Part 4 PowerPoints Fall 2024 PDF

Question: If LSD is “non- toxic”, why not take some LSD to expand your mind? Are there any risks we should be thinking about at this point? 1 Question: LSD “microdosing” (taking ~20% of the ED50 dose, often for several days in a row) has …emerged as Silicon Valley's favorit...

Question: If LSD is “non- toxic”, why not take some LSD to expand your mind? Are there any risks we should be thinking about at this point? 1 Question: LSD “microdosing” (taking ~20% of the ED50 dose, often for several days in a row) has …emerged as Silicon Valley's favorite illegal drug habit, with engineers, programmers, writers, and artists sharing their stories of microdosing. Many people say the practice improves their concentration or creativity; others, like writer Ayelet Waldman, claim it can treat symptoms of mental illnesses like depression and anxiety. How would you design a study 2  Pharmacodynamics o 5-HT2A receptors Tolerance and dependence 1 Flashbacks? Hallucinogen Persisting Perception Disorder (HPPD) 4 Case study 1. Yes, flashbacks totally exist. I was finally laying down at night and right as I shut my eyes; I saw myself in the bathroom mirror reflection but like in the shape of Slenderman which was mega creepy but it was like three second thing and then that was it. 2. I’d say yes, there’s times I’m walking and all of a sudden everything has tracers, or patterns. And the tracers I get from waving my hands back and forth have never actually gone away. 3. Personally, I think that when you trip, your brain is putting together all these patterns that are in your face. Once you sober up, you’ll know where to look for these patterns, and you might 5 notice them in places you would normally Question: How would you design a study to examine the frequency, severity, and prevalence of LSD flashbacks? What are some reasons why scientifically valid studies of psychedelic drug flashbacks are extremely difficult to do? (#1) 6 N, N - Dimethyltryptamin e (DMT) 3 Case study When I finally puked on the fourth night, I felt an odd sense of pride. I think: Just aim for the bucket and keep your ass above your head like the shaman told you. I try to wipe my face but can’t grab the tissue paper because it melts every time I reach for it. I finish vomiting and start crying and laughing and smiling all at once. Something has been lifted in this “purge,” something dark and deep I was carrying around for years. Relief washes over me, and I slowly make my way back to my mattress on the floor. For four consecutive nights, a group of 78 of us 8 Ayahuasca: DMT + harmine 9 Question: What are some risks and benefits of travel to the Amazon to use ayahuasca as prepared by a local shaman? (#2) 10  5-HT2A receptor actions and psychedelic effects 1 Question: It is sometimes claimed that the near- death experience results from the actions of endogenous DMT. What are some reasons it is difficult, if not impossible, to test this hypothesis? 12 Psilocybin and psilocin Psilocin Psychedelic mushrooms 1 o Sources and history of use Safety record 14 15 Questions: What are some reasons why psilocybin ranks so low on this scale, and specifically much lower than LSD? 16 Psychedelics and the mystical experience 17 Case study 18 Question: Of the two accounts of spiritual experiences described above, one occurred in response to a drug, and without occurred spontaneously. Can you guess which is which? 19  The Mystical Experience (summary) o Mystical: Internal and external unity; sacred; reveals fundamentals truths o Positive experience o Transcends time and space o Indescribable 20 21 Question: Entheogens are drugs that generate a nonordinary state of consciousness for religious or spiritual purposes. Mescaline, psilocybin, and DMT are used by various indigenous peoples for entheogenic purposes in religious and spiritual rituals. 1.Why are set and setting important for these experiences? 2.What are some ways that 22 An overview of the “psychedelic experience” 23 Question: Which aspects of the psychedelic experience were experienced by Albert Hofmann on the first day he ingested 250μg of LSD? Question: What might be some reasons why Dr. Hofmann did not have a mystical experience during that first intentional use of LSD? 24 Question: How might a psychedelic (e.g.,psilocybin)- induced mystical experience be able to reduce anxiety or depression? 