Category: LSD

Introduction

Lysergic acid diethylamide (LSD) also colloquially known as “acid” is a psychedelic drug often criticised as being dangerous and delusion inducing but is also heralded by many scientists and psychologists as mind expanding, wonder drug. LSD is a derivative of ergot; ergot is a fungus which frequently grows on both rye and wheat. For centuries ergot was utilised as a medicine, such as in childbirth in small dosages. It was used to aid childbirth via both quickening delivery and stopping the bleeding afterwards. So intuitively a pharmaceutical company began to research its potential medical benefits. Sandoz Laboratories tasked chemist Albert Hoffman in the early 20th century with identifying and isolating the compounds in ergot that were medically beneficial. In 1938 he tried a few variations which yielded little success. Although on a few animal experiments Hoffman noted that one variation, Lysergic acid diethylamide -25 or LSD-25 had a peculiar effect on the mice, resulting in the species bizarrely behaving in an excited manner. Despite this Sandoz thought very little of the compound and mostly forgot about it. For Hofmann however, this wasn’t the case, as 5 years later in 1943 he resynthesised the compound and one day, while working with it began to feel strange. Hoffman went home laid down and became the first person in the world to hallucinate on LSD. But he couldn’t determine what caused the hallucination, as he always took extra precautions avoiding ingestion knowing that LSD could be poisonous. This led Hoffman to conclude that he absorbed a minute amount through his fingertips. He then began to experiment on himself by dosing himself with 250µg. The rest is history, LSD became a centrepiece of the counterculture movement in the 60s and after the patents expired, millions saw LSD as means to expand their spiritual horizons. Although soon after there was a cultural and literal crackdown on any sort of drug and LSD became illegal in 1968. Since its illegalization it has become very difficult to study it because of legal restrictions. In Australia LSD is schedule 9 (S9) meaning it is a prohibited substance and in the United States it is still classified by the Drug Enforcement Administration as a Schedule I drug, cataloguing it as one of the ‘most dangerous drugs’ with ‘no currently accepted medical use and a high potential for abuse.’

Hows It Work and How Dangerous is it

[image: ]LSD unlike most other psychoactive drugs is active in the microgram (μg) range, in contrast to majority of other psychoactive drugs which are chemically similar like psilocybin dimethyltryptamine, however are active in the milligram range (mg). LSD affects various brain receptors such as the dopamine receptors, adrenergic receptors, and glutamate receptors with majority of research conducted is on the stimulatory serotonin receptor 5-HT2A. The above illustration in figure 1 shows a part of the 5-HT2A serotonin receptor. The light blue section is representative of the binding state of the receptor whilst the dark blue section is representative of the lid. LSD hits the receptor at an unexpected angle causing the lid to fold over the LSD and “trap” it in the receptor. It is this phenomenon which causes the elongated “trips” that are associated with LSD lasting in excess of 12 hours. The hallucination is caused as the LSD remains trapped resulting in continual firing of receptor. Clare Stanford, a psychopharmacologist at University College London hypothesises that ‘serotonin helps keep a handle on perception and actually stops us from hallucinating.’ So by blocking the serotonin receptors in your brain with psychedelics such as LSD, your brain loses its grip on perception and thus you hallucinate. Or another idea, which is presented by Andrew Sewell, a Yale psychiatrist who studies psychedelic drugs, is that LSD enhances some part of your perception and that such drugs lower activity to the thalamus. It sits in the center of your brain and filters your sensory information from all your nerves. Sewell thinks that by dampening down this filter, you become more aware of the information actually coming into your system like sights and sounds becoming louder or brighter, and by seeing things you have never noticed before. Or you might just start seeing things period. Recently, LSD research has seen a revival and using contemporary neural imaging techniques, researchers found that the drug causes parts of your brain to communicate in unique ways, especially in the visual cortex potentially explaining the vivid and complex hallucinations There’s also decreased blood flow in the default mode network, correlating to strong changes in consciousness, characterized as ego-dissolution, described as a feeling where the boundary that separates you from the rest of the world dissolves. Many people report this feeling brings a sense of reconnection with themselves, others, and the natural world. In fact, a study on 20 healthy volunteers receiving 75μg of LSD saw that 2 weeks after being dosed, they scored higher for the traits of optimism and openness, with increased creativity and imagination. This has led researchers to consider LSD as a therapy for patients with death anxiety and life-threatening illnesses. Researchers found that 12 months after treatment, patients reported a reduction in anxiety and rise in quality of life, as the drug helped them restructure their habits and worldview. It is also why the trend of micro dosing has emerged; this is where a person takes a sub-perceptual dose of LSD about 15μg. This dosage does not induce hallucinations but allegedly results in heightened alertness, energy, and creativity as well as increased productivity and reduced anxiety. LSD is non-addictive and researchers rate it as significantly less dangerous than other drugs such as cocaine, heroin, MDMA, and alcohol see figure 2 and 3 below. A study, published in the journal Lancet also lists LSD as one of the least harmful drugs, both to the user and to others. Another study published in the journal Psychopharmacology found that there’s no link between LSD and mental illness, and in fact it might be beneficial for those who suffer from depression.Figure 1. A part of the serotonin receptor 5-HT2A that binds LSD. (Left) Closed form. (Right) Open form.

Figure 2

Figure 3 Harm Caused by Drugs

Despite this there’s still a large lack of scientific studies on LSD to the explain the widespread micro dosing trend and use in general. Even experienced hallucinogen users sometimes experience “bad trips” which in severe cases can cause both temporary and long-lasting irrational fears, paranoia, and panic attacks. LSD can also cause flashbacks, where months after the drug has worn off, it can feel as if the user is experiencing the effects of the compound all over again. In some extreme occasions, people have developed Hallucinogen Persisting Perception Disorder (HPPD), which is described as “a never-ending trip”. But one study published in the journal of Drug and Alcohol dependence concluded that such flashbacks or HPPD, is incredibly rare. The notion that LSD can lead to psychosis and the risk of suicide are also overstated. The 14% of participants in the US national survey who had done psychedelics in their life had no increased risk of developing psychosis, depression, or suicide attempts, but the new research around LSD’s potential positive effects is also very new, so if anything is clear it is that more research is needed on this drug.

