Hallucinogens - YT - Summer 2024 PDF

02/01/1446 Hallucinogens Dr. Yahia Tabaza...

02/01/1446 Hallucinogens Dr. Yahia Tabaza 1 Course Contents  Introduction: 2. LSD. 1. Hallucinogens. 3. Alice in Wonderland Syndrome. 2. Addiction. 4. Ecstacy (MDMA). 3. Dependence. 5. Magic Mushrooms (Psilocin and psilocybin). 4. Natural Products. 6. Fungal Intelligence. 5. Biosynthetic Pathways of Secondary Metabolism. 7. The Stoned Ape Hypothesis.  Dopamine enhancers: 8. Psychedelic Art. 1. Cocaine.  GABA enhancers: 2. Methamphetamine. 1. CNS depressants (Barbiturates, benzodiazepines, sleep medications). 3. Khat and synthetic cathinones. 2. Gabapentinoids. 4. Levodopa. 3. Alcohol. 5. Bromocriptine.  Opioid Receptors Agonists:  Norepinephrine enhancers: 1. Opium (Morphine and Heroin). 1. Amphetamine.  Cannabinoid Receptors Agonists: 2. Harmaline. 1. Cannabis (Weed, marijuana, hashish, banjo). 2  Serotonin enhancers: 2. Synthetic Cannabinoids (Joker). 1. DMT. 1 02/01/1446 Introduction Hallucinogens Addiction Dependence Natural Products Biosynthetic Pathways of Secondary Metabolism3 Hallucinogens 4 2 02/01/1446 Hallucinogens  What are hallucinogens? What do they cause? 5 Hallucinogens 6 3 02/01/1446 Hallucinogens 7 Hallucinogens 8 4 02/01/1446 Hallucinogens 9 Hallucinogens 10 5 02/01/1446 Hallucinogens 11 Hallucinogens  Hallucinogens are a diverse group of drugs that alter perception (awareness of surrounding objects and conditions), thoughts, and feelings.  They cause hallucinations, or sensations and images that seem real though they are not. 12 6 02/01/1446 Hallucinogens  From were are hallucinogens obtained?  Hallucinogens can be found in some plants and mushrooms (or their extracts) or can be human-made. 13 Hallucinogens 14 7 02/01/1446 Hallucinogens  When did people started using hallucinogens? Why?  People have used hallucinogens for centuries, mostly for religious rituals. 15 Hallucinogens  How do people use hallucinogens?  People use hallucinogens in a wide variety of ways, including smoking, snorting, IV injections and absorbing through the lining in the mouth. 16 8 02/01/1446 Hallucinogens  How do hallucinogens work? 17 Hallucinogens  Hallucinogens interfere with actions of brain chemicals (neurotransmitters) responsible for functions that include: 1. Mood. 2. Sensory perception. 3. Sleep. 4. Body temperature. 5. Muscle control. 6. Pain perception. 7. Memory and learning. 8. Emotion. 9. Response to environment. 18 9 02/01/1446 Hallucinogens  How long are their effects?  The effects of hallucinogens can begin within minutes and can last 19 as long as hours to days. Hallucinogens  Hallucinogen (psychedelic) users refer to the experiences brought on by these drugs as “trips”, calling the unpleasant experiences “bad trips”. 20 10 02/01/1446 Hallucinogens 21 Hallucinogens  Along with hallucination, short-term effects of some hallucinogens may include: 1. Increased heart rate, blood pressure, breathing rate or body temperature. 2. Nausea. 3. Intensified feelings and sensory experiences. 4. Changes in sense of time: for example, time passing by slowly. 5. Sleep problems. 6. Mixed senses: such as "seeing" sounds or "hearing" colors. 7. Uncoordinated movements. 8. Excessive sweating. 9. Paranoia: extreme and unreasonable distrust of others. 22 10. Psychosis: disordered thinking detached from reality. 11 02/01/1446 Hallucinogens  Some long term effects: 1. Depression and suicidal thoughts. 2. Persistent psychosis: a series of continuing mental problems. 3. Flashbacks: recurrences of certain drug experiences. 4. Speech problems. 5. Memory loss. 6. Weight loss. 7. Anxiety. 23 Hallucinogens  Are hallucinogens addictive?  Some are addictive, some are not.  Is that accurate? 24 12 02/01/1446 Hallucinogens  What is “hallucigenia”?  The tiny sea creature - Hallucigenia - lived 500 million years ago, but all fossils appeared to be without heads. 25  https://www.youtube.com/watch?v=9-Z9Ssgb0Kg Hallucinogens 26  Attack on Titan spoilers in the next 3 slides! 13 02/01/1446 Hallucinogens 27 Hallucinogens 28 14 02/01/1446 Hallucinogens 29 Hallucinogens 30 15 02/01/1446 Addiction 31 Addiction  Addictus: a Latin word:  As a noun: a debt slave; a person who has been bound as a slave to his creditor.  As a participle: assigned, dedicated, having been assigned / handed over, having been handed over. 32 16 02/01/1446 Addiction 33 Addiction  What is addiction?  Is it a disease?  What does it cause?  Addiction is a chronic disease characterised by drug seeking and use that is compulsive, or difficult to control, despite harmful consequences. 34 17 02/01/1446 Addiction  Some people may mistakenly think that those who use drugs lack moral principles or willpower and that they could stop their drug use simply by choosing to.  In reality, drug addiction is a complex disease, and quitting usually takes more than good intentions or a strong will. Why?  Drugs change the brain in ways that make quitting hard, even for those who want to.  The initial decision to take drugs is voluntary for most people, but repeated drug use can lead to brain changes that challenge an addicted person’s self-control and interfere with their ability to resist intense urges to take drugs. 35 Addiction Reward circuit: Part of the limbic system. 36 Control and regulate our ability to feel pleasure. 18 02/01/1446 Addiction 37 Addiction 38 19 02/01/1446 Addiction 39 Addiction 40 20 02/01/1446 Addiction 41 Addiction 42 21 02/01/1446 Addiction 43 Addiction  Most drugs affect the brain's reward circuit by flooding it with the chemical messenger dopamine causing euphoria.  Surges of dopamine in the reward circuit cause the reinforcement of pleasurable but unhealthy activities, leading people to repeat the behavior again and again.  Over time, the brain adjusts to the excess dopamine, which reduces the high that the person feels compared to the high they felt when first taking the drug (tolerance). They might take more of the drug, trying to achieve the same dopamine high. 44 22 02/01/1446 Addiction  Why do people addict to drugs? 1. To feel good: sensation seekers, or anyone wanting to experiment with feeling high or feeling different. 2. To feel better: self-medicators, or individuals who take drugs in an attempt to cope with difficult problems or situations, including stress, trauma, or to lessen anxiety, fears, depression or 45 hopelessness. Addiction  Drug addiction is treatable and can be successfully managed.  Drug addiction is preventable.  Teachers, parents, and health care providers have crucial roles in educating young people and preventing drug use and addiction. 46 23 02/01/1446 Addiction  These brain changes can be persistent, which is why drug addiction is considered a "relapsing" disease—people in recovery from drug use disorders are at increased risk for returning to drug use even after years of not taking the drug.  It's common for a person to relapse, but relapse doesn't mean that treatment doesn’t work. As with other chronic health conditions, treatment should be ongoing and should be adjusted based on how the patient responds. Treatment plans need to be reviewed often and modified to fit the patient’s changing needs. 