25 Question: What are some pros and cons of allowing use of psychedelic drugs in palliative care of persons with end-of-life despair and demoralization, with debilitating PTSD, with treatment-resistant depression, and with drug use disorders? (#3) 26 Question: Read the following summary, and explain why such a study requires careful screening and supervision of patients, along with management of drug, set, and setting. Cancer patients often develop chronic, clinically significant symptoms of depression and anxiety. The effects of psilocybin were studied in 51 cancer patients with life-threatening diagnoses and symptoms of depression and/or anxiety. High-dose psilocybin produced large decreases in clinician- and self-rated measures of depressed mood and anxiety, along with increases in quality of life, life meaning, and optimism, and decreases in death anxiety. At 6-month follow-up, these changes were sustained, with about 80% of participants continuing to show clinically significant decreases in depressed mood and anxiety. Participants attributed improvements in attitudes about life/self,27 Psychedelics as therapy for depression, anxiety, and drug addiction 28 Case study At the start of his psilocybin session, Victor reported seeing “geometric patterns,” with his eyes closed. He was then led on a journey by a felt presence, what he described as a “spirit guide.” He witnessed his own conception, birth, and death, and described a vision in which he watched his family at his own funeral while feeling a “tremendously painful” helplessness. Victor noted that his session was dominated by emotional experiences and that, “whenever the affect would become overwhelming… the spirit guide would blast me out of that experience into a new setting.” Victor then said, “I didn’t have a body… I was just like this soul, this entity,” and spoke of himself shopping for a new body. The only body he could pick was his own, what he later described as a representation of the resolution of his issues with his body and illness. “I saw everything that has happened to my body, all the food I have eaten, the drugs I have taken, the alcohol [I have drunk], the people I have had sex with, the chemo, the exercise, everything that has ever happened to my body. I took it in at once,29 Question: This psilocybin “session” took place as part of a clinical trial of psilocybin as a treatment for death anxiety and depression stemming from a cancer diagnosis. Which aspects of this experience would qualify as mystical? Question: Do you think psilocybin would have the same effects on his death anxiety had 30 Question: Psychedelic drugs are currently listed on Schedule 1 (high risk of addiction; no medical use). Do you think this should be changed? Why or why not? Do you think these drugs could be supplied by a 30-day prescription? Why or why not? What safety measures do you think would be appropriate for the medical use of these drugs? 31 Mechanism of action of psychedelic-induced mystical experience Question: We discussed earlier that the default mode network (DMN) is activated during self- referential mental activity: internally directed cognition: rumination, autobiographical memory recall, and self-related judgments. How might DMN activity be altered in persons 32  LSD, psilocybin, and global brain connectivity 33 34 35 1. While LSD and psilocybin are both in clinical trials for treatment of several conditions, psilocybin is often preferred because it is a. less likely to cause addiction b. synthesized in the laboratory and not found in nature c. a partial, not a full 5-HT2A agonist d. less potent e. a 5-HT2A and 5-HT2B agonist 36 2. N,N dimethyltryptamine (DMT) is a. a 5-HT2A agonist b. used, along with mescaline, in rituals of the Native American Church c. the mediator of the near-death experience d. addictive, especially when combined with harmine in Ayahuasca e. fatal in overdose 37  Homewor k Award Winner receives the coveted syringe pen: The Nov 5 winner ALEX HUELSMAN is Legalized Psilocybin Use? 39 Question: Please vote “yes” or “no” on this Oregon ballot initiative from November 2020 and explain the reasons for your answer. Our Class: 40 Phencyclidine and ketamine : hallucinogenic anesthetics 6 Case studies 1. A 41-year-old male with a history of PCP use was brought to the hospital after being found nude and unconscious outside for an unknown period. At presentation he was awake but mute, not following commands nor tracking with his eyes. He was intermittently agitated. 2. “Richard” murdered his girlfriend while under the influence of PCP. Richard maintained no memory of the murder and further, no conscious motivation to commit such a heinous act. 3. A 37-year-old man was admitted to the hospital emergency unit ~2 h after PCP ingestion. The patient had high blood pressure and a rapid heart rate, displayed prominent signs of psychosis, and altered neurological status, as well as increased muscle tone with spastic leg postures. In addition, the patient gave no response to commands and only incomprehensible shouting. His level of consciousness was fluctuating, although he registered a verbal response to painful stimulus. Over the course of 3 h, the patient became fully alert, began cooperating completely, and his heart rate and blood pressure normalized. The patient reported complete amnesia for the duration of the episode. 42 Question: List some of the effects of PCP seen in the stories above. Question: What might be some factors that explain the wide variety of effects of this drug? Question: What clues to you see that this drug was originally developed as a general anesthetic? 43 Question: The only psychedelic drugs used compulsively by experimental animals are PCP and its close relative, ketamine. What does this tell us about the mechanism of action of these drugs? 