emilyrk39

Emily Krantz Chem 367


 * LSD. What happens when it enters the body? What in it’s structural formula makes it hallucinogenic? And some controversial case studies included.**

Abstract
The structure, metabolism, reception, structural affinity to receptors, flashbacks, bad trips, and a couple case studies are indicated in this review of the potent paper. Exactly what in the chemical structure of LSD attracts it to the receptors that provide the drug with its hallucinogenic properties is described in this paper. Also, throughout the 1950's and 1960's the drug was used, in what many describe as an ethically questionably environment, both clinically and medically as an experiment to test on human subjects. The results of two case studies one for treatment in alcoholics and another to treat schizophrenic children are reported in this paper.

Introduction
The origins of tripping dates back to Ancient Greece where for 2000 years the Greek community participated in an annual ritual where everyone would consume a drink called kykeon which induced a state of imperceptible visions (Webster). In 1938, Albert Hoffman accidently invented and introduced the world to a new drug called LSD that induces a state of tripping. He described the first trip on acid by stating, ‘as I lay in a dazed condition with eyes closed there surged up from me a succession of fantastic rapidly changing imagery of a striking reality and depth, alternating with a vivid kaleidoscopic display of colors.’(Whalen, 1998)

Lyseric acid diethlamide-25 induces a state deemed ‘tripping’ in its takers, which includes hallucinations and an altered state of perception. The drug is normally taken orally and the effects kick in about an hour after being taken and last generally 8-12 hours. Robert Kennedy, a United States Senator promoted LSD use stating ‘it can be very helpful in our society if used correctly’.(Pangburn, 2012)

In addition to contributing to the 1960’s peace era and references in media outlets such as Alice in Wonderland and Lucy in the sky with diamonds, LSD was used clinically and legally in the medical field. Experiments in psychoanalysis were conducted on patients with alcoholism, pain, headaches, and anxiety. The structure, metabolism, reception, structural affinity to receptors, flashbacks, bad trips, and a couple case studies are indicated in this review of the potent paper.

Despite approval from the authority of a senator after LSD entered the underground drug scene, it ws made illegal in 1968. In comparison to the 2 millennia span of the Greek’s annual spiritual days, America’s trip was short lived.

Molecular Structure of LSD


=Figure 1: Structural Forumula of d-LSD (Baker, 1972)=

Single crystal analysis of LSD reveals that LSD is a monoclinic crystal. The hydrogen atoms were located by difference syntheses using isotropic thermal parameters. While the non-hydrogen atoms were located using anisotropic thermal parameters. A water molecule is present in crystallization which forms hydrogen bonds to oxygen atoms of the benzoate molecules. (Baker, 1972)

The C5 and C8 atoms are asymmetric which allows for four isometries which are d and l-LSD and d and l-isolysergic acid dietylamide. The d-LSD is primarily described in this paper due to the fact that this isomer is the only isomer with psychoactive properties. (Baker, 1972)

LSD’s hallucinogenic capabilities are suggested to be attributed to the structural conformation. Structural strain, due to stereo-chemical requirements for C4, is apparent in the molecule. This strain causes some bond angles and torsion angles to depart from the normal values. (Baker, 1972) More on the structural dependence on hallucinogenic properties are discussed in a further section of this paper.

Metabolism of Lysergic Acid Diethlyamide
The metabolism rate of LSD varies greatly among different species. In 1957, Alexrod conducted multiple experiments with LSD and animals to draw conclusions about what happens to the drug after it enters the body. For monkeys, the biological half-life of LSD was found to be about 100 minutes, while cats were 130 minutes and mice were only 7 minutes. The rates for the monkey and cats were measured after giving 3 moneys and 3 cats .2mg/kg intravenously and determining the half-life by plotting a plasma decay curve. For the mice, 10 were given 2mg/kg of LSD intraperitoneally and killed 20 minutes after administration. The half-life was determined by plotting the concentration of the compound at the initial time and after 20 minutes on a semi-log paper. (Axelrod, 1957)

