Psychedelics Flashcards
Psilocybin and AUD clinical trial
Used to treat alcohol use disorder at NYU. Participants received 2 doses of psilocybin and therapy sessions over a period of 12 weeks. Each psychedelic trip was precipitated by a therapist. The NYU study recruited 93 participants who were randomly assigned to either psilocybin or a placebo. All of the participants received psychotherapy over a 12 week treatment period. Overall, the results were encouraging. In the psilocybin and psychotherapy group, the participants had a 50% reduction in drinking compared to the placebo group- it’s a clinically meaningful difference. If these results hold up, it would be a much larger effect than seen in current AUD medications.
Why might people with a personal or family history of psychotic disorders be excluded from a psychedelics clinical trial?
Psychedelics can precipitate a psychotic episode or a psychotic disorder in someone who is predisposed. People with histories of bipolar disorder, schizophrenia, or psychosis will likely be excluded from these studies
Psilocybin
Psilocybin is the mind altering molecule found in magic mushrooms- introduced to the US in 1957. It has been used by indigenous people in the Americas for thousands of years
Examples of psychedelics (4)
Psilocybin, mescaline (found in North American cacti called peyote) and synthetic chemicals like LSD and MDMA
Affects of psychedelics (4)
- They bring about an altered state of consciousness which can be accompanied by hallucinations or heightened sensitivity to colors, sounds, and patterns
- People can see illusory movements- thinking that an inanimate object is moving when it isn’t really
- Some people experience profound feelings of empathy and connections to others, or to the entire universe
- After the trip people can feel changed in positive ways
Why could psychedelic assisted therapy be more effective to treat AUD than conventional treatments?
Psychedelics can allow the brain to change rather than just suppressing symptoms. This includes changes in connectivity in regions like the amygdala (responsible for emotions associated with memories), striatum (reward and habitual behavior), and prefrontal cortex (makes decisions, oversees other areas of the brain).
How does alcohol damage the brain?
In normal brains the prefrontal cortex has top-down control- we can control our emotions and habits through strong PFC activity. Alcohol can erode the neurons that connect different regions of the brain- the neurons shrink and diminish the communication between brain regions. The amygdala becomes more hypersensitive with contexts associated with the drug- it’s basically “acting on its own”. When this happens- people can experience irresistible cravings for alcohol that override the PFC’s signals. Executive control from the PFC is diminished and people stop thinking about the bad outcomes.
How do psychedelics impact brain connectivity in AUD patients?
Psychedelics activate the serotonin receptors involved in mood and unusual states of consciousness. Activating these receptors may also lead to new neuron connections or growth. The psychedelics may restore the neuron branches that have been impacted by AUD. This improves communication in the brain and reduces cravings. Cocaine is used habitually, unlike psychedelics, producing too much growth of neuronal branches. Psychedelics seem to promote just enough nerve cell growth
When did research into psychedelics begin?
Research into psychedelics began in the 1940s after the accidental discovery of LSD. From the 1940s-1970s there was a large body of research looking at using psychedelics to treat AUD
Hoffman
Hoffman researched a fungus called ergot- a fungus that infects grain. He wanted to isolate the chemical that could reduce the risk of fatal bleeding in childbirth. In this process, he accidentally absorbed a small amount of LSD- he saw kaleidoscopic images. He then synthesized lysergic acid diethylamide (LSD-25)
CIA LSD experiments
The CIA attempted to weaponize LSD. They experimented on government employees and other participants to see if LSD could be used to control minds or erase memories. Ken Kesey (author of One flew over the cuckoo’s nest) was one of the CIA’s volunteers. He later became one of the leaders of the hippies.
Timothy Leary
In 1966, Timothy Leary (former Harvard psychology professor) promoted psychedelics as a means of personal and cultural transformation. Leary became a leader of a religious movement which used LSD for spiritual enlightenment, calling himself the “high priest”. He left Harvard in 1963. Nixon declared Leary the most dangerous man in America and declared a war on drugs
How were psychedelics impacted by the war on drugs?
