesses a core indole-containing structure, present in LSD and psilocybin. These indole-containing hallucinogens are analogues of the neurotransmitter serotonin, which is known to influence mood and behavior. DMT is also known to influence rodent behaviors often affected by depressive symptoms, such as sociability, mood, and anxiety. The results indicated no significant difference between the control group and the treatment group in their ability to produce anxiogenic effects or reduced anxiety symptoms. In a test traditionally used to measure the efficacy of antidepressants, rats treated with DMT exhibited antidepressant-like responses without any impairment to working or short-term memory or social interaction. This study corroborates reports that microdosing in humans alleviates depressive-like symptoms [2]. However, anxiety reduction, enhanced sociability, and enhanced cognitive function self-reported by users in the study conducted by Hutten et al. (2019) was not observed.
Nonchronic low-dosage psychedelic treatment
Anxiogenic effects were observed, however, in a controlled, randomized study that proposed psilocybin as a treatment to reduce anxiety and depression in patients with advanced-stage cancer. Ross et al. (2016) concluded that a single dose of psilocybin (0.3 mg/kg) produced significant, immediate, and sustained (up to 7 weeks after the dose) reduction of depression and anxiety symptoms [5]. However, this study did not practice microdosing, in contrast to the study conducted by Cameron et al. (2019). In another double-blind, controlled study, patients with obsessive-compulsive disorder (OCD) were administered up to four doses of psilocybin, ranging from mildly hallucinogenic to moderately hallucinogenic (100ug/kg-300ug/kg). Results indicated that patients experienced an acute reduction in OCD symptoms immediately after treatment, at all given dosage levels [6].
Although the studies conducted by Ross et al. (2016) and Moreno et al. (2006) target different populations, both studies showed promising benefits after psilocybin treatment [5,6]. However, in both studies, psilocybin was administered minimally, not often enough to be considered microdosing. In sum, psychedelic psilocybin treatment has shown promising results when administered minimally and at low doses.
Risks of microdosing
The safety risks associated with short-term or long-term microdosing are unclear, although research into the safety of recreational psychedelic use (~10 mg/kg) suggests that it is relatively safe. In a rating study conducted by European Union (EU) drug experts, van Amsterdam et al. (2015) concluded that, based on current data, alternative substances such as tobacco and alcohol are significantly more harmful than psychedelics in a physical and societal aspect [7]. This is attributed to the addictive quality of tobacco and alcohol, and their ability to induce long-term health disorders such as lung and heart cancers.
Longitudinal studies done with higher, recreational doses have demonstrated that long-term usage of psychedelics is associated with reduced psychological distress [8]. However, it is known that both low and high doses of DMT can alter the neuronal structure of the brain, promoting structural and functional plasticity [9]. These effects were observed long after DMT was cleared from the body. The effects of psychedelic use may also have metabolic effects. The data collected by Cameron et al. (2019) indicate that the male mice who were administered low doses of DMT had a reduced appetite yet gained significantly more weight. Metabolomic profiling of these mice revealed no significant differences in serum steroid levels, implying the interplay of unknown factor(s) in microdosing.
Conclusion
Recent publications regarding microdosing and general low-dose psychedelic drug use reveal several disparities between animal trials and human reports making it difficult to recommend microdosing based on current empirical evidence. Although psychedelics as a therapeutic show promising preliminary results, further research must be conducted to determine their clinical relevance. Future studies should explore the effects of a microdose and recreational dose within the same study and use a broader range of psychedelics such as non-indole-containing compounds. Additionally, researchers may want to vary the frequency of doses within a study, ranging from frequent (Cameron et al. 2019) to infrequent administration, (Ross et al. 2016) and aim to design longitudinal studies to determine the long-term effects of practicing microdosing. By investigating alternative approaches to enhance cognitive function and minimize mood disorder symptoms, researchers can provide further insight into the future of more comprehensive, personalized healthcare for all adults.
References:
- Polito V, & Stevenson, RJ. 2019 February 6. A systematic study of microdosing psychedelics. PLoS One. [accessed 2021 May 12]; 14(2). https://pubmed.ncbi.nlm.nih.gov/30726251/. https://doi.org/10.1371/journal.pone.0211023
- Cameron LP, Benson CJ, DeFelice BC, Fiehn O, Olson DE. 2019 Jul 17. Chronic, intermittent microdoses of the psychedelic N,N-dimethyltryptamine (DMT) produce positive effects on mood and anxiety in rodents. ACS chemical neuroscience. [accessed 2021 May 12]; 10(7): 3261–3270. https://pubmed.ncbi.nlm.nih.gov/30829033/. https://doi.org/10.1021/acschemneuro.8b00692
- Hutten N, Mason NL, Dolder PC, Kuypers K. 29 May 21. Motives and side-effects of microdosing with psychedelics among users. Int J Neuropsychopharmacol. [accessed 2021 May 12]; 22(7): 426–434. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600464/. https://doi.org/10.1093/ijnp/pyz029
- Vollenweider FX, & Kometer M. 11 Sept 2010. The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. Nature reviews. Neuroscience. [accessed 2021 May 12]; 11(9): 642–651. https://pubmed.ncbi.nlm.nih.gov/20717121/. https://doi.org/10.1038/nrn2884
- Ross S, Bossis A, Guss J, Agin-Liebes G, Malone T, Cohen B, Mennenga SE, Belser A, Kalliontzi K, Babb J, Su Z, Corby P, & Schmidt BL. 30 Dec 2016. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J Psychopharmacol. [accessed 2021 May 12]; 30(12): 1165–1180. https://pubmed.ncbi.nlm.nih.gov/27909164/. https://doi.org/10.1177/0269881116675512
- Moreno FA, Wiegand CB, Taitano EK, & Delgado PL. Nov 2006. Safety, tolerability, and efficacy of psilocybin in 9 patients with obsessive-compulsive disorder. J Clin Psychiatry. [accessed 2021 May 12]; 67(11): 1735–1740. https://pubmed.ncbi.nlm.nih.gov/17196053/. https://doi.org/10.4088/jcp.v67n1110
- Van Amsterdam J, Nutt D, Phillips L, van den Brink W. 2015 Jun 1. European rating of drug harms. J Psychopharmacol. [accessed 2021 May 12]; 29(6), 655-660. https://pubmed.ncbi.nlm.nih.gov/25922421/. https://doi.org/10.1177/0269881115581980
- Hendricks PS, Johnson MW, & Griffiths RR. Sept 2015. Psilocybin, psychological distress, and suicidality. J Psychopharmacol. [accessed 14 May 2021]; 29(9): 1041–1043. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4721603/. https://doi.org/10.1177/0269881115598338
- Ly C, Greb AC, Cameron LP, Wong JM, Barragan EV, Wilson PC, Burbach KF, Soltanzadeh Zarandi S, Sood A, Paddy MR, Duim WC, Dennis MY, McAllister AK, Ori-McKenney KM, Gray JA, Olson DE. 8 Aug 2018. Psychedelics promote structural and functional neural plasticity. Cell reports. [accessed 14 May 2021]; 23(11): 3170–3182. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082376/. https://doi.org/10.1016/j.celrep.2018.05.022