References

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3. Medium. (2018). The Cognitive Benefits of Microdosing Psychedelics. [online] Available at: https://artplusmarketing.com/the-cognitive-benefits-of-microdosing-psychedelics-599c5b5f7d98 [Accessed 2 Nov. 2019].
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5. Caymanchem.com. (2019). LSD and Its Structural Derivatives. [online] Available at: https://www.caymanchem.com/news/lsd-and-its-structural-derivatives [Accessed 2 Nov. 2019].
6. American Council on Science and Health. (2018). LSD Has Staying Power, Chemistry Explains Why. [online] Available at: https://www.acsh.org/news/2018/03/12/lsd-has-staying-power-chemistry-explains-why-12676 [Accessed 2 Nov. 2019].
7. Brandt, S., Kavanagh, P., Westphal, F., Stratford, A., Elliott, S., Hoang, K., Wallach, J. and Halberstadt, A. (2016). Return of the lysergamides. Part I: Analytical and behavioural characterization of 1-propionyl-d-lysergic acid diethylamide (1P-LSD). undefined, [online] p. Available at: https://www.semanticscholar.org/paper/Return-of-the-lysergamides.-Part-I%3A-Analytical-and-Brandt-Kavanagh/7570117f0345e4d09ca7d50b41c22a368d7c7dca [Accessed 2 Nov. 2019].
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10. Passie, T., Halpern, J., Stichtenoth, D., Emrich, H. and Hintzen, A. (2008). The Pharmacology of Lysergic Acid Diethylamide: A Review. CNS Neuroscience & Therapeutics, 14(4), pp.295-314.
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LSD, also known as Lysergic acid diethylamide-25 is a potent drug that is in fact, the most powerful out of all of the hallucinogens psychedelic drugs, this is due to the fact that is is approximately 100 times stronger than psilocybin and 4000 times stronger than mescaline. This drug changes a person’s mental state by changing, altering, and distorting the perception of reality to the point where at high doses hallucination occurs. LSD is synthetically made from lysergic acid, which is found in ergot, a fungus that grows on rye and other grains. The effects of LSD are so potent that its doses tend to be in the microgram range. This paper seeks to evaluate the effects, history and chemical mechanisms of LSD. In addition, this article attempts to uncover and bring to light some of the effects that LSD has on various brain structures and explain how those effects come into fruition, as well as the potential of it being a treatment. Ultimately, the paper suggests that more research is needed into LSD being a potential treatment and that the stigma against LSD needs to end.

Nearly half a century ago, psychedelics “fell from medical grace” and little to no research has been conducted about these substances, which is potentially detrimental if it does pose qualities that it can be a good medication. However, some new research and studies pose some suggestions that some researchers have faith that LSD can be studied more in depth in the future. (Langlitz, 2013). Hallucinogens do not always instigate hallucinations, despite it’s somewhat misnomer of a name. The user is under the false sensations, in which the experience is limited to themselves. Hallucinogens prompt and induce the user to act and say things that they would normally not do. In short, they shift and change the usual or typical personality of the individual. LSD has generally always been viewed as highly controversial in the North Americas and worldwide/internationally, however, this usually is due to the tragic fact that because people have been exposed to media bias or miseducated about its effects. Its physiological effects on the brain and body have continued to become increasingly well-known during the past few decades, a time when research in neuroscience was at its height and peak. The psychological effects of LSD have often been difficult to describe and document very well as they were first accidentally discovered on the fateful day of April 16, 1943 by the research chemist Albert Hofmann. This was due to a small amount of the drug soaking/leaking into his fingers during the interim of a routine scientific synthesis. Hofmann had described an experience in which he was situated in an imaginative, fantasy dream-like state for a 2-3 hour long timeframe. The drug is usually classified as an indocile hallucinogen. It is additionally, encompassed within the confines of the phantastica family. To make sense of this, what this means is that it contains the structure which is known and referred to as the indole nucleus, which is in conjunction with the simplest structure of serotonin, a neurotransmitter. This drug is entirely capable of altering and changing one’s perceptions while enabling the individual to remain in communication within the current world, this means that somebody who is high from LSD or under the influence of this drug will often be simultaneously conscious of both the ‘real’ world and the ‘fantasy’ world, which is the namesake of the category Phantastica (Ray & Ksir, 1996).

History of LSD

LSD has the presentation of being a white-coloured, odorless crystalline powder that has the unique characteristic of being water-soluble. It also has the feature of breaking down under the exposure to the ultraviolet (UV) light. Lysergic Acid Diethylamide, better known as LSD and was first synthesized by Albert Hofmann on November 16, 1938. The discovery took place in Basel, Switzerland, in Author Stroll’s Sandoz Laboratories. In 1943, the effects were discovered in 1943 by the Swiss chemist Albert Hofmann, who was working there and had accidentally dosed himself and was astonished by the psychoactive effects of a drug he had labeled LSD-25. Hofmann had been working with ergot, a rye fungus in the hope of creating a new and improved, as well as more advanced cardiovascular stimulant.

Worldwide, in clinical research settings revived investigations are taking place that are learning about and testing the use and consumption of psychedelic substances for treating illnesses such as addiction, depression, anxiety and posttraumatic stress disorder (PTSD). Since the termination of a period of research from the 1950s to the early 1970s, most psychedelic substances have been classified as drugs that have a high likelihood or chance of being abused with little to no recognized medical value. However, recent controlled clinical studies have been conducted to appraise the basic psychopharmacological properties and therapeutic adequacy of these drugs as additional appendages to already existing psychotherapeutic approaches. What is most integral to this revival is the re-emergence of an archetype that understands and acknowledges the crucial importance of set (i.e., psychological expectations), setting (i.e., physical environment) and the therapeutic clinician–patient relationship as the most essential elements for facilitating positive healing experiences and accomplishing positive and happy outcomes.1,2 The public is often well notified in the potential harmful effects and pitfalls of psychedelic drugs, but much of this knowledge stems from cases involving patients who used illicit substances in unsupervised nonmedical contexts without considering the usage of LSD in a more controlled environment. Emerging research for therapeutic purposes associated with human subjects needs to be discussed and addressed in a great amount of detail, in lieu of both the possible benefits and the potential risks and harms of using psychedelic agents as sidedicks to psychotherapy or counselling for profound psychological effects.