44 Question: Why do you suppose the following is true? Overall use of PCP by high-school seniors has decreased since 1979, when 7% of seniors used PCP. In 2014, 0.8% of high-school seniors used PCP at least once during the year before the study. PCP has retained the lowest lifetime prevalence and highest non- 45  Ketamine o History and medical uses o Receptor actions and psychological effects 3 Question: How would you distinguish between an individual with schizophrenia and an individual currently intoxicated with a large dose of PCP or ketamine? 47 Question: Long-term recreational use of ketamine is linked to the development of ulcerative cystitis, a severe form of inflammation of the bladder. What might be some reasons for this? Question: Studies of people who abuse ketamine recreationally find that they have cognitive and memory impairment. What are some possible reasons for this—and what else besides ketamine use might 48 Dextromethorphan (DXM) 49 Question: Dextromethorphan was patented in 1950 and has largely replaced codeine- based cough suppressants. Should DXM be regulated or restricted? List some pros and cons to changing its current status 50 alvia divinorum 1  Salvinorin A: a selective κ-opioid agonist 52  Some representative Salvia experiences: There was a broad swath of space surrounding me, encompassing my chair, the desk, the floor, the computer on the other side of the wall behind me, of which I literally felt to be a part of. As in, my "body" included these things. It sounds interesting, which I guess it was, but it ultimately wasn't fun whatsoever. My friends told me it was "like a legal weed". So I went into the experience expecting to get an effect comparable to that of marijuana. As soon as I took a hit from the bong, which was quite substantial, I could immediately tell it was nothing like cannabis. I remember initially having a feeling of "sharpness" in my limbs and throughout my body. I felt as though if I touched myself, I would somehow cut or scrape myself. The sensation was very odd. Question: What do these stories suggest might be some of the normal functions of 53 the brain’s κ-opioid receptor system? Stimulants: Amphetamines, cocaine, caffeine, etc. Question: What are some of the effects and side-effects shared by all drugs classified as CNS stimulants (“psychostimulants”)? (#3) 54 Methylenedioxy- methamphetamine (MDMA) 1 Case study It was Halloween and I was going to the parade with my then-girlfriend. She was really against drugs, so I didn’t tell her I’d done a pill [of MDMA]. I was dressed in this ridiculous cow outfit, with these hideous rubber udders. When the pill kicked in, I felt utterly incredible. I remember how clean the air tasted and how beautiful everyone looked. We ended up at a club and I remember turning to [my girlfriend] and saying, “I’m a cow on ecstasy.” It felt as if I were imparting some great cosmic secret. She laughed and we kissed. It felt like kissing for the56 Question: What drug effects described above fit with MDMA being classified as a stimulant? Question: Based on this story, do you think MDMA has addictive potential? Question: MDMA has been described as an “empathogen”— that is, a drug that evokes a feeling of empathy toward others. What evidence do you see for this in the 57 story? What therapeutic uses might  History of development of MDMA 58 Question: MDMA has a very high affinity for the serotonin transporter (SERT) and the transporter of serotonin into the synaptic vesicles (VMAT). Using the figure on the next slide, describe the synaptic action of MDMA, and explain why it is described as a “serotonin releaser”. 59 60 Question: Why might these synaptic actions cause “greater sociability, extraversion, heightened sense of closeness to other people, and greater tolerance of their views and feelings”? Question: What aspect of the synaptic mechanism of MDMA 61 MDMA neurotoxicity? Question: What are some limitations to studies of MDMA neurotoxicity in rats and mice? Question: Why is it difficult to establish whether or not human use of MDMA indeed causes serotonin neurotoxicity? Question: Compare and contrast MDMA with an SSRI like fluoxetine 62 MDMA purity 63 Case study Data collected by volunteers for the nonprofit organization DanceSafe, who tested samples of pills or powder at gatherings throughout the United States between July 2010 and July 2015. The testers would scrape a small amount of a pill or use part of the inside of a capsule. The first thing the volunteers found was that MDMA was present in only 60 percent of the 529 ostensible Molly samples collected. The others 64 Question: What are some pros and cons of providing free services that test the purity of drugs at events like raves? Question: What other ingredients might be expected to be adulterants of pills sold as “Molly” or “Ecstasy” at raves? Which of65 Question: In May 2021, a randomized, placebo-controlled double-blind study found that in 90 persons with treatment- resistant PTSD, adding MDMA to psychotherapy doubled the effectiveness of that therapy. What is the rationale for MDMA’s use as a component of treatment in this context? 