47 Addiction 48 24 02/01/1446 Dependence 49 Dependence  The words dependence and addiction are often used interchangeably, but there are important differences between the two.  In medical terms, dependence specifically refers to a physical condition in which the body has adapted to the presence of a drug.  Remember: Addiction: a chronic disease characterised by drug seeking and use that is compulsive, or difficult to control, despite harmful consequences. 50 25 02/01/1446 Dependence  Physical dependence: if an individual with drug dependence stops taking that drug suddenly, that person will experience predictable and measurable symptoms, known as a withdrawal syndrome.  Individuals with a physical dependence will feel pain and sickness when not using the drug they are addicted to. 51 Dependence  Physical dependence can occur with drugs as harmless as caffeine to drugs as dangerous as cocaine.  Think of that caffeine headache you get when you don’t have your morning cup of coffee, that’s withdrawal from your caffeine addiction.  Unlike caffeine, however, many physical addictions occur with drugs that are much more serious and that have much more dangerous withdrawal symptoms. 52 26 02/01/1446 Dependence 53 Dependence  Psychological dependence: cravings for a drug, occurs when a person does not have a physical need for a drug but rather a mental desire for it, e.g. marijuana smokers (is this example accurate?).  Psychological addiction can occur with essentially any substance.  If you use a substance or engage in an activity that is very simulating to your brain’s pleasure center, you are more likely to repeat that behavior again in the future. 54 27 02/01/1446 Remember - Hallucinogens  Are hallucinogens addictive? 55 Dependence  Please watch the following video:  https://www.youtube.com/watch?v=HUngLgGRJpo 56 28 02/01/1446 Natural Products 57 Natural Products  What are natural products?  Natural products are chemical compounds produced by a living 58 organism. 29 02/01/1446 Natural Products  Why are natural products important? 59 Natural Products Natural Products Primary Secondary metabolites metabolites 60 30 02/01/1446 Natural Products starch cellulose 61 phospholipid Natural Products digoxin morphine aspirin penicillin 62 31 02/01/1446 Natural Products  Are all natural products natural? 63 Natural Products  Are all natural products natural? 64 32 02/01/1446 Natural Products 65 Biosynthetic Pathways of Secondary Metabolism 66 33 02/01/1446 67 Biosynthetic Pathways of Secondary Metabolism 1. The acetate pathway. 68 34 02/01/1446 Biosynthetic Pathways of Secondary Metabolism 2. The shikimate pathway. 69 Biosynthetic Pathways of Secondary Metabolism 3. The mevalonate pathway. 70 35 02/01/1446 Biosynthetic Pathways of Secondary Metabolism 4. The alkaloids. 71 72 36 02/01/1446 Biosynthetic Pathways of Secondary Metabolism  Ornithine? 73 Biosynthetic Pathways of Secondary Metabolism 5. The non-ribosomal peptides. 74 37 02/01/1446 Dopamine enhancers Cocaine Methamphetamine Khat Synthetic Cathinones Levodopa75 Bromocriptine Cocaine 76 38 02/01/1446 Cocaine - Introduction  Cocaine is a powerfully addictive stimulant drug made from the leaves of the coca (Erythroxylum coca) plant native to South America. 77 Cocaine - Introduction 78 39 02/01/1446 Cocaine - Introduction  Cocaine was used for thousands of years by indigenous people of South America. They chewed its leaves to achieve its effects. 79 Cocaine - Introduction  When Spanish arrived in South America they declared the practice of chewing cocaine as "the work of the devil".  However, after they discovered that they indigenous people's claims that the leaf gave them strength and energy were true, they legalised and taxed the leaf, taking 10% off the value of each crop. 80 40 02/01/1446 Cocaine - Introduction  The cocaine alkaloid was first isolated by the German chemist Friedrich Gaedcke in 1855. He named it "erythroxyline". 81 Cocaine - Introduction  In 1860, Albert Niemann described every step he took to isolate cocaine in his PhD dissertation and named the alkaloid "cocaine".  In 1898, Richard Willstätter elucidated the structure of cocaine.  As cocaine was used as a local anesthetic, the suffix "-caine" was used later to form names of synthetic local anesthetics. 82 41 02/01/1446 Cocaine - Introduction 83 Cocaine - Introduction 84 42 02/01/1446 Cocaine - Introduction John Pemberton Coca-Cola: coca (cocaine) + cola (caffeine). The use of coca was discontinued since 1906. 85 Cocaine - Introduction Angelo Mariani 86 43 02/01/1446 Cocaine - Introduction 87 Cocaine - Introduction :‫ أكثر دولة مدمنة كوكاكوال في العالم – المكسيك‬  Mexico’s deadly Coca-Cola:  https://youtu.be/i6MTIg15OpI 88 44 02/01/1446 Cocaine - Introduction 89 Cocaine - Introduction 90 45 02/01/1446 Cocaine - Introduction  Street names of cocaine: Candy, Snow, Crack, Blow, Bump, C, Charlie, Coke, Flake, Rock, Toot.  Common forms: White powder, whitish rock crystal. 91 Cocaine – How it is used?  1. Snorting:  When people snort the drug (intranasal use), they inhale cocaine 92 powder through the nostrils, where it is absorbed into the bloodstream through the nasal tissues. 46 02/01/1446 Cocaine - How it is used?  2. Orally:  Users also may rub the drug onto their gums (oral use). 93 Cocaine - How it is used?  3. IV injections:  Dissolving cocaine in water and injecting it (intravenous use) 94 releases the drug directly into the bloodstream and heightens the intensity of its effects. 47 02/01/1446 Cocaine - How it is used?  4. Inhalation:  When people smoke cocaine (inhalation), they inhale its vapor or smoke into the lungs, where absorption into the bloodstream is 95 almost as rapid as by injection. Cocaine - Effects  Cocaine's effects appear almost immediately and disappear within a few minutes to an hour.  How long the effects last and how intense they are depend on the method of use, injecting or smoking cocaine produces a quicker and stronger but shorter-lasting high than snorting.  The high from snorting cocaine may last 15 to 30 minutes.  The high from smoking may last 5 to 10 minutes. 96 48 02/01/1446 Cocaine – Mechanism of action Reward circuit 97 Cocaine - Mechanism of action 98 49 02/01/1446 Cocaine - Mechanism of action 99 Cocaine - Mechanism of action 100 50 02/01/1446 Cocaine - Mechanism of action 101 Cocaine - Mechanism of action 102 51 02/01/1446 Cocaine - Mechanism of action 103 Cocaine - Mechanism of action 104 52 02/01/1446 Cocaine - Mechanism of action 105 Cocaine - Mechanism of action 106 53 02/01/1446 Cocaine - Mechanism of action Post synaptic cell hyperactivated = euphoria 107 Cocaine - Mechanism of action 108 54 02/01/1446 Cocaine - Mechanism of action  The same mechanism works for the three neurotransmitters: dopamine, norepinephrine and serotonin, with different extents. 109 Monoamines vs Catecholamines 110 55 02/01/1446 Monoamines vs Catecholamines  Catechols, Catecholamines: dopamine, norepinephrine, epinephrine.  