Effects of LSD

An ostensibly insignificant minute dose of LSD can dramatically adjust one’s perception of reality to the extent where of hallucination occurs. What this means is that the consumer’s perception of reality is changed by seeing things that do not exist and are not present in this reality. LSD is an intensely powerful substance which can dramatically alter the mood, perception, as well as a variety of cognitive processes of the human mind. It can also dramatically reshape the imagination as well as cause an effect, known as synesthesia. When the person takes LSD, they will feel that the very nature of reality itself is amplified and enhanced through this use. There are quite a large variety of effects for the use of LSD, both physically and mentally, as well as short and long term. Some physical effects include but are not limited to dilated pupils, higher or lower body temperature, sweating and/or chills, loss of appetite, insomnia, lack of saliva in the mouth, and tremors. Some mental effects include delusions, visual hallucinations, an artificial sense of euphoria, the distortion of one’s sense of time and identity, impaired depth and time perception as well as the distorted or false perception of the shape and size of movements, touch, objects, sounds, colour, and the user’s own body image, severe, terrifying thoughts and feelings, the fear of losing control, panic attacks, flashbacks, and severe long-term depression or psychosis. The long-term effects of LSD use can be both good and bad. There are cases of people who claim to have had their entire lives turned around, for the better, due to LSD use. On the other hand, some people have been hospitalized due to the effects of LSD psychosis. However, even though there are all of these effects, psychedelics are considered and contemplated to be safe physiologically and are said not to produce either the results of dependence or addiction. There are no recorded overdose deaths due to the ingestion of LSD at what are considered to be reasonable dosages. The user’s mood is very likely to adjust depending on how he/she feels emotionally at various stages during the usage of LSD. The quality of the outcome of the use of LSD is almost always dependent on two extremely important factors: the set and the setting. The set refers to a user’s expectations of how it feels to take the drug and how the mind changes. The setting is the environment in which the drug is taken. For example, an inexperienced user takes LSD while they are in a stressed condition or in a bad mood, a bad experience may most likely occur. By the same token, taking LSD in a chaotic environment like a noisy concert could turn into trouble for someone unsure of the drugs effects. When users on LSD become frightened or enter a state of panic, they can usually be relieved or calmed down by nearby.

Mechanisms of LSD

LSD affects the brain by stimulating the serotonin 5-HT2A brain receptor subtype. Psychedelics such as LSD are either agonists or partial agonists. This particular receptor is a member of the Family A type G protein-coupled receptors (GPCRs) and is widely expressed throughout the brain, being particularly dense on apical dendrites of layer 5 cortical pyramidal cells. Its canonical signaling occurs through coupling to Gaq, activating phospholipase C, resulting in phosphoinositide hydrolysis, formation of diacylglycerol, and leading to mobilization of intracellular calcium. Activation of the 5-HT2A receptors on the glutamatergic neurons within the brain leads to the cells to become more excitable. It generally does not, however, lead to the depolarization and the generation of action potentials. There is significant expression of the receptors in the 5th layer in the medial prefrontal cortex, reticular nucleus of the thalamus, ventral tegmental area, the amygdala, the locus coeruleus, as well as a few other key regions. However, the claustrum is the part of the brain which depicts the highest expression of 5-HT2A receptors in the brain. Psychedelics cause a brain effect that leads to cortical cell excitation through suppressing raphe cell firing in the brain stem through 2 methods: either directly (LSD and similar compounds) or indirectly (by phenethylamines). These generally lead to cortical cell excitation. The activation of 5-HT2A receptors in so many key brain regions lead to neuronal excitability and therefore would be expected to have marked effects on cognition. Regarding substance abuse, it has been proven and demonstrated that by multiple surveys, researchers, and analysts that anxiety and stress are very important triggers for a relapse. It is possible that the 5HT2A receptor downregulation by hallucinogens may help in stress-induced relapses. LSD may also trigger effects to the brain such as brain-derived neurotrophic factor (BDNF), and glial cell line-derived neurotrophic factor (GDNF). Both of these effects play important roles in neurogenesis, synaptic plasticity, learning, and memory. There is evidence that LSD may induce neuroplastic changes suggesting a basis for the persistent behavioral changes.

How can LSD be used clinically?

The pharmacology of LSD is inadvertently complex, even in today’s entrenched, incessant research, its mechanisms of action remain unclear to this day. LSD is physiologically well tolerated and there is no evidence of its virulency for long-lasting debacles to the brain and other comer parts of the human organism. The review of pharmacology, psychopharmacology, related preclinical research, as well as basic studies with human subjects are gleaned from the incessant research that was for the most part conducted in the 1950s and 1960s during an era that held great promise and fostering for LSD and related hallucinogens. Expentation, confidence, and sanguineness was placed in these unique substances for new and contemporary treatments for psychiatric conditions and discoveries that would enhance our circumscribed knowledge of the mind. The confidence placed on LSD and other hallucinogens showed promising results, as hallucinogen research did indeed lead to the discovery of serotonin, brain second-messenger systems, and a variety of other research techniques such as prepulse inhibition and the use of animals for detection of activation of specific sub-receptors. The once-innovative research of LSD diminished and was slowly phased out after these prodigious advancements. The clinical promises failed to be addressed by analysts and the public while illicit use of hallucinogens pressured governments into taking strict police action against such use of the new-found drug. Government funding of research dried up, as well, and a generation of scientists moved on to other more seemingly important topics. Today, LSD and other hallucinogens are once again being appraised and evaluated on, for specific purposes, such as for treatment of the “cluster headache” and as tools in therapy for working with those suffering from anxiety provoking end-of-life issues and for posttraumatic stress disorder (PTSD). As these new studies further advance in knowledge, and move forward, it is anticipated by today’s researchers and many people part of the medical industry the current research taking place will be a roadmap for also securing the data missing from our knowledge of the pharmacology of LSD from our past research. In the past LSD and other hallucinogens have been used in professional studies of the human mind. These studies have had mixed results, that always almost always vary, depending on the patient and his or her surroundings during consumption and testing. Emerging research is beginning to change the public and the industries perception of LSD from a drug that can negatively affect the mental and physical well-being, to one that can alleviate the visual and hidden symptoms of anxiety and depression. Its benefits are also being thoroughly studied in relation to helping struggling individuals who are trying to overcome drug dependency. The most remarkable and unique potential benefit of hallucinogens is what’s known as ‘ego death,’ an experience in which people lose their sense of self-identity and, as a result, are able to detach themselves from worldly concerns like a fear of death, addiction, and anxiety over temporary — perhaps thoroughly exaggerated — traumatic or amazing life events. When people take a potent dose of the psychedelic, they can experience watershed spiritual, hallucinogenic trips that can make the user feel like they’re transcending their own bodies and even time and space. This, in turn, gives people a lot of perspective — as if they can see themselves as a small part of a much broader, seemingly magical universe, it’s a lot easier, and often unhesitant of them to discard personal, relatively insignificant and inconsequential concerns about their own lives and death. Today, the studies of LSD have resumed and are being used regularly to clinical patients.