In humans, a 1964 study was conducted by George K. Aghajanian to determine the persistence of LSD-25 in the human plasma. Plasma levels were measured in humans for an 8 hour period after 2mcg /kg of LSD was administered. The results showed that there was a steep decline then a leveling off of the plasma levels after 30 minutes, then a gradual decline until after 8 hours there was minimal amounts of LSD-25 present in the plasma. The half-life was calculated after plotting on a semi-log plot and was discovered to be 175 minutes. (Aghajanian, 1964) However, more recently a study was conducted utilizing gas chromatography-negative ion chemical ionization mass spectrometry to measure the LSD in human plasma. The results of this study, conducted in 1990 on one male where blood was collected 10,30,60 minutes, and 2,3,4,6,8.12 and 24 hours after consumption, indicated a longer half-life than the previous study of 5.1 hours. The peak plasma concentration of 1.9ng/mL was discovered to be 3 hours after the initial ingestion. (Papac, 1990)

Alexrod was one of the first to publish the possible metabolic pathways for LSD transformation using rats. It was proposed that it could potentially involve N-demethylation which results in norLSD and formaldehyde. An indole ring was suggested to form from oxidation and lysergic acid was proposed to form from hydrolysis.(Axelrod, 1957) Although, in 1958 a couple more conclusions were drawn on the metabolites when at least four radioactive compounds were found in the bile of rats exposed to LSD. [Boyd]

In 2001, Canezin determined the metabolites of LSD in human fluids by utilizing liquid chromatography with electrospray tandem mass spectrometry. In this test, 1 ml of either blood or urine was used and the metabolism was examined using MS-MS neutral loss monitoring and 6 metabolites were found: lysergic acid ethlamide, 2-oxo-LSD, 2-oxo-3-hydroxy-LSD, lysergiv acid ethyl-2-hydroxyethylamide, 14-hydroxy-LSD glucuronide, and nor-LSD. The structural formula for the LSD metabolites discovered in Canezin’s experimental analysis are displayed in figure 2. (Canezin, 2001)

=Figure 2: LSD Metabolites as Proposed by Canezin (Canezin, 2001)=

In a recent study conducted in Switzerland the metabolism of LSD to 2-oxo-4-hydroxy LSD in human liver microsomes and cryopreserved human hepatocytes was observed. Although the intention of the report was to examine O-H-LSD metabolite, a more interesting conclusion of the study was the discovery of a new metabolite di-hydroxy-LSD in the human liver chromosomes. It was proposed that LSD oxidized to form 2-oxo-LSD which then turns into O-H-LSD. But the new metabolite found in Phase I metabolism suggests an alternate production pathway of O-H-LSD. The proposed pathways are shown structurally in figure 3. (Klette, 2000)

=Figure 3: LSD Breakdown Into Metabolites. A represents the new metabolic breakdown including 2-oxo-LSD (Klette, 2000)=

Alexrod studied the distribution of LSD in cats whom received 1mg/kg of the drug intravenously, were killed and analysis was conducted on the sacrificed tissue. LSD was found in increasing orders of magnitude in the fat, muscle, fluid, cerebrospinal fluid, spleen, intestines, brain, liver and lung. The notable concentrations in the brain are indicative of LSD being a substance that can pass the blood-brain barrier. A guinea pigs liver, brain, kidney, spleen and muscle were incubated with LSD and put in a Krebs-Ringer bicarbonate buffer in an oxygen and carbon dioxide rich atmosphere. It was discovered that the liver tissue is where the metabolic change occurs because ti was the only tissue that metabolized the drug. (Axelrod, 1957)

As mentioned previously, radioactive metabolites are a result of LSD consumption; Boyd experimented with rats and LSD to draw conclusions of the levels of radioactivity in various tissues at intervals starting at 5 minutes to 12 hours. The half-life of radioactivity in the blood was found to be 20 minutes. The radioactive material was most abundant in the G.I. track, of which 60%-80% was found in the bile after 3 hrs. (Boyd, 1955) =Figure 4: Table Displaying the Results of Boyd's study Radioactive Metabolites Concentraction of LSD in the Carcass of Rats (Boyd, 1955)=