Monoamine neurotransmitters: contain one amino group connected to an aromatic ring by a two-carbon chain. Examples: dopamine, serotonin, norepinephrine and epinephrine. 111 Monoamines vs Catecholamines 112 56 02/01/1446 Cocaine - Mechanism of action Positive reinforcement, reward, euphoria, pleasure, drive, dependency. Dopamine Fight or flight: Increased HR, contraction of blood vessels, energy, alertness, concentration, attentiveness. Noradrenaline Emotions, sleep, dreaming, learning. Perception, mood, sleep, body temperature regulation, appetite, pain, memory, obsession. Serotonin 113 Cocaine - Mechanism of action 114 57 02/01/1446 Cocaine - Effects  What are the main effects of cocaine? 1. Extreme happiness (artificial euphoria, extreme pleasure). 2. Extreme energy. 3. Mental alertness. 4. Hypersensitivity to sight, sound, and touch. 5. Irritability.  Cocaine acts as a local 115 anesthetic. How? Cocaine - Effects 116 58 02/01/1446 Cocaine - Effects 117 Cocaine - Effects 118 59 02/01/1446 Cocaine - Effects  What are the long-term effects of cocaine? 1. Dysphoria. 2. Loosing touch with reality. 3. Increased light sensitivity. 4. Impaired movements. 5. Paranoia. 119 Cocaine - Effects 120 60 02/01/1446 Cocaine - Effects 121 Cocaine - Effects  Some long-term health effects of cocaine depend on the method of use and include the following:  Snorting:  Loss of smell, nosebleeds, frequent runny nose, and problems with swallowing.  Smoking:  Cough, asthma, respiratory distress, and higher risk of infections like pneumonia.  Consuming by mouth:  Severe bowel decay from reduced blood flow.  Needle injection:  Higher risk for contracting HIV, hepatitis C, and other bloodborne122 diseases, skin or soft tissue infections, as well as scarring or collapsed veins. 61 02/01/1446 Cocaine - Effects  Mixing cocaine with heroin is dangerous and deadly combination.  Many people who use cocaine also drink alcohol at the same time, which is particularly risky and can lead to overdose.  Overdose of cocaine can lead to serious adverse effects, life-threatening symptoms or death. 123 Cocaine - Effects  Some of the most frequent and severe health consequences of overdose are: 1. Irregular heart rhythm. 2. Heart attacks. 3. Strokes. 4. Seizures.  Other symptoms of cocaine overdose include: difficulty breathing, high blood pressure, high body temperature, hallucinations, and extreme agitation or anxiety.  There is no specific medication that can reverse a cocaine overdose. Management involves supportive care and depends on the symptoms present. 124 62 02/01/1446 Cocaine - Effects 125 Cocaine - Addiction  "Pele scored more goals. Lionel Messi has won more trophies. Both have lived more stable lives than the overweight former cocaine addict who tops this list, whose relationship with football became increasingly strained the longer his career continued. If you’ve seen 126 Diego Maradona with a football at his feet, you’ll understand". ~ Andrew Murray / www.fourfourtwo.com 63 02/01/1446 Cocaine - Addiction  The reward circuit eventually adapts to the extra dopamine caused by the drug, becoming steadily less sensitive to it.  As a result, people take stronger and more frequent doses to feel the same high they did initially and to obtain relief from withdrawal.  Withdrawal symptoms include: 1. Depression. 2. Fatigue. 3. Slowed thinking. 4. Unpleasant dreams and insomnia. 5. Increased appetite. 127 Cocaine - Addiction  There are no FDA-approved medications to treat cocaine addiction.  However, behavioral therapy may be used to treat cocaine addiction. Examples include: 1. Cognitive-behavioral therapy. 2. Contingency management or motivational incentives: providing rewards to patients who remain substance free. 3. Therapeutic communities: drug-free residences in which people in recovery from substance use disorders help each other to understand and change their behaviors 128 64 02/01/1446 Dopamine enhancers Cocaine Methamphetamine Khat Synthetic Cathinones Levodopa129 Bromocriptine Methamphetamine 130 65 02/01/1446 Methamphetamine - Introduction  Methamphetamine is structurally close to both amphetamine and ephedrine. 131 Methamphetamine - Introduction  Ephedrine and pseudoephedrine were named "Ma Huang" and used in ancient China since Han dynasty as a stimulant and antiasthmatic.  Ephedrine and pseudoephedrine are obtained from the plant Ephedra sinica, which is also known as Ma Huang or Chinese ephedra. 132 66 02/01/1446 Methamphetamine - Introduction 133 Methamphetamine - Introduction  Ephedrine was chemically synthesised in 1885 by the Japanese chemist Nagai Nagayoshi.  Ephedrine and pseudoephedrine are now used as bronchodilators and decongestants.  Pseudoephedrine could be abused. When taken in excess it raises energy levels, causes ticklish feeling on the skin and induces a sense of euphoria, all for short time. 134 67 02/01/1446 Methamphetamine - Introduction  Methamphetamine was synthesised from ephedrine in 1893 by Japanese chemist Nagai Nagayoshi.  It was used with amphetamine in WWII for its performance-enhancing stimulant effects and to induce extended wakefulness.  Side effects were so serious that the army sharply cut back its usage in 1940. 135 Methamphetamine - Introduction  Historian Lukasz Kamienski says "A soldier going to battle on methampethamine usually found himself unable to perform effectively for the next day or two. Suffering from a drug hangover and looking more like a zombie than a great warrior, he had to recover from the side effects."  Some soldiers turned very violent, committing war crimes against civilians; others attacked their own officers. 136 68 02/01/1446 Methamphetamine - Introduction 137 Methamphetamine - Introduction  Methamphetamine was indicated in the 1950 for treatment of obesity under the name "Obetrol".  Obetrol became a popular diet pill in the 1950s and 1960s because of its psychological and stimulant effects.  The addictive properties of methamphetamine became known for governments which led to regulate the production and distribution of methamphetamine.  Methamphetamine is sold currently as a constituent of the prescription stimulant Desoxyn. 138 69 02/01/1446 Methamphetamine - Introduction  Street names for methamphetamine include: Crystal, Meth, Crank, Chalk, Fire, Glass, Go Fast, Ice, Speed.  It is a white powder or pill.  Crystal meth looks like pieces of glass or shiny blue-white "rocks" of different sizes. 139 Methamphetamine - Introduction  Meth could be swallowed, snorted, smoked or injected.  Because the "high" from the drug both starts and fades quickly, people often take repeated doses in a "binge and crash" pattern.  In some cases, people take methamphetamine in a form of binging known as a "run," giving up food and sleep while continuing to take 140 the drug every few hours for up to several days. 70 02/01/1446 Methamphetamine – Mechanism of action Reward circuit 141 Methamphetamine – Mechanism of action  At low doses: it inhibits the reuptake of dopamine by the presynaptic neuron. 