Nixon enacted the Controlled Substance Act in 1970. The Act classified drugs like heroin, cannabis, and psychedelics as having the highest potential for addiction and abuse. Alcohol and tobacco, which are very damaging, were not included in the act. Psychedelics really aren’t addictive.
Uses of psychedelics by indigenous people
Indigenous populations have used plant based psychedelics for thousands of years, usually in religious or healing ceremonies. In North America, Indigenous people used peyote- a cactus that grows in Mexico and Texas. It’s used to synchronize with the universe, and as a medicinal herb. They believe that part of the subconscious is connected to the universe, and peyote allows you to manifest things that you want. Indigenous people emphasize only taking these substances in the right environment and the right frame of mind
How does mindset impact a person’s experience with psychedelics?
The setting plays a crucial role in a psychedelic assisted therapy experience. The mindset and intention the person brings to the session is also important. People can have a bad trip if they bring the wrong mindset to the session. In therapeutic settings, it’s important for the person to have an intention in mind for what they want to get out of the session.
Psilocybin clinical trial for cancer
An oncologist in Maryland studied the use of psychedelics (psilocybin) in treating mental health issues in cancer patients, in a group therapy setting. As many as one third of cancer patients will experience major depressive disorder. Treated 30 people- 82% had more than 50% reduction in depression symptoms
How is the default mode network involved in depression?
Psychiatric disorders and addictions both involve being stuck in a negative or narrow patterns of thought or behavior. In patients with depression, there is suspicious activity in the default mode network- activity across brain areas associated with thinking about oneself, one’s past, and projecting yourself into the future
Default mode network
The default mode network typically becomes more active when a person is introspective and less active when a person shifts their attention to the outside world.
How is the default mode network impacted by psychedelics?
Under the influence of psychedelics, the default mode network becomes less active and other regions of the brain become more active and increase communication with each other. There is an increase in global communication- connections form between brain regions that don’t normally talk to each other. This makes people experience a heightened sense of awareness
How do psychedelics impact the claustrum?
The receptors targeted by psychedelic drugs are really densely expressed in the claustrum. Psychedelics seem to bind to receptors in the claustrum and disrupt/disorganize the claustrum, or to take away its control. This changes the way that brain regions talk to each other. People may experience learning or rewiring of the circuits that govern our behavior and therefore the radical reorganization cause people to experience new insights they haven’t encountered before. The disruption of the claustrum may be what allows rigid thought patterns and behaviors to reset- like reprogramming the operating system
Claustrum
The claustrum is a thin sheet of gray matter tucked into a deep area of each hemisphere. It is connected to nearly every region of the brain and regulates communication between other brain regions. It turns these regions on and off.
Rick Doblin
Rick Doblin founded the multidisciplinary association for psychedelic studies to revive psychedelic research in 1986. He wanted to focus on the therapeutic benefits of psychedelics with a focus on MDMA (ecstasy) for PTSD. Since 2000, over 200 PTSD patients have received MDMA assisted therapy in MAPS clinical trials
Why is MDMA successful in therapy?
MDMA is successful in therapy because it builds self confidence and self acceptance. MDMA increases the amount of oxytocin- important for bonding. Therefore, the therapeutic bond and the setting is important for creating these positive mood states. MDMA allows people to feel more connected to themselves/their inner world, and also the people that they’re with. The feeling of connectedness and love paired with an altered mental state can make people uniquely vulnerable
How is MDMA different from other psychedelics?
Unlike other psychedelics, MDMA has stimulant properties that can cause toxic side effects. It can impact dopamine and norepinephrine, can cause chills, nausea, increased heart rate
MDMA and PTSD clinical trials
Participants in the trial had “breakthrough” moments that they remember later on. 70% of the participants in phase 3 of the MDMA assisted therapy trial no longer qualified for a PTSD diagnosis. MDMA works for combat related PTSD and more difficult PTSD cases- but goal is to get FDA approval to use MDMA for PTSD of any cause. Trials are also in place for people of color that have experienced racism/racial trauma
How does MDMA work to treat PTSD?