66 Question: Why are the effects of MDMA reduced if a person is taking an SSRI? 67 Amphetamines Some phenylethylamines 68 History of Amphetamines 1887 Amphetamine is first synthesized 1919 Methamphetamine, more potent and easier to make, is synthesized 1930’s Amphetamines first marketed as an over-the-counter inhaler for nasal congestion 1 Question: Use the figure below to describe the actions of amphetamine and methamphetamine at the synapse, and compare this action with that of MDMA: 70 Question: Why are amphetamines effective decongestants? Question: Oxymetazoline (Afrin®) is stimulant currently available over the counter to treat nasal congestion. Ideally, what property of a stimulant does it have—and what does it 71  1937 Amphetamine is first available in tablet form for treatment of narcolepsy and ADHD Question: Narcolepsy is a genetic disorder involving sudden onset daytime sleep episodes that occur without warning. Why are amphetamines used to treat it? 72 WW II Amphetamine and methamphetamine are widely distributed to soldiers to keep them fighting Case study In sharp contrast to drugs such as heroin or alcohol, methamphetamines were not about escapist pleasure. Rather, they were taken for hyper-alertness and vigilance. Aryans, who were the embodiment of human perfection in Nazi ideology, could now even aspire to be superhuman—and such superhumans could be turned into supersoldiers. “We don’t need weak people,” Hitler declared, “we want only the 73 Question: What are some reasons why amphetamines improve the performance of soldiers? Are there any side effects that might harm that performance? 74  1930’s Amphetamin es used to treat depression Question: What depression symptoms are helped by amphetamines ? 1  Appetite and weight control Question: Amphetamines – and stimulants more generally – cause weight loss via both “central” (in the brain) and “peripheral” (outside the brain) actions. What might be some of 76 Methamphetamine 77 Case studies 1. “A few puffs gave me the energy to clean the apartment, do Cameren’s [her baby’s] laundry, run some errands, and still be wide awake whenever she cried. I was very careful, though, never to smoke around Cameren. I’d wait until Derek got home, and the two of us would put our baby down securely in her crib, turn on an air purifier to keep smoke away from her, and go downstairs to light up. I somehow managed to convince myself that by doing it this way, I could take care of my habit — and my baby.” 2. I took about 2-3 hits and, Oh my lord, the feeling is f****ng great. I feel like doing things, talking to everyone, saying ‘hi’ to everyone in my contacts (luckily I didn’t). They said do you have anything to do? I suddenly remembered I had a f****ng proposal that I have been delaying for a while. I then went to open my laptop and started doing it. Oh lord, the words and phrases just came out from my mind like a piece of cake and by the time I was so into that, I realized that the work is done. I was like “Wow, it this f****ng real?” The 2-months-work was done 78 in 79 80 81 Question: What are some of the acute effects of methamphetamine that you see in these stories? Question: What withdrawal effects would be expected from this or other stimulants? 82 Question: Based on these stories, what would be your estimate of the half- life of methamphetamine? 83  Methamphetamine can be ingested, smoked, or injected intravenously: o “Crystal meth” or “Ice” and “smoking” methamphetamine 84  Pseudoephedrine used as the basis for home manufacture of methamphetamine 85 o Industrial-scale production by Mexican drug cartels 86  Methamphetamine transportation routes 87 Question: Based on the previous three figures, compare and contrast production, distribution, and sales differences between methamphetamine provided by Mexican cartels and methamphetamine produced from pseudoephedrine by “mom- and-pop” operations, and use these to explain why the cartels have come to dominate the American market. 88  The drug cartel business model Manufacturing cost, per kg, in a Mexican “superlab”: $300 Street price, same kg, in Juarez $3,500 Street price, same kg, in Albuquerque $7,200 Street price, same kg, in New England $20,000 89 Methamphetami ne: Chronic effects 90 Case studies 1. “Smoked again, need more than usual now, and literally did nothing useful. My body is now in pain, lost a lot of weight, getting insomnia, and my emotions are f****ng unstable when sober. Sometimes feel just fine, sometimes feels like s*** that I need meth to feel good. Spend like half of my scholarship on meth.” 2. “Meth has given me the best feeling I have ever had in my life. That huge confidence, alertness, socializing, etc. It’s hard to say goodbye when I’m thinking that I’m not gonna feel these feelings again but at the same time it given me the loss of weight, sunken face, unstable emotions, loss of my girlfriend, insomnia