142 71 02/01/1446 Methamphetamine – Mechanism of action  At high doses: in addition to the inhibition of the reuptake of dopamine from the receptors, it also increases the release of dopamine from the presynaptic neuron and acts as MOAI.  Methamphetamine also acts on norepinephrine and serotonin. 143 Methamphetamine – Mechanism of action Positive reinforcement, reward, euphoria, pleasure, drive, dependency. Dopamine Fight or flight: Increased HR, contraction of blood vessels, energy, alertness, concentration, attentiveness. Noradrenaline Emotions, sleep, dreaming, learning. Perception, mood, sleep, body temperature regulation, appetite, pain, memory, obsession. Serotonin 144 72 02/01/1446 Methamphetamine - Effects  Short-term effects of meth include: 1. Euphoria and rush. 2. Increased wakefulness and physical activity. 3. Increased attention and decreased fatigue. 4. Decreased appetite. 5. Faster breathing. 6. Rapid and/or irregular heartbeat. 7. Increased blood pressure and body temperature. 145 Methamphetamine - Effects  Meth mouth 146 73 02/01/1446 Methamphetamine - Effects 147 Methamphetamine - Effects  Faces of meth 148 74 02/01/1446 Methamphetamine - Effects 149 Methamphetamine - Effects 150 75 02/01/1446 Methamphetamine - Effects 151 Methamphetamine - Effects  Long-term effects of meth include: 1. Meth mouth: severe dental problems. 2. Faces of meth: intense itching, leading to skin sores from scratching. 3. Violent behavior. 4. Extreme weight loss. 5. Anxiety. 6. Confusion. 7. Paranoia. 8. Hallucinations. 152 76 02/01/1446 Methamphetamine - Effects  Methamphetamine overdose can lead to stroke, heart attack, or organ problems— such as kidney failure—caused by overheating. These conditions can result in death.  If taken during pregnancy, meth leads to premature delivery; separation of the placenta from the uterus; low birth weight; lethargy; heart and brain problems.  METH DOES CROSS PLACENTA AND CAN PASS INTO HUMAN MILK.  It also increases risk of HIV, hepatitis, and other infectious diseases from shared needles. 153 Methamphetamine - Addiction  Methamphetamine is highly addictive and causes physical dependence.  Withdrawal symptoms can include: 1. Fatigue. 2. Severe depression. 3. Anxiety. 4. Psychosis. 5. Intense drug cravings.  Like cocaine, there are no FDA-approved medications to treat meth addiction.  However, behavioral therapies may be of benefit. 154 77 02/01/1446 Dopamine enhancers Cocaine Methamphetamine Khat Synthetic Cathinones Levodopa155 Bromocriptine Khat 156 78 02/01/1446 Khat - Introduction  Catha edulis is a flowering plant, native to the Arabian Peninsula and the Horn of Africa. It is also called: Khat, qat, ‫قات‬. 157 Khat - Introduction 158 79 02/01/1446 Khat - Introduction  The Khat chewing habit started before thousands of years in the Horn of Africa and Arabian Peninsula.  Khat was sacred for Ancient Egyptians imperial cults. They consumed the plant in attempts to transcend into “apotheosis” and realise divinity.  Khat was first described in “Kitab Al-Saidala Fi Al-Tib”" that was written in the 11th century by Al- Bairuni. 159 Khat - Introduction  Cathine was isolated and identified in 1930, while cathinone was isolated and identified in 1975.  Cathinone is more active than cathine and is much more abundant in younger plants.  Nowadays khat consumption is limited to East Africa and South Western Arabia: Djibouti, Ethiopia, Kenya, Somalia, Uganda, and Yemen. 160 80 02/01/1446 Khat - Introduction  Street names: Abyssinian Tea, African Salad, Catha, Chat, Kat, Oat.  Common forms: Fresh or dried leaves. 161 Khat - Introduction  How is Khat used? 162  Khat is chewed or brewed as tea. 81 02/01/1446 Khat - Mechanism of action  Does cathinone cross blood-brain barrier?  How much of the cathinone is unionised at physiological pH?  What is the pKa of cathinone?  Is the unionised cathinone hydrophobic or hydrophilic?  Remember that hydrophobic molecules cross blood-brain barrier. 163 Khat - Mechanism of action  Cathinone stimulates the release and inhibits the reuptake of dopamine, norepinephrine and serotonin.  Cathine is less powerful than cathinone, and both are less powerful than methamphetamine and cocaine. 164 82 02/01/1446 Khat - Mechanism of action Positive reinforcement, reward, euphoria, pleasure, drive, dependency. Dopamine Fight or flight: Increased HR, contraction of blood vessels, energy, alertness, concentration, attentiveness. Noradrenaline Emotions, sleep, dreaming, learning. Perception, mood, sleep, body temperature regulation, appetite, pain, memory, obsession. Serotonin 165 Khat - Effects  What are the short-term effects of Khat? 1. Euphoria. 2. Increased energy. 3. Increased alertness. 4. Loss of appetite. 5. Increased sociability. 6. Cheerfulness. 7. Sense of well-being. 8. Reduction of boredom. 166 83 02/01/1446 Khat - Effects  However, after 2 hours of consumption the user will experience: 1. Tension. 2. Depression. 3. Emotional instability. 4. Insomnia. 5. Lack of concentration. 6. Restlessness. 7. Loss of short-term memory. 167 Khat - Effects  Other long-term effects include: 1. Dental staining. How? 2. Gastrointestinal disorders such as constipation, ulcers, and stomach inflammation. 3. Increased risk of heart attack. 4. Psychotic reactions such as fear, anxiety and grandiose delusions. 5. Hallucinations. 6. Paranoia. 168 84 02/01/1446 Khat - Effects 169 Khat - Addiction  Does Khat cause physical dependence?  Withdrawal symptoms include: 1. Depression. 2. Lack of energy. 3. Nightmares. 4. Low blood pressure. 170 85 02/01/1446 Synthetic Cathinones 171 Synthetic Cathinones - Introduction  Synthetic cathinones are human-made stimulants chemically related to cathinone.  They are part of a group of drugs that concern public health officials called “new psychoactive substances” (NPS). 172 86 02/01/1446 Synthetic Cathinones - Introduction 173 Synthetic Cathinones - Introduction  Street names: Bath Salts, Flakka, Bloom, Cloud Nine, Cosmic Blast, Ivory Wave, Lunar Wave, Scarface, Vanilla Sky, White Lightning.  Common forms: White or brown crystalline powder, tablet, capsule, liquid.  Common ways taken: Swallowed, snorted, injected. 174 87 02/01/1446 Synthetic Cathinones - Introduction  Flakka's powder is usually sold in small plastic or foil packages labeled “not for human consumption” and sometimes sold as jewelry cleaner. 175 Synthetic Cathinones - Introduction 176 88 02/01/1446 Synthetic Cathinones - Introduction 177 Synthetic Cathinones – Mechanism of action  Their mechanism of action is not known yet.  However, few studies were published in this regard.  One study found that 3,4-methylenedioxypyrovalerone (MDPV), affects the brain in a manner similar to cocaine, but is at least 10 times more powerful. 178 89 02/01/1446 Synthetic Cathinones – Mechanism of action  In another study, methylone was found to be equally as potent as methamphetamine at inhibiting reuptake of norepinephrine and dopamine, due to inhibition of monoamine uptake transporters.  