Studies were also conducted on the distribution of LSD into the reproductive system of rats with respect to the radioactive material found in Boyd’s study. Male rats were administered LSD killed and during the autopsy seminal vesicles, coagulating gland, prostate gland, epididymides, testes, and ductus deferentes were removed and the radioactive material content was determined using liquid scintillation spectrometry. Female pregnant rats were also administered LSD, after they were killed the uterine horns were removed, and the radioactive content was determined. Radioactive material, LSD and, all LSD metabolites were apparent in all male reproductive tissues. In late terms of pregnancy, LSD was apparent in the fetus after 5 minutes in concentrations of .5% which indicated placental transfer of the drug to the fetus. (Back, 1977)

Identification of the radioactive metabolites was later conducted in 1961 by Slaytor. By conducting tests on male and female albino rats dosed with LSD in levels of 45mg/kg and examining the bile using a paper chromatography method two radioactive metabolites were identified. The two metabolites are hydrolysized by a saccharic acid which supports a finding by Boyd that the LSD metabolites are glucuronides. (Slaytor, 1962)

Interactions with Receptors
Serotonin is a neurotransmitter that is biochemically derived from tryptophan. In 1988, Titeler used radioligand binding evidence to prove the 5-HT2 serotonin receptor as the site of action for LSD. The study revealed the 5HT2 receptor had 100 times higher attraction for the 5HT2 receptor than the 5HT1C. The affinity for 5HT2 was 2000 times greater than 5HT1B, and 5000 times greater than the 5HT1 receptors. (Titeler, 1988)

LSD was suggested to act as a dopamine agonist in a study conducted by Peter Kelly in 1975. Kelly tested control rats and rats subject to the in-vivo model. This model involves injecting 6-hydroxydopamine into rat nucleus accumbens septi there is a destruction of the mesolimbic dopamine innervation of the nucleus. When the rats are injected with dopamine there is a noticeable enhancement in locomotor activity. The study revealed that LSD significantly increased locomotor activity of the rats that underwent the in-vivo model but marginally increased the motor skills of the rats that were un-operated. The findings in this study are consistent with the hypothesized theory that LSD has the ability to act as an agonist at mesolimbic dopamine receptors. (Kelly, 1975)

Conditional Avoidance Response is when a rat is placed in a two compartment shuttle box. Each side of the box presents the rat with a neutral stimulus, a delay, and an aversive unconditioned stimulus. The animal is able to avoid the aversise response by running to the other compartment after the neutral stimulus. When rats were dosed with .32mg/kg doses of LSD It failed to block at least 20% of conditioned avoidance responding. (Martin, 1989)

Structural Conformation of LSD effect on 5HT Reception
It was proven that 5HT is the receptor for LSD, this binding is necessary for the chemical reactions to occur to induce a state of tripping. It is of interest to understand what exactly in the structural makeup of LSD leads to the high affinity to bind to that receptor.

McKenna studied the effects of n-alkylation, using 21 different tryptamine derivatives. The tryptamines with rings that were unsubstituted and N-cycloalkyl tryptamine had lower affinities to the 5HT receptor. A notable difference between N-metyl, N-isopropyltrptamine and benzofuran was that the indole had 13 times greater addinity to the 5HT2A and 67 times greater affinity to the 5HT1A than the benzofuran substituent. The nitrogen apparent in the indoles therefore plays an important part in the affinity to that receptor. (McKenna, 1990)

In 2004, Clare developed a series of quantum equations to prove that orientation of the pi orbital nodes is a major factor contributing to the hallucinogenic properties of tryptamines. The model was consistent for every tryptamine drug, but the model was unable to explain LSD’s hallucinogenic properties; when the structural parameters were put into the equation LSD was determined to be inactive. However, it was regarded that results for 9,10 di-hydro-LSD was consistent for tryptamines. The difference in 9,10 di-hydro-LSD and LSD-25 is the double bond length. This relationship is indicative that the double bond in LSD that doesn’t allow it to work in the mathematical models. (Clare, 2004)