and many more. It got me thinking, is it really worth it?” 3. “In the end, what lead me to quit was a moment of clarity. When I took a look at my situation. I used to be a straight A’s kid, with a future. Now I was a high school dropout, working at a dead- end job where I never spoke to anyone, and at that moment I was sitting in a trailer with five other filthy guys. One was a gay man who had his relationship destroyed by meth, and he was busy picking at a sore on his forehead that had grown to the size of a half dollar. No one had bathed in days. Everyone had been up for 91 days on end. There was a bunny that someone had caught Question: What are some chronic effects of methamphetamine that you see in these stories? Can you explain why this stimulant causes some of these effects? Question: During a meth “binge”, the user will take more methamphetamine soon after the initial rush has passed. Why does binging lead to “crashing”, such that addicts are often are in a “binge/crash” cycle of use? Question: Although the half-life of methamphetamine is 11 hours, the “rush” of intravenous or smoked drug is only 15 92 –  YUCK WARNIN G 93 “Meth Mouth” 94 Case report A 40-year-old man presented to our hospital with a chief complaint of badly decayed teeth and poor aesthetics. Intra- oral examination revealed 24 residual roots, four residual crowns, and only one pulp cavity was not exposed. The erosive carious lesions extending to the gums were leathery and brown. The patient reported no pain on cold testing and percussion, but pain when probed into the pulp cavity. Periodontal examination revealed supragingival dental plaque and calculus deposits with bleeding on probing, but no bone loss was found, 95 96 97 Question: What are some reasons why methamphetamine use can cause such severe dental problems? 98 Question: Methamphetamine can cause persons to develop paranoia, or experience hallucinations that bugs are crawling under skin. Why does the mechanism of action of these drugs make these effects predictable? What are some social and health risks associated with these two drug effects (see figure below)? 99 Question: Use the figure below to describe some of the mechanisms involved in the neurotoxicity (damage or death of dopamine neurons) seen with chronic use of methamphetamine. Specifically, explain what is happening at steps 1, 2, 3, and 9. 100 101 Methamphetamine addiction treatment 102 Case study According to meth users, the crash down from meth, much worse than a hangover from alcohol, is at its most unbearable in the first couple of days, or until sleep takes over. Users are unanimous about this: nothing, they say, is tougher than coming down from a binge on meth. The addict feels flat, drained from all energy, with no will to do anything, and experiencing the worst kind of depression. The craving for meth drives them crazy, with a majority of users succumbing to it and going back for more meth. 103 Question: What are some factors that account for the severity of this acute state of withdrawal? Question: Binge drinking is associated with methamphetamine use. What is a possible cause-effect relationships that may link the use of these two drugs? 104 Question: In Contingency Management interventions, patients receive a voucher or another prize for a negative urine toxicology screen. Prizes increase over time with repeated clean drug tests; a failed drug test resets the prizes to the starting level. What are some strengths and weaknesses of treating methamphetamine addiction 105  General physical health: 5 years of methamphetamine addiction 106 107 108 YUCK WARNING 109 The Faces of Meth 110 Question: What are some reasons why chronic, heavy methamphetamine use leads to declines in physical health, specifically in terms of the cardiovascular system, skin, and 111 Question: About 12,000 Americans die from a methamphetamine overdose each year. What would be some possible lethal effects of an overdose with this drug? 112 Methamphetamine and criminal behavior Question: Persons with methamphetamine use disorder tend to exhibit psychopathic personality traits (e.g., Machiavellian egocentricity, rebellious nonconformity, blame externalization, carefree nonplanfulness, fearlessness, and stress immunity). What are some factors that may account for this, 113 Catha edulis, cathinone, and “Bath salts” (synthetic cathinones) 114  Cathinone is a stimulant that is found in the leaves of the Catha edulis shrub native to the horn of Africa (below): 115 116 Question: Why do so few problems arise from the practice of Catha edulis leaf chewing, which is popular across these regions in Africa? 117  Synthetic cathinones (sometimes called “bath salts” 118 Case study A 30-year-old man with no history of mental disorder was brought to the hospital in a state of paranoia, agitation, violent behavior, and an abrupt change in mental status. He had been restrained by police because of combative behavior during transport to the hospital. His heart rate was 150 bpm, and his creatine phosphokinase (CPK) was 32,899 U/L (normal