Conclusion

The recent rejuvenation of scientific interest in psychedelic medicine is generating new knowledge about a class of unique pharmacologic substances that patients and medical professionals have long used and needed. As this field of research continues to evolve with resumed research, the current educational system for many medical schools may need to be updated to include the latest knowledge, breakthroughs, and research about psychedelic drugs. This would include new scientific evidence about the relative risks and harms of psychedelic drugs – which is profoundly absent in current drug control scheduling classifications and advertisements, they should also consider the adverse outcomes from uncontrolled recreational use rather than supervised clinical settings (Nichols, David). So considering new laws and regulations revolving around the use of pharmacologic substances is important. In addition to all of that, it would encompass knowledge about the potential therapeutic uses of these agents, particularly because patients may query their physicians about research findings reported in the media. If further scientific evidence accumulates on the therapeutic value of psychedelic medicines, specialized, professional clinical training for physicians, nurses, psychologists and other health professionals will need to be required to meet a future with an increased demand for such treatments. It is important for policy-makers to be aware of and open to new approaches to treatments emerging in the field of psychedelic medicine. This is thoroughly important for those who are concerned about the vastly growing prevalence of mental illness, including addiction, as well as its associated human, social and economic costs. Currently, international drug control scheduling classifications and popular misconceptions about the relative risks and harms of psychedelic drugs make research involving humans difficult. However, continued medical research and scientific inquiry into psychedelic drugs may offer new ways to treat mental illness and addiction in patients who do not benefit from currently available treatments.

The re-emergence of the studies of psychedelic medicine has the potential to allow gaping access to therapeutic and clinical doors that were closed for far, far too long. The dangers of LSD are considered miniscule when compared to other drugs, despite the fact of it being one of the most potent out of all hallucinogenic drugs. It doesn’t promote either addiction or dependence, which are damning feature of most drugs. There is new evidence that supports the idea of a new age of psychedelic medicine may be upcoming and plausible in the future, as suggested by the legalisation of marijuana as well as the use of medical marijuana.

At first, you feel nothing. As the tablet dissolves, reality does as well. You look around the room. The room is spinning almost pulsating. It’s as if the world is breathing. It all started by taking a small tablet. This tablet is a form of Lysergic acid diethylamide (LSD). LSD is a widely used drug that has affected various people in America. Thus, to understand the gravity of the effect of this drug, one must address the pharmacology, biological impact, population risk, interventions, and recommendations for future work.

Lysergic acid diethylamide (LSD) was created in 1938 by Swiss scientist Albert Hofmann. He discovered LSD, because he was working on a chemical that is found in a fungus called ergot. (history.com). Despite his original discovery in 1938, the full effects of LSD was not yet known. In fact, Hofmann did not know the side effects of Lysergic acid diethylamide until 1943 when he accidentally ingested the substance. At first, he did not feel any effect, but later that day Hofmann began to feel the effects. In Albert Hofmann’s book LSD: My Problem Child , he recalls that day and stated that when he went home, he sank into a not unpleasant intoxicated like condition, characterized by an extremely stimulated imagination. In a dreamlike state, with eyes closed (he) found the daylight to be unpleasantly glaring), (he) perceived an uninterrupted stream of fantastic pictures, extraordinary shapes with intense, kaleidoscopic play of colors. After some two hours this condition faded away (LSD: My Problem Child, 1980).

It took 5 years for Hofmann to test the effects of the drug. When he discovered the effects, he found that LSD is a psychedelic drug, which means that it causes hallucinations (merriam-webster). Three days after his accidental ingestion, Hofmann intentionally took the substance to feel the full effects of the drug. Due to the scientist being unaware of the entry level dose of the drug, he ingested almost 10 times the amount of the now known entry dosage. Thus, Hofmann had to be assisted to exit the laboratory where he resided. After he exited the lab, Hofmann started to ride his bike back to his home. This is where he truly felt the psychedelic positive and negative effects of LSD. During his bike ride,he was frightened to the point that he contacted a physician. Yet, the physician found nothing unusual about Hofmann’s demeanor except his dilated eyes (cite?). Hofmann felt elation and found himself appreciating “the unprecedented colors and plays of shapes that persisted behind (his) closed eyes. Kaleidoscopic, fantastic images surged in on (his), alternating, variegated, opening and then closing themselves in circles and spirals, exploding in colored fountains, rearranging and hybridizing themselves in constant flux” (LSD: My Problem Child, 1980). This shows how LSD did not cause noticeable effects on Hofmann’s appearance at first. Therefore, that day, April 19, 1943 marked the first instance of an LSD trip, which catalyzed the beginning of the psychedelic movement (What Is Bicycle Day?,n.d.). Although there was a delay in Hofmann discovering these effects of LSD, his experience was the foundation of discovering and experimenting with other psychedelic drugs.

Hofmann’s documented experience catalyzed research and interest in the chemical form and biological impact of Lysergic acid diethylamide. Lysergic acid, which is found in a parasitic rye fungus called Claviceps purpurea, is the derivative of LSD (Passie, Halpern, Stichtenoth, Emrich & Hintzen, 2008). Thus, LSD comes from a grain. Despite LSD being derived from an organism in nature, it must go through synthesization to become the form of LSD that is for human ingestion. The chemical make-up of LSD includes the following elements: Carbon, Hydrogen, Oxygen, and Nitrogen, and the molecular formula is C20H25N3O (National Center for Biotechnology Information, n.d.). The chemical composition and molecular formula of LSD shows how various natural chemicals are manipulated to make this hallucigen. LSD also has various chemical names such Acid Diethylamide, Lysergic Diethylamide, Lysergic Acid, LSD 25