Another study showed that mephedrone, compared to MDMA (ecstasy, not methylone), was less potent at increasing serotonin brain concentrations, but caused a greater increase in dopamine. The rate of return of neurotransmitters to the baseline concentration was rapid, ten times faster than the rate of return with MDMA and two times faster when compared to amphetamine. 179 Synthetic Cathinones – Effects  You can watch this video, but please note that it is disturbing.  https://www.youtube.com/watch?v=BMJMujPoa4Y 180 90 02/01/1446 Synthetic Cathinones – Effects  https://www.mirror.co.uk/news/weird-news/man-possessed-devil- 181 arrives-hospital-9941979 Synthetic Cathinones – Effects 182 91 02/01/1446 Synthetic Cathinones – Effects 183 Synthetic Cathinones – Effects  While long-term use of synthetic cathinones leads to death, the short-term effects of synthetic cathinones include: 1. Euphoria. 2. Excited delirium: Violent behavior and extreme agitation. 3. Increased sociability and sex drive. 4. Paranoia and panic attacks. 5. Reduced motor control. 6. Increased heart rate and blood pressure. 7. Sweating. 8. Insomnia. 9. Irritability and dizziness. 10. Cloudy thinking and hallucinations. 184 92 02/01/1446 Synthetic Cathinones – Addiction  Do synthetic cathinones cause physical dependence?  Taking synthetic cathinones can cause strong withdrawal symptoms that include: 1. Depression. 2. Fatigue. 3. Anxiety. 4. Tremors. 5. Problems sleeping. 6. Paranoia.  Behavioral therapy can be used to treat addiction to synthetic cathinones. 185 Dopamine enhancers Cocaine Methamphetamine Khat Synthetic Cathinones Levodopa186 Bromocriptine 93 02/01/1446 Levodopa 187 Levodopa - Introduction  Levodopa is a precursor of dopamine.  Can dopamine cross blood-brain barrier passively? Why?  Can levodopa cross blood-brain barrier passively? Why?  How does it cross the blood-brain barrier and reaches the nigral neurons? 188  In the brain, levodopa is decarboxylated to dopamine. 94 02/01/1446 Levodopa - Introduction  Levodopa can be obtained naturally from Mucuna pruriens (velvet bean). 189 Levodopa – Mechanism of action and effects  Levodopa replaces dopamine lost in Parkinson's disease, Thus it is used as treatment of Parkinson's disease. 190 95 02/01/1446 Levodopa – Mechanism of action and effects  Levodopa is converted to dopamine in the periphery as well as in the CNS.  Thus, it is administered with a peripheral dopamine decarboxylase inhibitor such as carbidopa. 191 Levodopa – Mechanism of action and effects 192 96 02/01/1446 Bromocriptine 193 Bromocriptine - Introduction 194 97 02/01/1446 Bromocriptine - Introduction  Bromocriptine is a semisynthetic alkaloid derived from ergocriptine, which is obtained from rye ergot fungus (Claviceps purpurea). 195 Bromocriptine – Mechanism of action and effects  It has potent dopaminergic activity, enabling its use for Parkinson's disease. 196  It stimulates dopaminergic receptors of the CNS. 98 02/01/1446 Question  Could levodopa and bromocriptine be abused? How? Reward circuit 197 Norepinephrine enhancers Amphetamine Harmaline 198 99 02/01/1446 Amphetamine 199 Amphetamine - Introduction 200 100 02/01/1446 Amphetamine - Introduction  Amphetamine was first synthesised in 1887 in Germany by Romanian chemist Lazăr Edeleanu.  Its stimulant effects was discovered in 1927 by the American chemist Gordon Alles who reported the sympathomimetic properties of the compound.  Smith, Kline & French (SKF, that was later acquired by GSK) began selling the drug in 1933 as decongestant. 201 Amphetamine - Introduction  In WWII, amphetamine and methamphetamine were widely used by soldiers for their stimulant and performance- enhancing effects.  Amphetamine is addictive and became a controlled substance.  It is used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) and narcolepsy. 202 101 02/01/1446 Amphetamine - Introduction  Fenethylline (captagon) is a prodrug that releases both amphetamine and theophylline.  Both of amphetamine and theophylline are stimulants. 203 Amphetamine - Introduction  Prescription stimulants are medicines generally used to treat attention-deficit hyperactivity disorder (ADHD) and narcolepsy (uncontrollable episodes of deep sleep).  They increase the activity of the sympathetic nervous system, increasing alertness, attention, and energy. 204 102 02/01/1446 Amphetamine - Introduction  Examples of actives in prescription stimulents are dextroamphetamine, dextroamphetamine/amphetamine combination and methylphenidate. 205 Amphetamine - Introduction  Popular slang terms for prescription stimulants include Speed, Uppers, and Vitamin R. 206 103 02/01/1446 Amphetamine - Introduction 207 Amphetamine – Mechanism of action  Amphetamine mainly increases the activity of the brain chemicals norepinephrine.  Norepinephrine (noradrenaline) switches on the “fight or flight” response, affects blood vessels, blood pressure and heart rate, blood sugar, and breathing.  Dopamine is a little bit affected as well, and it is involved in the reinforcement of rewarding behaviors. 208 104 02/01/1446 Amphetamine – Mechanism of action Positive reinforcement, reward, euphoria, pleasure, drive, dependency. Dopamine Fight or flight: Increased HR, contraction of blood vessels, energy, alertness, concentration, attentiveness. Noradrenaline Emotions, sleep, dreaming, learning. Perception, mood, sleep, body temperature regulation, appetite, pain, memory, obsession. Serotonin 209 Amphetamine – Mechanism of action 210 105 02/01/1446 Remember  Catecholamine hormones, such as adrenaline (epinephrine) or noradrenaline (norepinephrine), facilitate immediate physical reactions associated with a preparation for violent muscular action and: 1. Acceleration of heart and lung action. 2. Paling or flushing, or alternating between both. 3. Inhibition of stomach and upper-intestinal action to the point where digestion slows down or stops. 4. General effect on the sphincters of the body. 5. Constriction of blood vessels in many parts of the body. 6. Liberation of metabolic energy sources (particularly fat and glycogen) for muscular action. 7. Dilation of blood vessels for muscles. 8. Inhibition of the lacrimal gland (responsible for tear production) and salivation. 9. Dilation of pupil (mydriasis). 10. Relaxation of bladder. 11. Inhibition of erection. 12. Auditory exclusion (loss of hearing). 13. Tunnel vision (loss of peripheral vision). 14. Disinhibition of spinal reflexes. 211 15. Shaking. Amphetamine - Effects  Why do people abuse amphetamine?  Because it increases alertness, attention and energy.  It also causes increased blood pressure and heart rate, narrowed blood vessels, increased blood sugar and opened-up breathing passages. 212 106 02/01/1446 Amphetamine - Effects  The long-term use and misuse of amphetamine, including overdose, can also lead to: 1. Psychosis. 2. Anger. 3. Paranoia. 4. Heart, nerve, and stomach problems.  These issues could lead to a heart attack or seizures. 213 Amphetamine - Addiction  Does amphetamine cause physical dependence?  Withdrawal symptoms include fatigue, depression, and sleep problems. 