PTSD involves overactivation of the amygdala. People are reminded of the traumatic event by neutral stimuli (like a door slamming) and have a fear response. MDMA calms the amygdala by making people less hypersensitive to negative emotional states. The PFC can dampen the amygdala and reduce the hypersensitivity to distress or old memories that cause the amygdala to be overactive. The PFC control helps to remind people that the trauma is in the past and helps them to rationally think through things and make executive decisions. It can override the amygdala’s fear response
Broadly, what are psychedelics? (3)
Broadly, drugs that alter:
1. Perception- sensory disturbances
2. Conscious awareness
3. Also mood, thinking processes, and physiology
More than 90 different species of plants and many more synthetic agents produce these kinds of effects. Some of these drugs don’t produce hallucinations- cannabis counts as a hallucinogenic drug
4 subgroups of psychedelics
- Serotonergic hallucinogens
- Methylated amphetamines
- Anticholinergic hallucinogens
- Phencyclidine
Salvinorin may be a subgroup, but it is very poorly understood
Serotonergic hallucinogens
All of these drugs influence serotonergic transmission in the brain, and all bind to 5-HT2A (serotonin receptor)- causes vivid visual hallucinations. Serotonin increases connectivity between brain regions that have a high density of these receptors. Examples include LSD, mescaline (peyote), psilocybin (mushrooms), DMT
Methylated amphetamines
This subgroup is structurally similar to amphetamines. They produce changes in mood and consciousness- few sensory changes, and act on dopamine, norepinephrine, and serotonin synapses. They do not bind to the 5-HT2A serotonin receptor. Examples include MDA and MDMA
Anticholinergic hallucinogens
These drugs are less well known. They produce a dream-like trance, and users often have no memory of the experience. Antagonists of acetylcholine- blocks its effectiveness by acting on muscarinic receptors. Examples include mandrake, henbane, belladonna, jimsonweed
Phencyclidine
Dissociative anesthetics- produce surgical anesthesia while patient remains semiconscious- in non-human animals. Thought to antagonize glutamate, an excitatory neurotransmitter. Examples are PCP (angel dust is a street name), ketamine
Salvinorin
Poorly understood, could potentially be a 5th subgroup. Seems to act on opiate receptors (kappa receptors)
History of serotonergic hallucinogens
Often used by indigenous peoples of Central and South America and different groups across Africa. Frequently used in religious ceremonies, as all produce vivid visual hallucinations. These drugs entered mainstream European and American culture in the 1960s
Medical uses of ergot derivatives
Treatment of migraines and uterine contractions during pregnancy
Hoffman’s experiences were used to develop which innovation?
LSD was distributed by Sandoz for use during psychotherapy. He argued that the drug would break down a person’s ego. Many famous people used this drug, such as Cary Grant, Timothy Leary (Harvard psychologist), and Ken Kesey (writer)
LSD and popular culture
Over time, earnest experiments on the potential uses of LSD transformed into parties with faculty, students, and celebrities. Ken Kesey (author of one flew over the cuckoo’s nest) hosted LSD parties with hundreds of people in California. LSD began to make an impact on hippie culture, and started to influence music. Grateful Dead, Jefferson Airplane, and Jimi Hendrix (acid rock) are examples
LSD use in the 1960s
By 1960 LSD was the most controversial drug in the world. Over 2 million people in the US had tried it. There was a lot of negative publicity, which led to a dramatic decrease in use by 1980.
LSD negative publicity
There was a lot of misinformation circulating, such as the idea that LSD will cause chromosome damage, insanity, suicide, acts of violence, homicidal behavior. There was also concern about LSD impacting fertility. There was no evidence that these claims were true
Hallucinogen use in the 1990s
Hallucinogen use started to make a comeback in 1990, although it had decreased throughout the 1980s. In 1996, 8.8% of high schoolers reported using LSD. Over time, interest in other hallucinogens grew and generally replaced LSD- in 2016, 4.3% of high schoolers reported using LSD
How long does LSD stay in the body?
For around 3 days after using it.
