Week 8- LSD, Psilocybin, and MDMA

Question 1

What does the word Psychedelic derive from?

Answer 1

‘psyche’=soul/mind and ‘delos’=to make visible or clear, are defined in different ways

Question 2

Psychedelics are defined by lexico

Answer 2

relating to or denoting drugs that produce hallucinations* and apparent expansion of consciousness

These drugs induce profound subjective effects – vary widely

Question 3

How does the illegality of psychedelics effect how they are thought of?

Answer 3

-Due to worldwide illegality, they are often thought of negatively

-Legality also influences education – knowledge is not comparable to alcohol, nicotine, caffeine etc.
‘Niche’ knowledge or interest – Psychonauts (those who do explore the mind through use of psychedelics.

-Lack of education can feed into negative perception

Question 4

‘Psychedelic Renaissance’

Answer 4

• Effect of media = Netflix – Fantastic Fungi, How To Change Your Mind

-Many psychedelics are being investigated for their potential therapeutic properties

-Altered mental states may provide great insights into consciousness and the brain generally

Question 5

What does LSD stand for / alternative names

Answer 5

Lysergsäurediethylamid
acid
L
Lucy

Question 6

Is LSD found in nature?

Answer 6

nope

Question 7

Myths surrounding LSD

Answer 7

-OJ man
-Blue star (kids lick stick on tattoos gonna be exposed)

Question 8

LSD history + origin

Answer 8

-Lysergic acid (and many other alkaloids) are synthesized by Ergot – a group of fungi that grow on grains

-In the past, significant Ergotism (ergot poisoning, St. Anthony’s Fire). Major effects = dizziness, constriction of blood flow to limbs, convulsions, hallucinations, delusions

-Ergotism resulted in the Salem Witch Trials in which ‘witches’ were punished for its effects

Question 9

How is LSD synthesized?

Answer 9

-LSD is synthesized via combination of lysergic acid and diethylamine

-Using LSA (amide) from morning glory seeds

Question 10

When was LSD first synthesized?

Answer 10

-First synthesized by Swiss chemist Albert Hoffman (1938)

-Part of a Sandoz research program to find medically useful derivatives of ergot

Question 11

When was LSD returned to (after first synthesis in 1943)?

Answer 11

Returned to LSD in 1943:
- Apparent unintentional ingestion – strange feelings
-April 19th – Ingested 250μg
-Was escorted home by his assistant via bicycle

Question 12

When did LSD become widely used and for what?

Answer 12

Used widely for psychiatric illness from 1947 (Delysid)

Question 13

Flower power!

Answer 13

Late 60s, acid reigns supreme, hippy counter-culture is flourishing

Question 14

Response to flower power?

Answer 14

-LSD outlawed in 1966, classified as schedule 1 (high risk, no medical use)

-Officially the war on drugs starts in 1971

-Reduction in use as time went on, although LSD use continues “underground”. Influences in music are widespread, “psychedelic music”

Question 15

Psilocybin Mushrooms: names

Answer 15

-Shrooms
-Mushies

-4-phosphoryloxy-N,N-dimethyltryptamine (4-PO-DMT)

A prodrug for psilocin (4-HO-DMT)

Question 16

How long have Psilocybin mushrooms been used for? How do we know?

Answer 16

-Millenia

-Used worldwide today

-Various mythologies, religions as well as art and writings provide evidence for widespread use of mushrooms e.g. the mushroom people and statues

Language evidence: Monanacahuia (Aztec) – to “mushroom oneself” Teonanácatl – god mushroom

Question 17

Different types of mushrooms in NZ

Answer 17

-Psilocybe subaeruginosa “Subs”
-Psilocybe semilanceata “Liberty caps”
-Psilocybe weraroa

Question 18

LSD – Dosage and Form

Answer 18

-LSD is a crystal in pure form – often in liquid form

-Subjective effects can be felt at varying doses, usually >50μg

-100 - 150μg is a common dose, lower doses appear more common now than during the 60s

-Microdosing has also recently become popular

Question 19

Mushrooms – Dosage and form

Answer 19

-Mushrooms are digested either fresh or dried. When dried, mushrooms are often ground up

-Typical dose is 1-2 grams, 5+ grams known as a “heroic dose”

-0.5-2.0% of dried mushroom weight is psilocybin (the active ingredient)

Question 20

Is it easy to calculate a dose of mushrooms with high accuracy?

