LSD as a Antidepressant!

LSD Microdosing as a Sub-perceptual Antidepressant

LSD bound to a receptor in the brain

Introduction

Depression is a wide spectrum of psychological ailments that affect a large portion of the population. Nearly every living adult has at one point or another experienced a depressed mood. It can range from a subtle sense of unhappiness to a debilitating illness that can and often does drive people to self-harm or suicide. Unsurprisingly, depression is one of the main causes of suicide. When depression is severe enough to last for a longer period of time, it is called major depressive disorder (MDD). Depression can be caused by life events, an underlying condition or certain medication, or even be idiopathic. Depression can be diagnosed by a specialist and treated with an array of modern antidepressant
drugs and treatments but in many cases, mild to severe depression may go completely undiagnosed.

The reasons for undiagnosed and untreated depression include the social stigmata associated with being seen as depressed, stigmata with seeking psychotherapeutic help or taking antidepressants or it may simply be due to the patient's unwillingness or inability to seek help for themselves. Other equally important reasons may include avoiding antidepressants due to their adverse side effects, namely changes in sex drive and increased suicidal thoughts. In the United States, one report states that around ⅔ of those who suffer from depression do not seek treatment. [1]Currently, the main form of drug treatment for depression are selective serotonin re uptake inhibitors (SSRIs). They are the most widely prescribed antidepressants in the world [2] , and many have severe side effects, especially in adolescents and infants but also in adults. The most worrying of all adverse effects of SSRIs is an increase in suicidal ideation, or a higher tendency to have suicidal thoughts [3] . Another major class of adverse effects are sexual dysfunction, such as impotence in men and
decreased libido and anorgasmia in both genders. Serotonin syndrome can also be caused by SSRIs, which can manisfer itself as increased heart rate, shivering, and even death. The mechanism of action of SSRIs is understood to be the increased concentration of serotonin in the synaptic clefts by inhibiting its reuptake. However, exactly how this effect counters depression, anxiety and other ailments is not entirely clear.

Figure 1. Lysergic acid diethylamide (left) compared to one of the most commonly prescribed SSRIs, Sertralin (right).

Other classes of antidepressants include serotonin-norepinephrine reuptake inhibitors (SNRIs) which share their mechanism of action and most side effects with SSRIs. An older generation of antidepressants include tricyclic antidepressants , which have mostly been replaced by SSRIs and monoamine oxidase inhibitors (MAOIs), which can cause addiction, and can be lethal when combined with other SSRIs or certain food supplements. It is then clear that there is ample place for improvements in antidepressants. Here I propose that LSD microdosing as a subperceptual antidepressant may be a more effective medication against certain cases of depression due to its very few side effects, wide therapeutic window, virtually unreported toxicity, short acting day-to-day effects and very low dose.

LSD and the Current State of Research

LSD is an extremely potent psychedelic drug that acts on a variety of receptors in the brain, mainly the 5-hydroxytryptamine family. It is highly illegal in most of the world, and was so illegal in the latter part of the 20th century that virtually no research on the substance was published or even possible. In more recent years, much research has been undertaken to better understand the mechanism of action, effects, toxicity and potential benefits of LSD. Much speculation and anecdotal evidence can be found about the purported benefits of the drug. LSD is used as an illegal drug for its psychedelic properties. There is a wealth of evidence that psychedelic experiences have long-lasting (14 months) antidepressant, antiaddictive and anxiolytic effects on the users, usually after a single experience. LSD has an extremely low potential for addiction [5] . For example, a 2014 paper published in The Journal of Nervous and Mental Disease found that LSD is a useful drug in the treatment of anxiety associated with life-threatening diseases: sNeither the experimental dose (200 μg of LSD) nor the active placebo (20 μg of LSD) produced any drug-related severe adverse events, that is, no panic reaction, no suicidal crisis or psychotic state, and no medical or psychiatric mergencies requiring hospitalization. [4] When considering the toxicity of LSD at perceptual doses (starting at around 75-100 μg), there is little to no evidence of organ damage or neuropsychological deficits, even at very high doses [7] .