A study was conducted to compare the effects of 2,3 Di-hydro-Lysergic Acid is LSD-25. The compound being compared has a reduced 2,3 bond of the indole nucleus. The slight change had a great effect on the potency of LSD in rabbits. The 2,3 Di-hydro-Lysergic Acid had 1/25th of the potency of LSD-25 and the onset of the effects were prolonged. (Gorodetzky, 1964)

The amide binding region was determined to be an important factor that determines the ability for LSD to have hallucinogenic properties. The isomers were tested on rats and displaced from the 5HT2 receptors. The R configuration had 4 times the potency of the S-amine.(Oberlender, 1992) Further studies in the amide binding showed that increasing the length of the alkyl substituent resulted in less LSD activity in mice.The (R)-petyllysergamide was roughly 20 times more effective than the (S) configuration. (Monte, 1995)

The Bad Trip
The second trip on acid by Albert Hoffman proved the shear inconsistency of the drug. By the second time of ingestion a ‘bad trip’ was acknowledged. Despite knowing the possible negative effects LSD production ensued.

In an online reminiscence report of an adverse acid trip an anonymous writer, who defined himself as NewRainbowChild, told of the time he ‘overdosed’ on acid and had a bad trip after taking 10 blots on his tongue. He locked himself in his room but the acid came on too strong and too hard, he had feelings of light headedness and stumbled his way to the bathroom. Despite the images, his mind was still in control he knew that LSD wouldn’t kill him; he just needed to get through the trip and not do anything to inflict pain on him. He described how he felt as, “I felt violently ill and my mind kept going back to how the current trip must compare to ergot poisoning.” He rode out the trip and afterward questioned why he couldn’t just focus his mind positively. The male ultimately described his trip ‘like a freight train that gathered and gathered speed until I did the only thing I could- became unconscious’. Despite his bad trip, he still advocated the use of psychedelics and decided he would continue his own use. (NewRainbowChild, 2010)

This 20 year old male's trip is just one recollection of a number of collections on bad trips available at this website. The bad trip is noted by unappreciated visuals, an overwhelming feeling, sickness, anxiety, and more.

In the United Kingdom in December 1968, the same year LSD became illegal in the United States, a survey was sent out to doctors who used LSD on human subjects. The data covered 4,300 patients and 49,000 LSD sessions and 170 experimental subjects who underwent 450 LSD sessions. (Malleson, 1971)

Of the health care providers, 5 ceased the use of LSD noting its dangers, 9 ceased the use of LSD noting its ineffectivity, and 11 providers ceased the use of LSD for miscellaneous reasons such as retirement. A good majority of the doctors concluded that the intensive treatments should not go unsupervised and the patients should be chosen carefully. (Malleson, 1971)

In the United Kingdom study mentioned above there were three LSD patients who committed suicide after medical treatment, a psychotic, an atypical maniac with a depressive illness, and neurotically depressed person with character disorder. In addition, there were 9 attempted suicides. (Malleson, 1971) Psychoses were noted in 37 cases of which 10 resulted in chronic psychoses. For some of those cases it was the doctor’s opinion that these patients would have succumb to psychosis despite the LSD use. (Malleson, 1971)

Flashbacks: Recurrent Intrusive Images After the Use of LSD
Flashbacks from LSD are the return of an image for extended periods of time well after the drug has worn off. People have recorded a random return of distortions in image perception. A patient described his distortion as ‘now I often see a bright shiny halo around people, especially at the dark edges- sometimes it’s rainbow colors- like during the trip’. People with repeated use reported that visual imagery occupies a greater proportion of their thinking and that reality seems more vibrant. The vibrant imagery has been noted to reduce over time and is a function of the dosage. (Horowitz, 1969)

A 16 year old male high school student reported that he had used LSD 10 times and smoked marijuana 100 times. Normally he’d experience ‘interesting, wild, intense and usually pleasant’ images. However, on his last trip he saw a human being pulled into the vortex of a whirpool. The image return three weeks after the initial drug taking and lasted for an additional 3 weeks. (Horowitz, 1969)