LSD-25,Lysergic Acid Diethylamide, Lysergic Acid Diethylamide Tartrate, Lysergide ( National Center for Biotechnology Information, n.d.) The various forms of Lysergic Diethylamide are” sold in tablets, capsules, liquid form, or dissolved onto blotter or other absorbent paper and cut into squares. Called acid, blotter, window pane, dots, mellow yellow, boomers, and yellowsunshines” (LSD and the Dangers of Microdosing, 2019). In spite of Albert Hofmann’s documented experience, LSD can cause a lot more side effects. The full biological impact of LSD is more extensive because there are short and long term side effects of the drug. The short term psychological side effects of LSD are visual and auditory hallucinations distorted sense of time and body perception, sensitivity to sounds, smells and other sensations, blending of the senses (synesthesia), heightened sense of understanding and identity, mystical or religious experiences. So, LSD can cause people to sense and perceive various things that are not realistic. The short term physical effects include blurred vision, dizziness, chills, sweating, dry mouth, dilated pupils, nausea, weakness, palpitations, elevated body temperature, tremors, and rapid heartbeat (Gonzales, 2018), LSD not only causes these side effects, but also long term effects which are far more serious. The long term effects of continual LSD use may include chronic psychosis, which is “a serious mental illness (such as schizophrenia) characterized by defective or lost contact with reality often with hallucinations or delusions” (“psychosis”, n.d.). Although chronic psychosis is not always a side effect of LSD, it still exposes how detrimental LSD can be to a person’s mental health. Lysergic acid diethylamide can also cause people to struggle with articulating and rationalizing with other people (Gonzales, 2018). Therefore, usage of LSD can completely change a person’s mental capability. In some cases, Lysergic acid Diethylamide can even cause people to develop “hallucinogen persisting perception disorder, a condition characterized by repeated, spontaneous distortions in reality similar to those caused by acid” (Gonzales, 2018). Thus, Lysergic acid Diethylamide can have an immense psychological and biological impact on humans.

After understanding LSD’s chemical components as well as biological impacts, it is also important to address which population is most at risk for LSD usage and addiction. In relation to income, it is difficult to identify which socioeconomic class is most at risk. This is due to the price of LSD being sold “for around $5-$10. A quarter ounce usually sells for around $25-$30. The drug can even be found cheaply on the Internet or for free from dealers looking for new clients” (Hilbink, n.d.). This exposes how accessible and inexpensive LSD is to the population of America. The price of LSD may also explain the most at risk age group. Overall, from 2012-2014, the average usage of psychedelics such as Lysergic acid Diethylamide was only 0.1% of all age groups in America. ( How many people use LSD, n.d.). So, LSD is not only inexpensive, but it is also not common in any American age groups. In fact, In 2014, 0.3% of 12-17 year olds and 18-25 year olds were current users while 0.1% of 26 and older individuals were current users of LSD ( How many people use LSD, n.d.). Therefore, from the individuals that were tested for the statistic, the 12- 17 years olds had the highest percentage of usage. However, this statistic does not account for all of America. In 2017, the National Institute on Drug Abuse reported that the highest percentage of LSD usage was in adults 26 and older. (10.6%), but this is within a lifetime. (NIH,2017). So, the statistics and trends change for LSD usage throughout different years and decades. As for race, Non-hispanics, specifically White people have the highest amount of hallucinogen usage (32,229) and 12 year olds and older have the highest amount of hallucinogen usage (SAMHSA, Center for Behavioral Health Statistics and Quality, National Survey on Drug Use and Health, 2016 and 2017). Although there is a high number of usage in White people and 12 year olds and older, people of all ages and races report usage of hallucinogens such as Lysergic acid Diethylamide. The gender that has the most incidences of LSD abuse is the male population (Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality, National Survey on Drug Use and Health, 2016 and 2017). After understanding these statistics, one can infer that White males who are 12 years old and above are the most at risk population for LSD abuse and addiction. Moreover, income is not a determining risk factor in usage of LSD.

Due to LSD’s side effects and group that is most at risk, there must be action taken to prevent usage of the drug. Before discussing recovery, one must undertsand that LSD is typically not a physically addictive drug. Instead, acid addiction is generally psychological” (“LSD Addiction Treatment Programs”, n.d.). This means that recovery from LSD does not involve physical withdrawal symptoms but is still concerning due to mental obstacles that arise from LSD usage. When searching for LSD addiction recovery options, Substance Abuse and Mental Health Services Administration or SAMHSA has a national helpline that is dedicated to talking to people who are seeking help for substance abuse for themselves or others. If needed, they also transfer people to other services. These services include inpatient, outpatient, and 12-step programs. In patient programs can span from 30 days to 90 days and can include group meetings; outpatient programs allow treatment options that allow a patient to attend therapy 3-5 days a week for 2-6 hours; On the other hand, 12-step programs are free programs that incorporate 12 steps into a person’s journey to recovery ( How to Find the Best Residential LSD Recovery Center, n.d.). Thus, there are various ways to receive recovery treatment for LSD abuse. Behavioral therapy and group therapy are also important methods associated with the recovery of LSD addiction. Behavioral therapy allows an addict to find habits and activities to replace drug usage while group therapy offers a support group to recovering addicts to encourage staying clean of drugs (LSD Addiction Treatment Programs, n.d.). Behavioral therapy can be useful to an LSD addict, because it addresses the effects of the psychological impacts of LSD. On the other hand, group therapy helps a person with other recovering LSD addicts, which can allow each addict to set an example and be accountable for one another. This means that behavioral therapy can help to address the detrimental effects that LSD has had on a recovering addict. Individual and family therapy are also other methods that could be used to intervene and help with recovering from LSD (Recover from LSD Abuse, n.d.). Individual therapy may help a recovering person to allow themselves to focus on their recovery instead of other people’s as well. Family therapy can help a patient’s family to be involved in supportive in the patient’s recovery process. Therefore, there are multiple ways for a recovering LSD addict to seek help and recover.