One concern however is hallucinogen persisting perception disorder or HPPD which has been reported, though not clinically, especially in younger users who use LSD recreationally in combination with moderate to high consumption of cannabis. As microdosing is subperceptual, this should not be of great concern. Up to recently, this was the most common use of LSD. In recent years however, users have started dosing at subperceptual levels (no mind-altering effects). This has been called microdosing. Here, I will define LSD microdosing as a dose of a subperceptual (non-psychedelic) quantity (5-25 μg) of lysergic acid diethylamide. Generally, a dose is only taken once every 2-3 days or simply based on the needs of the user.

Microdosing

The effects of microdosing are not psychedelic and should be subperceptual in order to be considered a microdose – no perceptible mind-altering effects found at ‘normal’, perceptual dose levels (around 75-100 μg). Generally, a microdose will be taken sometime in the morning (usually 12h before the patient intends to go to sleep). Effects begin after 1-2h. Dosing can be repeated for more than one day in a row, though tolerance quickly builds up and effects may disappear after a few consecutive days. Thus, it is can be recommended that a microdose be taken with one to three days' interval.
At the moment, no large scale scientific research has been conducted on LSD microdosing, although a substantial amount of anecdotal evidence exists, which should be taken into critical consideration in light of the lack of peer-reviewed research on the subject.

The reported effects of microdosing include an increased sense of well-being, increase sense of creativity and novelty, increased alertness and concentration, reduced fatigue, hunger suppression and reduced depression. More subjective effects reported are feeling a sense of ease in social situations or in communication, feeling calm or at peace, and an increased sense of control over one's life, actions or emotions. Other effects, especially at higher microdoses (15-25 μg) may include a slight sense of euphoria within the first hours, increased heart rate and sweating, pupil dilation and vasoconstriction. Microdosing thus has effects similar to caffeine to some degree, being perhaps more mentally stimulating and calming. The overall effect of microdosing is a sense that depression is no longer or not as crippling for the day or days following administration. This, along with the fact that there are very few side effects at such low doses, makes microdosing perfect for a day-to-day type of dosing, where patients may choose to dose on the days when they feel they need it, and not dose when they feel it is unnecessary. This is a considerable advantage over SSRI antidepressants which may take months to start taking effect, and dosing must be kept regular regardless of the patients' day-to-day, week-to-week state of mind. Indeed, this fundamental difference in the purported antidepressant mechanism of action of microdosing as compared to traditional antidepressants is the main reason why such a drug could help relieve those cases of depression that have escaped modern antidepressants, either due to the ineffectivity of the drugs themselves or simply because the patients did not wish to seek treatment or is unable or unwilling to continue treatment regularly. Whether such a drug should be available only upon prescription by a professional will be discussed here below.

Developing an LSD Microdose Drug

In order for a drug to be approved, it must go through years of extensive testing. Here, I claim that much of preclinical tests that include target optimization would be mostly unnecessary at this stage as LSD is the already the desired target, and due to the low toxicity, nearly nonexistent side effects and minute dosing involved, the need for optimization would likely not outweigh its cost. LSD has desirable pharmacokinetics for the purpose of low-dose antidepressant treatment. It has a high bioavailability (71%) and very short half-life (3.6 hours) [6] , meaning that small doses will reach the brain and be eliminated from the body rapidly. This is ideal for intermittent or irregular dosage, as two consecutive dose-days will not constructively interact. In addition, tolerance develops immediately which reduces the potential for
misuse. LSD is perorally active, which is the ideal way of administration for any drug.