214 107 02/01/1446 Amphetamine - Addiction  Behavioral therapies can be effective in helping people stop amphetamine misuse, including: 1. Cognitive-behavioral therapy: it helps modify the patient's drug-use expectations and behaviors, and it can effectively manage triggers and stress. 2. Contingency management: it provides vouchers or small cash rewards for positive behaviors such as staying drug-free. 215 Harmaline 216 108 02/01/1446 Harmaline - Introduction  Harmaline is a psychoactive indole alkaloid found in Peganum harmala (‫ (الحرمل‬and the hallucinogenic beverage Ayahuasca which is brewed using Banisteriopsis caapi (Harmaline) and Psychotria viridis (DMT). 217 Harmaline - Introduction 218 109 02/01/1446 Harmaline - Introduction 219 Harmaline – Mechanism of action 220 110 02/01/1446 Harmaline – Effects  The seeds of harmaline have stimulant and hallucinogenic effects at low doses (3-4 g when eaten) in humans.  It causes unconsciousness, hypertension, tachycardia, and tachypnea. 221 Hallucinogenic Plants Lecture 6 Dr. Yahia Tabaza 222 111 02/01/1446 Serotonin enhancers DMT LSD Alice in Wonderland Syndrome Ecstasy (MDMA) Psilocin & Psilocybin Fungal Intelligence The Stoned Ape Hypothesis Psychedelic Art 223 Serotonin enhancers - Introduction  Serotonin enhancers are also called “Psychedelics”.  The term psychedelic is derived from the Greek words psyche, "soul, mind" and delein, "to manifest, reveal".  "Soul-manifesting“ or "mind revealing": psychedelics can access the soul and develop unused potentials of the human mind. 224 112 02/01/1446 Serotonin enhancers - Introduction  Psychic as an adjective: having a special mental ability, for example so that you are able to know what will happen in the future or know what people are thinking.  Psychic as a noun: a person who has a special mental ability, for example being able to know what will happen in the future or what people are thinking. 225 Serotonin enhancers - Introduction  As their name indicates, they trigger psychedelic experiences via serotonin receptor agonism. 226 113 02/01/1446 Serotonin enhancers - Introduction Positive reinforcement, reward, euphoria, pleasure, drive, dependency. Dopamine Fight or flight: Increased HR, contraction of blood vessels, energy, alertness, concentration, attentiveness. Noradrenaline Emotions, sleep, dreaming, learning. Perception, mood, sleep, body temperature regulation, appetite, pain, memory, obsession. Serotonin 227 Serotonin enhancers - Introduction  Serotonin helps regulate your mood naturally.  When your serotonin levels are normal, you feel: happier, calmer, more focused, less anxious and more emotionally stable. 228 114 02/01/1446 Serotonin enhancers - Introduction  A number of studies over the past decades provided evidence that serotonin also is involved in structural and functional remodeling of cortical circuits.  Neurons in cortical areas that process sensory information such as vision, audition, and somatic sensation can modify their response properties following prolonged alterations in input activity, especially during early postnatal life. 229 Serotonin enhancers - Introduction  Moreover, it was found that some psychedelics increased the number of dendrites in nerve cells, increased the density of dendritic spines, and increased number of synapses.  Altogether, these findings suggest that psychedelics induce structural changes to the brain. 230 115 02/01/1446 Serotonin enhancers - Introduction Petri G, Expert P, Turkheimer F, Carhart-Harris R, Nutt D, Hellyer PJ, Vaccarino F. 2014 231 Homological scaffolds of brain functional networks. J. R. Soc. Interface 11: 20140873. http://dx.doi.org/10.1098/rsif.2014.0873 Serotonin enhancers - Introduction  Moreover, serotonin imbalance in locus coeruleus leads to bizarre sensory experiences (auditory, visual and tactile hallucinations). 232 116 02/01/1446 Serotonin enhancers - Introduction Carhart-Harris, RL & J Nutt, D. (2017). Serotonin and brain function: A tale of two receptors. 233 Journal of Psychopharmacology. 31. 026988111772591. 10.1177/0269881117725915. Serotonin enhancers - Introduction  Speaking about brain’s plasticity, please watch the following video:  https://youtu.be/N-StEDndtPI 234 117 02/01/1446 DMT 235 DMT – Introduction 236 118 02/01/1446 DMT - Introduction  DMT is one of the principle components of Ayahuasca.  Ayahuasca is brewed using Banisteriopsis caapi (Harmaline) and Psychotria viridis (DMT). 237 DMT - Introduction 238 119 02/01/1446 DMT - Introduction Ayahuasca is a strong smelling brown liquid with a bitter taste. 239 DMT - Introduction  Ayahuasca literally translates from the Quechua language of the North Andes as “soul vine” or “vine of the dead”.  Ayahuasca is most commonly consumed by indigenous communities in Amazon River regions in liquid form as part of shamanic rituals designed to communicate with celestial supernatural forces or the spirits of the forest. 240 120 02/01/1446 DMT - Introduction  DMT was first synthesised by the German chemist Richard Helmuth Fredrick Manske in 1931.  It was later (1946) isolated from natural sources by the efforts of the Brazilian chemist Oswaldo Gonçalves de Lima.  DMT is found naturally in more than 50 plant species. 241 DMT - Introduction  For example, it occurs naturally Mimosa tenuiflora and Diplopterys cabrerana. 242 121 02/01/1446 DMT – Introduction  In 2013, researchers reported finding DMT in the pineal gland of rodents.  The pineal gland in the brain produces melatonin (a hormone derived from serotonin) which affects sleep patterns and circadian rhythms.  This study sparked the widespread assertion that DMT occurs in the human pineal gland and is released during dreams as well as at or shortly before birth and death.  However, the claim still needs to be scientifically verified with further research. 243 DMT – Introduction  DMT is called “the spirit molecule” 244 122 02/01/1446 DMT - Introduction  Some street names for DMT are "dimitri" and "businessman's trip".  DMT could be smoked, injected or consumed orally as a constituent of “ayahuasca” or “blue elephant” pill.  It is a white or yellow crystalline powder. 245 DMT – Mechanism of action  Does DMT cross blood brain barrier passively? Why?  How does DMT cross blood brain barrier?  Is DMT absorbed more from stomach or intestine? Why? 246 123 02/01/1446 DMT – Mechanism of action  DMT is called “businessman’s trip” because it has short duration of action if ingested orally “5 to 15 minutes”.  The presence of MAO inhibitor extends this duration of action up to 15 hours.  The inhibition of MAO allows DMT to diffuse unmetabolised past the membranes in the GIT, and eventually cross the blood–brain barrier to activate serotonin receptor sites in the brain.  It is acts as a 5-HT receptor agonist. 247  DMT activates dopamine receptors as well, but to a lesser extent. DMT – Mechanism of action Carhart-Harris, RL & J Nutt, D. (2017). Serotonin and brain function: A tale of two receptors. 248 Journal of Psychopharmacology. 31. 026988111772591. 10.1177/0269881117725915. 