Although there is a lot of information on Lysergic acid Diethylamide, there are still some unanswered questions as well as issues that have recently arisen. One big issue is about microdosing, which is “ the action or practice of taking or administering very small amounts of a drug in order to test or benefit from its physiological action while minimizing undesirable side effects” (“microdosing”, n.d.). Microdosing is controversial, because it allows drugs such as LSD to be used by humans. Recently, people have voluntarily allowed scientist to see how microdosing affects humans. In fact, in 2016, a study from Imperial College in London addressed and questioned if LSD could affect optimism and openness over a short and extended amount of time. The researchers tested 20 people who were over 21 years old. Minutes after they were given a microdoses of LSD, most of the participants experienced positive instead of negative feelings during the first few minutes and even 2 weeks after their micro-dosage (Weintraub, 2016). The study showed that microdoses of LSD may help increase optimism, which can help many people who have certain mood disorders. For example, Weintraub stated that this study opens up the question of “ Could LSD one day be used to treat maladies such as major depressive disorder? Would the short-term psychological discomfort of giving an individual therapeutic LSD be worth the potential long-term benefits? Would the positive effects of LSD persist longer than two weeks?” (2016). The study did help to show that LSD may be beneficial to many people, yet more research must be done to completely accept the wide usage and acceptance of microdosing for psychedelics.

Lysergic acid diethylamide (LSD) is a synthetic drug that changed not only Albert Hoffman’s life but also the world. It is so unique that there is even a holiday dedicated to Hoffman’s first trip on LSD. Although the side effects vary LSD can drastically change a person’s mental state and capabilities. Despite the drug not being as widely used by any age group, it has the potency to change a person for the rest of their life. However, there is research on the beneficial impacts of LSD with controlled amounts. Therefore, to truly understand all of the benefits and drawbacks of LSD, it must be carefully monitored and studied for years to come.

Introduction

Lysergic acid diethylamide (LSD) was first synthesized in 1938 by Albert Hofmann (Passie, Halpern, Stichtenoth, Emrich, & Hintzen, 2008). It is a prototypical hallucinogen and has one of the most potent hallucinogenic effects (Wacker et al., 2017). LSD is derived from lysergic acid and there are four optically-active isomers known (Passie et al., 2008). Out of four isomers, d- and l-LSD and d-l and l-isolysergic acid diethylamide, only d-LSD isomer has psychoactive properties (Passie et al., 2008). There are many homologs and analogs, but only one’s with comparable potency to LSD are derivates substituted at the N-6 (Passie et al., 2008).

LSD was initially used to study psychotic-like states but it later showed promising results for the treatment of various psychological disorders, including depression, substance abuse, and anxiety (De Gregorio, Enns, Nunez, Posa, & Gobbi, 2018; Passie et al., 2008; Strajhar et al., 2016; Wacker et al., 2017). LSD can produce long-lasting positive psychological effects if taken under controlled conditions, however, if taken under uncontrolled conditions, it can lead to traumatic experiences and flashback phenomena (Passie et al., 2008). Moreover, it can impair psychomotor functions and cognition, lead to mild autonomic, biochemical and endocrinological changes and also induce changes in sleep cycle (Passie et al., 2008).

Since LSD gained popularity between recreational drug users in 1950s and 1960s, it was made illegal, which consequently paused the research on humans (Carhart-Harris et al., 2016). In 2008 Passie et al. reported that since 1966 no study has been conducted regarding the effects of LSD on the human brain. However, in the last decade there has been renewed interest in research with psychedelics, including LSD (De Gregorio et al., 2018; Dolder, Schmid, Haschke, Rentsch, & Liechti, 2015; Dolder et al., 2017; Strajhar et al., 2016; Wacker et al., 2017). The current paper will, therefore, focus on the pharmacokinetics (PK) and pharmacodynamics (PD) of LSD and the neurological changes induced by it.

Absorption / Resorption

If LSD is administrated preoral (p.o.), it is completely absorbed in the digestive tract (Passie et al., 2008). A dose of 200 μg in humans produces maximal concentration after 1.5 hours (Dolder et al., 2015) Absorption, however, is dependent on the pH of the stomach and can be influenced by the fullness or emptiness of the stomach (Passie et al., 2008).

Distribution

Axelrod, Brady, Witkop, and Evarts (1957) have researched the distribution of LSD in a cat. The animal received 1 mg/kg of LSD intravenously (i.v.) (Axelrod et al., 1957). After 90 minutes they found that LSD was mostly localized in the bile and plasma but only a small amount of it was present in the fat and feces. Authors suggested that, although LSD was secreted into the intestines, it was then reabsorbed. They also examined the presence of the drug in the brain and cerebrospinal fluid (CSF) and concluded that it can pass the blood-brain barrier (BBB) but found no differences in the distribution between different brain regions (Axelrod et al., 1957).

This finding differs from Snyder and Reivich (1966) who found that LSD is differently distributed between the brain regions. They conducted an experiment on squirrel monkeys to investigate the distribution of LSD in the brain tissue (Snyder & Reivich, 1966). Four monkeys received 2, 2, 1 and 0.5 mg/kg of LSD and were killed 20 minutes after the i.v. administration. They found the highest concentrations of LSD in pituitary and pineal glands, which were 7-8 times higher than in the cortex (Snyder & Reivich, 1966). Higher concentrations than in cortex were also found in the limbic system structures, visual and auditory areas of the deep cerebral structures and hypothalamus. However, LSD was not notably concentrated in the visual cortex, although its concentration in iris was 18 times higher than in cortex. Snyder and Reivich (1966) also reported that the concentration of LSD in the blood matched the cortical concentration. They concluded that uneven distribution between brain regions is not due to the regional blood flow, lipid solubility and consequent predilection for white matter.

Metabolism and Excretion

The metabolism rate of LSD varies between species. The half-life in mice is 7 minutes, compared to cats where half-life is 130 minutes and in humans 175 minutes if LSD is administrated p.o. (Axelrod et al., 1957; Passie et al., 2008). Administration of 2 μg/kg LSD i.v. to humans persists in plasma for about 8 hours, with half-life of 3 hours (Snyder & Reivich, 1966). Siddik et al. (1979) further investigated metabolism of LSD in rats (1 mg/kg i.p.), guinea pigs (1 mg/kg i.p.) and rhesus monkeys (0.15 mg/kg i.m.). They found out that most of the drug is metabolized before excretion and also identified metabolites – glucuronides of 13- and 14-hydroxy-LSD (Siddik, Barnes, Dring, Smith, & Williams, 1979). However, metabolites varied between species, for example, urine of rhesus monkeys contained at least nine metabolites, where 13- and 14-hydroxyl-LSD were represented only in small amounts (Siddik et al., 1979).