In a study conducted on 31 people, 22 had high LSD drug use, 3 had moderate LSD use and 6 had never used LSD. The study reported that of the people with high LSD use, tripping at least 15 times, 3 had perceptual distortion, 4 had heightened imagery formation and 1 have recurrent unbidden images. Of the people that tripped less than 6 times, 1 had heightened imagery formation and 1 had recurrent unbidden images. Seven of the 8 people who had flashbacks had massive drug intake, the other person had never used LSD. Two of the 8 people were diagnosed with ambulatory schizophreniform psuchosis, four had personality pattern or neurotic diagnoses and two didn’t have sufficient problems to create a diagnosis. (Horowitz, 1969)

Case Study: Psychedelic Therapy Utilizing LSD in Treatment of Alcoholic Patient
During the mid-1960s, in Spring Grove State Hospital experiments were conducted on 69 male alcoholic patients exploring the effects of LSD.

The heavy drinkers consisted of people who on average consumed 10 to 12 years of drinking were analyzed by doctors for a period of two weeks to get a deeper understanding of the individual and how they think. After the therapeutic relationship is developed he schedules the LSD session.

The psychotherapy goal is to use LSD to attack the idea of alienation and loneliness inherent in alcoholic patients in order for them to move forward with life. All of the patients were required to write a full report of the day they were administered LSD. A quarter of the patients did not have experiences that had the reduction in alienation effect while the 75% majority did.

One patient who described the day he used LSD as ‘the most satisfying and majestic day in his life’ reported that he had a hallucination where he described seeing what he defined as hell where a bottomless pit was being poured what seemed to be ‘all the whiskey in the world’. This hallucination caused the patient to cry and caused an onset feelings of deep guilt and remorse. He ‘realized the significance of this episode for my own experience with alcohol’. After that hallucination, he described his state of being: Sense of time was lost, music, pictures, and life were described as beautiful, he felt a sense of overwhelming ecstasy, his self-worth was discovered and all these realization led to deeper understanding and connection to society.

Despite these feelings, one month after his trip the patient was in an extreme state of anxiety and consumed multiple alcoholic beverages which reactivated his addiction. He contacted the facility and wished to use another dose of LSD but was denied due to facility regulations. Only 23 of the 69 patients maintained abstinence up to the six month follow up. Regardless of the effectiveness to treat alcoholism Dr. John Buck described the benefits inherent in several of the patients as realizations which conventionally would take a year or longer to recognize that had the ability to return patients to the human race. (Malleson, 1971)

Case Study: Autistic Schizophrenic Children: An Experiment in the use of D-Lyseric Acid
A study was also conducted in 1962 on 12 austistics children who all attend a school for schizophrenic children. Of the children 10 were boys and 2 were girls, aged 5 years and 11 months to 11 years and 10 months, 7 were mute and 5 occasionally used words for no reason. The drug kicked in from 15 to 30 minutes varying among the students and lasted from 4 hours to a little over 5 hours. Three of the students suffered from cataonia which is a state of immbolity while one had ataxia which is a lack of voluntary coordination. All students noted a loss of appetite, one child attempted to eat but the amount he ate was negligible.

The study was done with the hopes that LSD would increase the social skills of the children with schizophrenia. Some of the students were noted to have an increase desire for physical contact, the kids wished to sit on their teachers laps. Two of the children tried to experiment with sounds, there was a note of increased vocalization and increased remoteness. Ultimately the effects were positive but LSD did not change the state of muteness for the children. (Freedman, 1962)

Conclusion
LSD is a drug that has the ability to change the perception of the people who ingest it. Due to the nature of the drug and the fact that it is clinically and medically illegal to use in the United States it is hard to obtain reliable current data on the drug. Studies conducted in other countries have been analyzed for that reason and studies from the past of the legal days of the drug were also utilized. The structural formula and how that formula exactly ensues a state of hallucination during metabolic breakdown is covered in this research. The idea of a bad trip, flashbacks, and case studies were also reported.

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[2] Whalen, John. "The Trip." //- Page 3//. N.p., 01 July 1998. Web. 13 Dec. 2013. .

[3] Pangburn, DJ. "When Bobby Kennedy Defended LSD." //Death and Taxes//. N.p., 11 July 2012. Web. 13 Oct. 2013. .