The clinical phase I of drug development for an LSD microdosing antidepressant drug would require tests on a small number of healthy volunteers in order to assess the pharmacokinetic and pharmacodynamic properties of LSD at subperceptual doses, and evaluate any side effects or toxicity in patients.
Phase II of clinical trials would require a larger group (over 100) patients suffering from mild to major depression. It is at this stage that I would acquire the first scientific evidence (or lack thereof) of efficacy of LSD as an antidepressant. It is also during phase II that the dose response could be properly assessed at subperceptual doses. Toxicity and side effects would continue to be monitored. Phase III would mean a much larger scale blind trial where LSD microdosing would be tested in random controlled trials on 1000s of patients. At this point, there should be more evidence of whether
microdosing is safe for patients with a more varied psychiatric background, such as people with underlying mental issues or current issues such as schizophrenia, bipolar disorders and other factors that would make regular SSRI treatment more difficult. The first three phases could be expected to take five to seven years. Following a large scale trial, regulatory review and approval from governing bodies should be obtained. Should the drug be approved
for marketing, after one or two years, it could finally be put on the market. Challenges in Drug Development
Because LSD is currently a very tightly regulated illegal drug in most of the world, obtaining proper permits for research on humans would surely prove difficult and time consuming. This is one of the main reasons for the current lack of antidepressant drugs based on LSD or other psychedelic drugs. Another serious challenge with developing an LSD microdosing base would be the potential for abuse of the drug. If a single dose is subperceptual, many doses could be compounded to produce psychedelic effects and this could mean that the drug could be sought out by those not suffering from depression but seeking recreational use of LSD. One solution to this problem would be to include an
emetic agent in small enough quantities in the drug that larger doses would induce vomiting and thus reduce the absorption of the drug, reduce likelihood of adverse psychedelic effects and also be a strong deterrent to those who seek to use the drug for recreational purposes. As there is a potential for abuse in so far as the drug being used in larger doses for its psychedelic effects, any LSD microdosing medication should only be available to patients upon prescription by a specialist.

Conclusion

In this text, I sought to examine how an antidepressant drug based on minute, non-psychedelic and subperceptual doses of the powerful hallucinogenic drug LSD would come to be developed, for what purposes, with what advantages over current antidepressants, and what kind of obstacles such a challenge would present us. Because of the varied and severe, sometimes fatal side effects of the most widely prescribed class of antidepressants, it is quite obvious that there would be a demand for a new generation of antidepressants with the low toxicity, virtual absence of adverse side effects, low potential for addiction and flexible treatment options such as LSD microdosing could offer
us. While these properties are seemingly true and have garnered much attention in certain spheres of society, there remains no systematic review of the effects of microdosing LSD. The current state of research on the wide variety of benefits of psychedelic drugs such as LSD and psilocybin seems to point to a future where the medicinal properties of these drugs could be developed into a new and better generation of antidepressants, anxiolytics and even antiaddiction drugs. However, much needs to change in how these drugs are classified, how easy it is to conduct scientific research on them, and most importantly, how they are viewed in society at large.

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REFERENCES

[1] http://www.psychiatry.wustl.edu/depression/depression_facts.htm. [Accessed 14 May 2018]

[2] Preskorn SH, Ross R, Stanga CY (2004). "Selective Serotonin Reuptake Inhibitors". In Sheldon H. Preskorn, Hohn P. Feighner, Christina Y. Stanga, Ruth Ross. Antidepressants: Past, Present and Future. Berlin: Springer. pp. 241–62. ISBN 978-3-540-43054-4.

[3] Stone MB, Jones ML (2006-11-17). "Clinical review: relationship between antidepressant drugs and suicidal behavior in adults" (PDF). Overview for December 13 Meeting of Psychopharmacologic Drugs Advisory Committee (PDAC). FDA. pp. 11–74. Retrieved 2007-09-22.

[4] Gasser P, Holstein D, Michel Y, et al. Safety and Efficacy of Lysergic Acid Diethylamide-Assisted Psychotherapy for Anxiety Associated With Life-threatening Diseases. The Journal of Nervous and Mental Disease . 2014;202(7):513-520. doi:10.1097/NMD.0000000000000113.

[5] Halpern, John H.; Suzuki, Joji; Huertas,, Pedro E.; Passie, Torsten (June 7, 2014). Price, Lawrence H.; Stolerman, Ian P., eds. Encyclopedia of Psychopharmacology A Springer Live Reference . Heidelberg, Germany: Springer-Verlag Berlin Heidelberg. pp. 1–5

[6] Dolder PC, Schmid Y, Haschke M, Rentsch KM, Liechti ME (2015). "Pharmacokinetics and Concentration-Effect Relationship of Oral LSD in Humans". Int. J. Neuropsychopharmacol . 19 (1): pyv072. doi:10.1093/ijnp/pyv072. PMC 4772267 Freely accessible. PMID 26108222.

[7] Hwang KAJ, Saadabadi A. Lysergic Acid Diethylamide (LSD) [Updated 2017 Dec 31]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2018 Jan- . Available from: https://www.ncbi.nlm.nih.gov/books/NBK482407/