Hallucinogens mechanism of action
The mechanism seems to be related to the functions of serotonin- LSD, psilocybin, and several others have chemical structures that resemble serotonin. It is generally accepted that these hallucinogens are serotonin agonists. However, one problem with this theory is mescaline- much more closely resembles amphetamine. This is problematic because mescaline also produces vivid visual hallucinations. It also shows cross tolerance with LSD. High doses of cocaine and amphetamines can also produce hallucinations
LSD-like drugs work on which receptor?
Serotonin receptors (5-HT2A). Drugs in this class vary in potency, duration, etc. They include psilocybin and mescaline
Pharmacokinetics of LSD
LSD is the most potent hallucinogen- 25 micrograms can produce effects through oral administration. LSD is rapidly absorbed and effects are felt 20-60 minutes after consumption. The effects often persist 8-12 hours
Pharmacokinetics of psilocybin
Dosing is more difficult, but typically 5-10 grams are taken. The effects last 4-6 hours
Pharmacokinetics of mescaline
1/3000 as potent as LSD. It is normally taken orally (5-20 buttons). Duration is 10-14 hours
Johns Hopkins psilocybin clinical trials (2)
- Moderate doses with advanced stage cancer- causes reduction of anxiety and depression
- Benefits with alcohol and nicotine SUDs
Mechanisms of psychotherapeutic uses for psilocybin
Mechanisms are not well understood, and the drug needs to be administered by a therapist. Recreationally microdosing by people who are self medicating is not considered therapeutic use
Common parts of a trip (6)
- Vivid visual hallucinations
- Synesthesia
- Bizarre cognitive experiences
- Mood alterations
- Experiences of “magical” thinking
- Often long lasting, increases in sense of well being
Visual hallucinations on hallucinogens
Hallucinations are common with certain medical conditions, like migraines. However, they are among the most frequently reported experiences of people who take hallucinogens. People may see spiral explosions and vortex patterns
Synesthesia
The fusing of the senses- certain sounds or letters or numbers can have an associated color. This is sometimes experienced when someone takes a hallucinogen
What mood alterations can occur when someone takes hallucinogens?
Usually you have a good mood, but can be mad if you’re having a bad trip. This can also depend on the state of mind the person is in when they take the drug
What type of magical thinking do people experience on hallucinogens?
Insights and enlightenment. People may have experiences where individuals or animals talk to them. Some people can also experience frightening things- panic or paranoia, can increase risk of harm to self or others
What makes a bad trip more likely?
Being exposed to the drug without knowing it, like if someone consumes a substance or another drug laced with hallucinogens
Negative effects associated with LSD (2)
- Flashbacks
- Long term psychosis
Flashbacks on LSD
When a person reexperiences some portion of the trip that occurred much earlier- can occur weeks, months, or even years after consumption of the drug. This is usually a visual disturbance. It tends to be precipitated by a person feeling stressed or fatigued
Long term psychosis due to LSD
Doesn’t seem to be causally linked, but LSD may exacerbate other problems. It may interact with other drugs, or could make it more likely that predisposed people experience psychosis, or make the experience of psychosis more intense
Methylated amphetamines (3)
MDMA, MDA, and MDE
MDMA
Street name is molly. It is used as a club drug that also has psychotherapy benefits. Use increased throughout the 1990s. It is a methylated amphetamine that is more similar to amphetamine in its effects. It was legal until 1985, but is now a schedule 1 drug. Some scientists consider these drugs to be more like empathogens than hallucinogens- they increase empathy and positivity toward others
Effects of MDMA (5)
- Openness toward new experiences
- Warmth toward the people around you
- Mild euphoria
- Lack of defensiveness
- Produce sympathomimetic effects
People experience few if any visual hallucinations, but MDMA can be mixed with other drugs that can have additive or synergistic effects
Myths regarding MDMA
MDMA was one of the most popular drugs of abuse, and there were a lot of myths and urban legend. One prevalent myth is that MDMA will blow holes in your brain
Administration of MDMA
Usually taken orally- can be injected or snorted. It is absorbed rapidly and effects last 6-8 hours
MDMA impacts which neurotransmitters?