124 02/01/1446 DMT – Mechanism of action Positive reinforcement, reward, euphoria, pleasure, drive, dependency. Dopamine Fight or flight: Increased HR, contraction of blood vessels, energy, alertness, concentration, attentiveness. Noradrenaline Emotions, sleep, dreaming, learning. Perception, mood, sleep, body temperature regulation, appetite, pain, memory, obsession. Serotonin 249 DMT – Effects 250 125 02/01/1446 DMT – Effects Trip 1 - Ayahuasca: 251 DMT – Effects “The puking was quiet intense and I broke into a cold sweat. As soon as the puking and retching stopped I could feel my heart racing really fast and my body going limp. I had started to breathe heavily and perspire profusely. My eyes were semi closed and my mouth open. I had no idea what was happening to me and for a second there I thought I might be dying, and 252 may be that this was a heart attack or a stroke. ”. 126 02/01/1446 DMT – Effects "I started to panic and began tapping my feet really fast and hard to attract the shaman’s attention. He came over along with his wife and they both started singing and chanting Icaros standing right in front of my almost paralysed body". 253 DMT – Effects "As the chanting intensified I felt my breathing relax and I was suddenly transported to an entire different dimension it seemed. I saw brilliant colours and bright lights. I still cannot completely fathom what all I saw as the visuals moved at a very 254 fast pace and it was difficult to keep track of all the information that I was being bombarded with". 127 02/01/1446 DMT – Effects "But one thing is for sure that it wasn’t just an out of the world experience, it was out of body as well. Devoid of a physical form, I felt like a molecule made out of pure energy that has been beamed into the middle of the cosmos and the 255 universe was showing me its enormity and complexity through a display of lights and colours". DMT – Effects "I had never seen anything like it before. I was travelling through solar systems and galaxies. Stars passed me by as I flew through space at incredible speeds. There were flares of rapidly changing colours all around that looked like the pictures of 256 solar flares that I’ve seen on the internet but alive and changing right in front of me". 128 02/01/1446 DMT – Effects "I saw stars being born and starts exploding, spreading all the matter & energy inside their guts into the void of space, filling up the emptiness with new planets and celestial objects. I also saw geometrical shapes and patterns- triangles, cubes, 257 tetrahedrons, hexagons etc all made of light". DMT – Effects "I saw the Pyramids of Egypt and the ruins of ancient cities, it was like a crash course in all human knowledge and history. I tried to open my eyes a little bit and to me the entire room and everything in it seemed to be made out of hexagonal blocks, like a 258 beehive". 129 02/01/1446 DMT – Effects "As I closed my eyes again, I saw eyes everywhere. Every shape, every object, everything I saw had an eye in the middle of it with its gaze directed upon me. I saw a few animals too. First I saw cattle of some sort, it was either a bull or a buffalo I’m not really sure which. Then I saw a bird. It was some sort of magical creature made out of radiant lights. It had a small head, wide wings, a long tail and prominent eyes staring right at me as it took me through a journey into the vast cosmos. Lights exploded from every pore of its being, it was unlike anything I’ve ever experienced in my fraction of 259 a lifetime in this existence". DMT – Effects "When I managed to open my eyes, I saw giant humanoid beings inside the room. There were about 4 or 5 of them standing at different positions in the room and looking at us. They didn’t seem scary or intimidating at all. In fact I got a feeling that 260 they were benevolent beings, kind of like guardian angels of some sort who cared about us and loved us". 130 02/01/1446 DMT – Effects Trip 2 - Ayahuasca: 261 DMT – Effects “My first instance of seeing complex geometric patterns was experienced with no other effects beyond the beautiful imagery. Shortly after, I realised my body was becoming limp and I slouched further into my sleeping bag and sought comfort as my 262 primary focus; all the while clutching my bucket as the vomiting seemed imminent”. 131 02/01/1446 DMT – Effects “The geometric patterns and colors began happening at hyper speed. The blazing fury of images, shapes, and patterns quickly overwhelmed me. Each time, I felt a need to assess what was I seeing and then decide how I felt about it. It felt like a test for me to see how fast I could comprehend what I was seeing and how fast I could I accept it. Imagine walking into a dark room, turning the lights on, looking around, assessing what’s in the room, and determining if there’s anything that could be dangerous for you—and then imagine that happening in your mind at a rate of what feels like several thousand times a second. Add to this that everything you see in the room is also twisted, distorted, warped and 263 weird. It was exhausting”. DMT – Effects “As the ayahuasca was assaulting me with these images, it’s sheer power took over 99% of my mind and at least 50% of my body. And in what was left of me physically and mentally, I summoned the strength to not fight but surrender. I knew that if I tried to change the images or to stop them, it would cause me suffering. In the greatest act of surrender and submission I have ever known, I chose to let go and allow these nano-images wash over me; which lasted for probably 12 of the 17 total 264 hours the ayahuasca affected me”. 132 02/01/1446 DMT – Effects "It was a decision of submission to that which cannot be controlled. In what we believe is our everyday life, where we think we are consciously aware, people spend, including myself, so much time attempting to control everyone and everything. To have tried to fight the speed, intensity, and comprehensiveness of the ayahuasca’s effects would have been unbearable; submitting, enduring seemed to be the better of the two options". 265 DMT – Effects “A decent visual for what I saw during my Ayahuasca trip, except that this is a still image and what I saw was moving at 1,000 mph, 266 for hours on end”. 133 02/01/1446 DMT – Effects 267 DMT – Effects 268 134 02/01/1446 DMT – Effects  When the skin of some toads (e.g. the Bufo toad) is licked, a psychedelic experience results. 269 DMT - Effects 270 135 02/01/1446 DMT - Effects  How a DMT trip can look like, note the kaleidoscopic patterns: 271 DMT - Effects 272 136 02/01/1446 DMT - Effects 273 DMT - Effects 274 137 02/01/1446 DMT - Effects 275 DMT - Effects 276 138 02/01/1446 DMT - Effects 277 DMT - Effects 278 139 02/01/1446 DMT – Effects  Video simulations: 1. https://www.youtube.com/watch?v=95FxKgcgjN0 2. https://www.youtube.com/watch?v=-IQbpHQPJxY 3. https://www.youtube.com/watch?v=UxtkoE-HV-k 4. https://www.youtube.com/watch?v=TZRJBJs7Qx0 5. https://www.youtube.com/watch?v=nwjOJ9vPwcI 279 DMT – Effects  DMT is most renowned for: 1. Visual hallucinations. 2. Auditory and olfactory hallucinations. 3. Intensified feelings and sensory experiences. 4. Altered perception of time and body image. 