Answer 20

-Difference in active compounds per species

-Difference between individual mushrooms

-Difference within the mushroom parts (cap vs. stem)

-Only real way to dose accurately is through consumption of laboratory synthesized compounds

Question 21

LSD- Neurophysiology

Answer 21

-LSD binds to receptors within a crystal type structure and gets trapped there by a lid

-This explains why the experience of LSD lasts

-The lid moves occasionally to the side and the LSD can unbind and psychedelic experience is halted.

Question 22

Physiological effects

Answer 22

-SYstemic = increased temp

-Pupil dilation

-Mouth dryness

-High blood pressure

-Profuse sweating (not always)

-Increase heart rate

-Nusea = super common in early stages

-Muscles (numbness: weakness, tremors) : more just that you think this is the case rather than muscles actually getting weaker, number etc.

Question 23

Psychedelic effects

Answer 23

-Euphoria
-Tactile enhancement
-Visual perception changes (distortion of edges, flowing)
-Time distortion
-General stimulation
-Increase sense of humor

Question 24

Tolerance to LSD

Answer 24

Tolerance develops rapidly in humans. After a single use.

-Cross tolerance between LSD and psilocybin and mescaline. Not between LSD and amphetamine or THC.

-Tolerance appears to be mediated by downregulation of the 5-HT2A receptor.

Question 25

Is there withdrawal associated with LSD?

Answer 25

-No withdrawal.

-In fact often have afterglow where you feel better the next day although this has not been properly explored i.e could just be relative to stressor/ cognitive effort required to be on the drug?

Question 26

Toxicity of LSD

Answer 26

-No known lethal overdose directly related to LSD or mushrooms

-Toxicity can occur when taking various NBOMe

-Toxicity can occur when taking poisonous mushrooms by mistake

-Some cases of poisoning through consumption of other mushrooms (Galerina marginata)

Question 27

Cardiac Valvulopathy and LSD

Answer 27

-Some risks but still unclear

-If used regularly

-At sufficiently high doses

-5-HT2B mediated

Question 28

Bad trips on LSD

Answer 28

• acute panic, or psychosis-like episodes

-User can forget their subjective experience in caused by a drug – fear anxiety increases (just think they are going crazy)

-Can usually be talked down via comforting words and a change of environment

-Like essentially all drugs, can also precipitate psychosis in people with psychotic disorders

-However, ‘bad trips’ are often described as an overall beneficial experience i.e. learn from them. This can be true in some cases but also it’s important to remember not all experiences are good

Question 29

Hallucinogen Persisting Perception Disorder (HPPD)

Answer 29

-Often linked to accidental consumption of extremely high doses

-Not well understood, links with other disorders

-Can be transient (“flash back” or persistent)

-Can severely impact quality of life, but usually resolves (mixed treatment success)

Question 30

Why might it be difficult to measuring human performance under hallucinogens use?

Answer 30

-Inattention
-Impaired reaction time and intellectual performance
-Working memory deficits
-Other impairments in problem solving/cognitive functions

Question 31

Why might claims of improved creativity under psychedelic use be difficult to substantiate?

Answer 31

-Difficult to substantiate; does inspiration count?
-Are these improvements?

Question 32

Why is blinding an issue to psychedelic research?