Increased release of the monoamines in general, but specifically serotonin. MDMA also blocks the reuptake of serotonin and dopamine (to a lesser extent)
Monoamine neurotransmitters (4)
- Norepinephrine
- Dopamine
- Serotonin
- Epinephrine- did not cover this one in class
Sympathomimetic effects of methylated amphetamines (5)
- Increased heart rate, blood pressure, pupil dilation, body temperature
- Increased muscle tension
- Teeth grinding (bruxism)
- Decreased appetite
- Insomnia
Reinforcing effects of MDMA
MDMA is more reinforcing than amphetamines- users prefer MDMA to other amphetamines. Additionally, in laboratory settings, mice exhibited more lever pressing with MDMA when compared to cocaine and other drugs like amphetamines. Humans also report a preference for MDMA
Residual/toxic effects of MDMA (3)
- Dehydration, heat stroke, heat exhaustion
- Muscle breakdown
- Kidney failure, stroke, seizures
Why do toxic effects of MDMA occur?
The effects can occur after relatively low doses- it is unclear if this is because of MDMA or other additives added to the pills. Also, these drugs can cause you to neglect paying attention to your own homeostasis. You also tend not to be concerned with maintaining homeostasis in a party setting. This may lead to dehydration and heat stroke
Impact of MDMA on the brain
After several administrations of MDMA, rats in one study exhibited depletion of serotonin. This is caused by degradation of serotonergic neuron terminals. The results have been replicated in many species, including primates. It has not been studied in humans. However, the studies used one large dose (20 mg/kg) or several small doses (5 mg/kg) over consecutive days- these are very high doses. Researchers have found that MDMA does seem to cause reductions in serotonergic function. However, there is some evidence that the system recovers after a period of abstinence
Psychotherapeutic uses of MDMA
MDMA was previously used for couples’ counseling, but it is no longer used in that manner. In clinical trials, MDMA is used in combination with therapy in PTSD patients. The openness felt because of the drug leads them to discuss things they normally would not. Mithoefer et al (2011, 2013) found therapeutic benefits at 2 year follow up- currently several ongoing phase 2 trials
How does MDMA work to treat PTSD?
Its allows people to “rewrite” the memory as they call it back into short term memory. This can start re-conditioning or restructuring your relationship with the traumatic experience
Dissociative anesthetic hallucinogens (2)
- PCP
- Ketamine
Phencyclidine (PCP)
A dissociative anesthetic hallucinogen that was discovered in 1956 and was initially used for its general tranquilizing effects. It left animals conscious- but not feeling pain. Used as a tranquilizer in veterinary practices. Can cause a hyperexcited, agitated state in humans. It emerged as street drug in the 1970s- in the 1980s, 20% of high school seniors had tried PCP. The use of PCP has dropped since the 80s as it was replaced with other drugs
Effects of PCP in humans (4)
- Hyperexcitability
- Delirium
- Visual disturbances
- Can still tranquilize pain
Ketamine
A dissociative anesthetic hallucinogen is often included among club drugs. It is smoked, injected, taken orally, or snorted. Hopfer et al (2006)- over 18% of clients are in treatment for substance use used ketamine, which makes it one of the most popular street drugs
Effects of PCP and ketamine in moderate doses (3)
A moderate dose would be 1-10 mg/kg.
1. Feelings of euphoria and numbness
2. General motor discoordination
3. Users may be catatonic or hyperactive
Effects of PCP and ketamine in large doses (3)
- Hallucinations
- Long term cognitive impairments
- Far more likely (compared to LSD) to create psychotic symptoms in people who are predisposed to psychosis
What kinds of hallucinations may be experienced with large doses of PCP or ketamine?
Include feelings that different body parts are shrinking or growing- this is described as the K-hole and can last for days or weeks. Additionally, people may experience paranoia and sometimes violence that can last for several days
Therapeutic uses for ketamine
Ketamine is used for treatment resistant depression- a single dose of ketamine may improve unrelenting depressive symptoms within minutes or hours when administered in a therapeutic setting. However, the effects don’t last long and may wear off after a few days-a week. A short time of relief of symptoms could still be beneficial, as it buys time for other drugs or psychotherapy to begin to work