In humans, LSD is metabolized by NADH-dependent microsomal liver enzymes to the inactive 2-oxy-3-hydroxy LSD (O-H-LSD) and other metabolites, namely lysergic acid ethylamide (LAE), nor-LSD, di-hydroxy-LSD, 2-oxo-LSD, 13- and 14-hydroxy-LSD, lysergic acid ethyl-2-hydroxyethylamide (LEO) and trioxylated LSD (Passie et al., 2008). However, the major metabolite in urine is O-H-LSD, which is also detectable for a longer period than LSD (Dolder et al., 2015).

Siddik et al. (1979) also investigated elimination of LSD in rats, guinea pigs and rhesus monkeys. Rats excreted 73% in feces and 16% in urine, guinea pigs 40% in feces and 28% in urine and rhesus monkeys 23% in feces and 39% in urine (Siddik et al., 1979). In humans LSD excretion is maximum after 4-6 hours after administration of 200 μg p.o. (Passie et al., 2008). Within the first 8 hours of orally administrated 200 μg, approximately 56% of nonmetabolized LSD was excreted through urine and renal clearance was approximately 1.6% of total clearance, which predicted oral bioavailability of 71% (Dolder et al., 2015).

A recent study combined date of two similar studies where 24 and 16 healthy subjects were administrated 100 and 200 μg of LSD, respectively (Dolder et al., 2017). In both studies, LSD was detected in subjects up to 24 hours after administration. Mean maximum plasma concentration (Cmax), area under the concentration-time curve, plasma half-lives and Tmax (estimated time to reach Cmax) were not significantly different between the doses (Dolder et al., 2017). Concentration-time curves revealed first-order kinetics for both doses, with avarage half-life of 2.6 hours (Dolder et al., 2017). However, in study with the administration of 200 μg of LSD, the authors noticed an inconsistent slower decrease in concentration after 12 hours, suggesting a redistribution of LSD from tissue or less precise quantification of low plasma levels (Dolder et al., 2015).

Toxicology and tolerance

LSD shows no acute tolerance after administration of 200 μg in humans (Dolder et al., 2015). The study also reported no severe adverse effects, however acute adverse effects include impaired concentration, headaches, exhaustion and dizziness, all which can last up to 24 hours (Dolder et al., 2015). There have been no known deaths from LSD overdose in human, however LD50 for rabbits, rats, and mice is 0.3, 16.5, and 46-60 mg/kg i.v., respectively (Passie et al., 2008). Klock, Boerner, and Becker (1974) reported a case of accidental intranasal consumption of LSD, which resulted in plasma levels of 1000-7000 μg per 100 ml blood plasma. Subjects experienced comatose states, hyperthermia, vomiting, light gastric bleeding, and respiratory problems but left the hospital without residual effects (Klock et al., 1974). Passie et al. (2008) also reported no known teratogenic, mutagenic or carcinogenic effects after LSD use in humans and teratogenic effects in rodents only after extremely high dose of 500 μg/kg.

PK-PD relationship

Dolder et al. (2017) reported increased blood pressure (BP), heart rate (HR), and body temperature (BT) in humans administrated 100 or 200 μg LSD p.o., compared to placebo (Dolder et al., 2017). Moreover, Dolder et al. (2015) observed a linear relationship between the LSD concentration and its dynamic effects (BP, HR, BT). The EC50 mean value was 1.3 +/- 0.7 ng/ml after 200 μg of LSD (Dolder et al., 2015). Authors also noticed higher dynamic values later in time, compared to plasma concentration.

Neurophysiological actions

Early studies of neurophysiological changes induced by LSD were mostly conducted with electroencephalography (EEG) (Passie et al., 2008). Their conclusions were brief; they reported reductions in oscillatory power, increase in the frequency of alpha rhythms, and activation of medial temporal lobe regions (Carhart-Harris et al., 2016; Passie et al., 2008). Modern neuroimaging techniques allowed more deeper understanding of brain connectivity patterns (De Gregorio et al., 2018).

More recently, Carhart-Harris et al. (2016) conducted a study with multimodal neuroimaging. Twenty healthy participants were i.v. administrated 75 μg of LSD or 10 ml of placebo. They conducted an fMRI scan, followed by the magnetoencephalography (MEG) and arterial spin labeling (ASL) scan, and blood oxygen level-dependent (BOLD) measures. Findings of the study revealed that LSD increases visual cortex cerebral blood flow (CBF) and resting state functional connectivity (RSFC), and decreases alpha and delta power, default-mode network (DMN) integrity, and decreases RSFC between parahippocampal-retrosplenial cortex (PH-RSC) (Carhart-Harris et al., 2016). Those changes predicted the magnitude of visual hallucinations and also correlated with changes in consciousness. Moreover, the changes in consciousness correlated more positively with DMN disintegration than with visual system, revealing the mechanism by which LSD alters one’s consciousness (Carhart-Harris et al., 2016).

Interaction with receptors

LSD mostly interacts with serotonin (5-HT) receptors where it inhibits serotonergic cell firing but leaves postsynaptic receptor intact (Passie et al., 2008). It mostly binds to 5-HT1A and 5-HT2A receptors where it produces an effect in agonistic manner (De Gregorio et al., 2018). However, when bind to 5-HT1 receptor LSD produces an inhibitory effect, whereas bind to 5-HT2 the effect is stimulatory (Passie et al., 2008).

Considering psychotic-like properties of LSD, it is not surprising that it also produces an effect on dopaminergic system (De Gregorio et al., 2018). LSD interacts with D1 and D2 receptors especially in the ventral tegmental area (VTA) (De Gregorio et al., 2018; Passie et al., 2008). Interestingly, after administration LSD first activates 5-HT2A and later D2, suggesting an interaction between both systems (Passie et al., 2008).

Although LSD does not bind to glutamate receptors directly, it has become clear that they play an important part in the overall effect (De Gregorio et al., 2018; Moreno, Holloway, Albizu, Sealfon, & Gonzalez-Maeso, 2011). Moreno et al. (2011) conducted an experiment with LSD on metabotropic glutamate receptor 2 (mGluR2) knock out (KO) mice. They have discovered that LSD did not produce an effect in mGluR2-KO mice, suggesting the necessary involvement of mGluR2 in producing a hallucinogenic effect (Moreno et al., 2011).

According to the Australian Institute of Health and Welfare, in 2016 more than 3 million Australian’s used illicit drugs and the statistics are continuing to increase (“Illicit use of drugs Overview – Australian Institute of Health and Welfare”, 2019). The serious consequences of using drugs continues to rise as 1 in 10 people had been victimized due to drug related incidents. It further explained that this continued abuse of drugs was causing disabilities, disorders and in the worst cases, death.