5. Depersonalisation: the experience of feeling unreal, detached, and often, unable to feel emotion. 6. Sometimes, short lived euphoria. 280 140 02/01/1446 DMT – Effects  DMT may cause some physical effects like hypertension, increased heart rate, agitation, seizures and dilated pupils.  At high doses, cardiac and respiratory arrest may occur.  The long term use of DMT causes persistent psychosis and flashbacks. 281 DMT – Addiction  Does DMT cause physical dependence?  No  Does it cause addiction? 282 141 02/01/1446 Serotonin enhancers DMT LSD Alice in Wonderland Syndrome Ecstasy (MDMA) Psilocin & Psilocybin Fungal Intelligence The Stoned Ape Hypothesis Psychedelic Art 283 LSD 284 142 02/01/1446 LSD - Introduction  LSD stands for lysergic acid diethylamide. 285 LSD - Introduction  LSD is a semisynthetic alkaloid derived from lysergic acid, the precursor of ergoline alkaloids, which is obtained from rye ergot fungus (Claviceps purpurea). 286 143 02/01/1446 Remember - Bromocriptin 287 LSD - Introduction  On November 16, 1938, the Swiss chemist Albert Hofmann first synthesised LSD at the Sandoz Laboratories in Basel, Switzerland.  This work was a part of a large research program searching for medically useful ergot alkaloid derivatives. 288 144 02/01/1446 LSD - Introduction  The psychedelic properties of LSD was not discovered until 5 years later, when on Friday, April 16, 1943 Hofmann resynthesised the compound and accidentally ingested an unknown quantity of the chemical.  He was compelled to go home in mid afternoon and lay down. He experienced a dazed and dream-like state, in which he sensed a distortion of time and was flooded with vivid, highly colored, kaleidoscopic images of extreme plasticity and unusual dimension. Several hours later he returned to normal. 289 LSD - Introduction  The first intentional ingestion of LSD occurred on Monday, April 19, 1943 when Hofmann ingested 250 µg of LSD. He said this would be a threshold dose based on the dosages of other ergot alkaloids.  About 40 minutes after ingesting LSD, the hallucinations and emotions that he had previously experienced returned. He spoke and wrote only with difficulty, and requested that his laboratory assistant accompany him home. 290 145 02/01/1446 LSD - Introduction  As they rode their bicycles to his home, Hoffmann's field of vision alternately wavered and became distorted, and he had the sensation of not being able to move from place to place, even though his assistant later confirmed that they had traveled rapidly.  When he arrived home, he thought that his neighbor is a witch and that a demon took control of his body and soul.  He recovered in about 14 hours. 291 LSD - Introduction  Moral of the story? 292 146 02/01/1446 LSD - Introduction  By the way, April, 19th is celebrated as the “bicycle day”! 293 LSD - Introduction  Street names of LSD: Acid, Blotter, Blue Heaven, Cubes, Microdot, Yellow Sunshine.  Common forms: Tablet; capsule; clear liquid; small decorated squares of absorbent paper that liquid has been added to (acid blotter). 294 147 02/01/1446 LSD - Introduction 295 LSD - Introduction 296 148 02/01/1446 LSD - Introduction 297 LSD - Introduction 298 149 02/01/1446 LSD – Mechanism of action Carhart-Harris, RL & J Nutt, D. (2017). Serotonin and brain function: A tale of two receptors. 299 Journal of Psychopharmacology. 31. 026988111772591. 10.1177/0269881117725915. LSD – Mechanism of action  LSD binds to 5HT2A at an unexpected angle, causing the receptor to fold over the molecule, highly minimising its uptake. 300 150 02/01/1446 LSD – Mechanism of action  Eventually, though, an acid trip ends. Some LSD molecules pop off their receptors as the lid moves around. Also, brain cells eventually respond to this strange molecule by sucking the receptor into the cell, where it - 301 along with the LSD—is degraded or disassembled for recycling LSD – Mechanism of action  Moreover, LSD has a limited dopaminergic activity. 302 151 02/01/1446 LSD – Mechanism of action Positive reinforcement, reward, euphoria, pleasure, drive, dependency. Dopamine Fight or flight: Increased HR, contraction of blood vessels, energy, alertness, concentration, attentiveness. Noradrenaline Emotions, sleep, dreaming, learning. Perception, mood, sleep, body temperature regulation, appetite, pain, memory, obsession. Serotonin 303 LSD – Effects 304 152 02/01/1446 LSD – Effects  If taken in a large enough dose, the drug produces delusions and visual hallucinations. The user's sense of time and self changes. Sensations may seem to "cross over," objects seem to move in a wave-like fashion or melt; and sensory impressions become overwhelming. 305 LSD – Effects 306 153 02/01/1446 LSD – Effects 307 LSD – Effects 308 154 02/01/1446 LSD – Effects Don’t :p 309 LSD – Effects 310 155 02/01/1446 LSD – Effects 311 LSD – Effects 312 156 02/01/1446 LSD – Effects 313 LSD – Effects 314 157 02/01/1446 LSD – Effects  As with many other hallucinogens, users refer to their experience with LSD as a "trip".  Trips could be either good or bad. 315 LSD – Effects  "Bad trip" is a term used to describe several different types of adverse experiences.  Mild bad trip: only the images and feelings during the experience were unpleasant.  Extreme bad trip: a serious panic reaction, accompanied by immense anxiety and fear. Some users experience severe, terrifying thoughts and feelings, fear of losing control, fear of insanity and death, and despair.  Bad trips are common, but most of them do not reach the severe level. However, in some cases, fatal accidents have occurred during states of LSD intoxication. 316 158 02/01/1446 LSD – Effects 317 LSD – Effects  Video simulations: 1. https://www.youtube.com/watch?v=9CUMzaCQwOs 2. https://www.youtube.com/watch?v=dncWTBP1zfk 3. https://www.youtube.com/watch?v=ZHsf17gvHpw 4. https://www.youtube.com/watch?v=TI2BkZnPqP4 318 159 02/01/1446 LSD – Effects  During the 1950s, a researcher (Oscar Janiger, a University of California-Irvine psychiatrist known for his work on LSD) gave an artist two 50 µg doses of LSD (each dose separated by about an hour), and then the artist was encouraged to draw pictures of the doctor who administered the drug.  Nine portraits were drawn over the space of eight hours. 319 LSD – Effects  First drawing is done 20 minutes after the first dose (50ug).  An attending doctor observes.  Patient chooses to start drawing with charcoal.  The subject of the experiment reports – “Condition normal, no effect from the drug yet”. 320 160 02/01/1446 LSD – Effects  2: 85 minutes after first dose and 20 minutes after a second dose has been administered (50µg + 50µg):  The patient seems euphoric.  “I can see you clearly, so clearly. This... you... it's all... I'm having a little trouble controlling this pencil. It seems to want to keep going”. 321 LSD – Effects  3: 2 hours 30 minutes after first dose:  Patient appears very focused on the business of drawing.  “Outlines seem normal, but very vivid, everything is changing colour. My hand must follow the bold sweep of the lines. I feel as if my consciousness is situated i