Considering both the initial claim ‘consumed substances greatly impact the internal environment’ and gathered information, a broad research question was developed, ‘how does the consumption of drugs permanently effect the central nervous system?’. The way drugs affect the brain is through disrupting the natural system of neurotransmitters, some drugs even mimic the natural neurons, and this causes abnormal messages to be sent through the network. Additional research explained that there are three main type of drugs, depressants, stimulants and hallucinogens. Depressants cause a relaxing feeling by slowing down the messages sent to the brain, this also reduces your reaction response to situations. In contrast, stimulants speed up the connection between the brain and neurotransmitters, this can increase the heart rate, blood pressure, body temperature, agitation and cause sleep deprivation. Finally, hallucinogens affect emotional and physiological reactions, usually implementing feelings that vary between euphoria, panic and paranoia. With further research on neurological disorders related to drug use and specifically hallucinogens, a refined research question was achieved.

Moreover, one of the most common class of drugs associated with neural functional disorders is psychedelic drugs, specifically Lysergic Acid Diethylamide (LSD) (“How Drugs Affect the Brain and Central Nervous System”, 2019). In some cases, after consuming this drug symptoms of Hallucinogen Persisting Perception Disorder (HPPD) appeared, proving itself a sudden and long-term risk of using LSD.

From this detailed information, the following research question was developed: ‘Does the consumption of the psychedelic drug Lysergic Acid Diethylamide (LSD) have a connection to an increased probability of developing hallucinogen persisting perception disorder (HPPD)?’.

Background

LSD is a psychedelic drug that is categorized as a hallucinogen, this drug has a profound effect on the central nervous system, in particular, the brain. Due to similarities between LSD and natural neurotransmitters, this drug specifically affects the serotonergic system (Goodman, 2002). Serotonin is the neurotransmitter responsible for regulating moods, emotions, sleep patterns, memory and digestion (“How Drugs Affect the Brain and Central Nervous System”, 2019). As a result of the similarity shown above, this affects the brain by distorting the senses, irrationalizing emotions and corrupting one’s mentation. LSD was first established in 1938 by a man named Albert Hofmann, at first, he experimented on the drug with a thought that it could potentially provide therapeutic benefits due to its hallucinogenic qualities. However, Albert later discovered the harmful effects when he accidentally ingested the chemical himself (Martinotti et al., 2018). Developing symptoms such as hallucinations and drossiness. At that time HPPD wasn’t considered a disorder and therefore, couldn’t be diagnosed. This continued, and even now, is still easily misunderstood as HPPD can manifest in various ways and cause multiple conditions.

In the following years, this disorienting drug is still in affect. During a 2016 survey conducted by the National Drug Strategy Household, it was discovered that 9.4% of Australians from the age of 14 had experimented with hallucinogens (NSW, 2017). One of the continuing effects discussed about digesting hallucinogens was a potential disorder development, HPPD. This disorder is the recurrence of visual disturbances for inconsistence amounts of time (Halpern, Lerner, & Passie, 2016). It is categorized in two groups, HPPD Type 1 and Type 2. Both varieties cause similar symptoms, however, the difference between each is the amount of time the symptoms last. HPPD Type 1 is a short-term side effect, whereas HPPD Type 2 is long-lasting. Specifically, this disorder induces halos around objects, seeing geometric patterns, size confusion, flashes of color and feelings of uneasiness. These symptoms cause and intensify hallucinations, paranoia and insomnia (Halpern, Lerner, & Passie, 2016). This information suggested that LSD can also cause the increased development of disorders such as HPPD. This disorder can also remain dormant until it is triggered by substances such as alcohol (Halpern, Lerner, & Passie, 2016).

Evidence

The British Association for Psychopharmacology reported a 33-year-old woman who had developed symptoms of HPPD after using LSD at the age of 18. With a thorough investigation, it was confirmed that LSD is the main causative agent relating to HPPD symptoms. Also verifying LSD’s contribution to the symptom’s further development (Hermle, Simon, Ruchsow & Geppert, 2012).

Cases reporting HPPD symptom’s lasting for a large period of time are becoming more frequent. A study published by the British Journal of Medical Practitioners explain about a man who experienced varying symptoms of HPPD for more than 20 years, as a result of consuming LSD in much earlier years. He reported that these symptoms were affecting his daily life dramatically, such as having an inability to cross the road, reading difficulties, and struggling to determine what was the difference between reality and fantasy. These long-lasting symptoms were described as “it was like drinking alcohol, waking up drunk and being drunk from that point on”. Amongst the symptoms, he also experienced anxiety, depression and lack of coping skills. This report concluded that HPPD is certainly associated with LSD consumption and symptoms of this disorder can have a long-lasting effect on the user (“No | British Journal of Medical Practitioners’, 2015).

Evaluation

There are issues associated with the evidence presented as there are limited sources that have reported on LSD induced HPPD. This is because previously, HPPD disorder has been misunderstood as it comes in many forms, anxiety, depression and therefore, is identified as a rare disorder. Consequently, this provides a limited range of sources and data to potentially study. Therefore, limiting the reliability of this investigation.

The National Survey reporting on the consumption of LSD are not conducted every year because of financial issues and the need for attention elsewhere. This means the survey conducted in 2016 isn’t as current as needed to collect sufficient and reliable data.

The data that’s refers to HPPD Type 2 only consists of male subjects, this limits reliability of the data as it doesn’t provide enough variety to support the claim of the experiment conducted.

Despite LSD being the main drug contributing towards HPPD symptoms developing, there are other substances such as cannabis and alcohol examined. This creates a possibility that other substances are contributing towards the finale diagnosis of the subjects experimented and therefore, decreases the reliability of the data.

Conclusion

In conclusion, the evidence supports the claim, “Does the consumption of the psychedelic drug Lysergic Acid Diethylamide (LSD) have a connection to an increased probability of developing hallucinogen persisting perception disorder (HPPD)?”. During the research process, it was discovered that HPPD can develop very suddenly, due to multiple triggers, after previous intake of LSD and can last for decades. Another significant discovery was that LSD is usually the main drug involved in HPPD development but isn’t the only source. To fully understand the impact of LSD on the development of HPPD, further research is required. This includes various credible sources that provide detailed reports and if possible, survey’s that are more recent.

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