Answer 32

-Pretty easy to tell when you are in the drug condition so blinding not really possible

-This makes it hard to control for placebo effects

Question 33

LSD and effects on neuroplastic mechanisms i.e. applications of administration

Answer 33

-Administration can impact neuroplastic mechanisms

-Can acutely enhance emotional empathy and sociality – implications for therapy (Dolder et al., 2016)

-LSD has seen previous success with treatment of tobacco and alcohol dependence – being trialled now!

-Current research generally suggests a role for LSD in treatment mental disorders

Question 34

Griffiths et al 2016

Answer 34

-Participants with life-threatening cancer and subsequent depression and anxiety

-1mg/70kg vs. 22mg/70kg oral psilocybin

-Improvements across multiple measures – clinician- and self-report

-Mystical-type psilocybin experience on session day mediated the effect of psilocybin dose on therapeutic outcomes

-The drug was given in comfy setting with a clinician carrying out talk therapy with the participant -> not muhc control surrounding the nature of this therapy.

Question 35

Roseman, Nutt & Carhart-Harri, 2018

Answer 35

-20 participants with treatment-resistant depression -> 2 psilocybin sessions – 10mg and 25mg

-Assessed 25mg experience with ASC questionnaire -> OBN = mystical-type, DED = challenging/anxiety

-Outcomes measured by Quick Inventory Depression Score (self-rated)

-Non-perceptual scores were the best predictors of long-term mental health outcomes

Question 36

Petri et al., 2014 (connectivity study)

Answer 36

Different functionally connectivity between a) no drug and b) psilocybin -> connectivity is massively increased in drug use condition

Question 37

Roseman, Nutt & Carhart-Harri, 2018 (Study with responders and non-responders)

Answer 37

-11 sub-dimensions of OBN, DED and VRS

-Responders (≥50% reduction in QIDS score) have a different experience profile to non-responders : Spiritual experience, blissful state, insightfulness higher with responders. Anxiety higher with non-responders.

-Links to “mysticism and healing”

Question 38

Moliner et al., 2013

Answer 38

-Psychedelics promote plasticity by directly binding to BDNF receptor TrkB

Question 39

Psilocybin- assisted treatment of alcohol use disorder

Answer 39

Psilocybin reduced the number of heavy drinking days over the 32 week period

Question 40

Microdosing of LSD: what are the proposed benefits?

Answer 40

Lots of purported benefit:
-Greater health motivations and lower anxiety + depression (vs. non-microdosers; Rootman et al., 2021)

-Greater mood and mental health at one month (vs. non-microdosers; Rootman et al., 2022)

-May be strong placebo (self-blinding; Szigeti et al., 2021 )

One trial out of Auckland – naturalistic:
-Healthy males, 10ug of LSD every third day for 6 weeks (vs. placebo)
-“While microdosing elicited transient increases in scales associated with mood-elevating effects, it was not sufficient to promote enduring changes to overall mood or cognition” (Murhphy et al., 2023)
-LSD group slept 24.3 minutes extra per night on the night after microdosing (Allen et al., 2023)

Question 41

Harm reduction for LSD + mushrooms

Answer 41

-Presumed LSD - “If it’s bitter, it’s a spitter!” – avoid NBOMe’s, which have a bitter taste (unlike LSD)

-Mushrooms – be careful with identification

-Set and setting are important! Right headspace, right environment

-Be careful when mixing with other drugs

-Look after your body

-Tell people you trust when you plan on tripping

Question 42

MDMA: chemical name

Answer 42

-3,4-methylenedioxymethamphetamine

Question 43

MDMA – History and Origin

Answer 43

-Traditionally synthesized from Sassafras oil

-Synthesized by Merck (1912) and patented in 1914

-Never developed or used until 1960
Prior to July 1985, some psychotherapists gave MDMA to patients because of the close relationship between patient and therapist it fostered

-Heavily involved in rave culture, particularly in Europe

-Made a Schedule 1 drug in 1986

-From the 90s onward, MDMA became the most widely used recreational amphetamine for young people

Question 44

MDMA - dosage and form

Answer 44

Sold in crystal/powder form in large quantities or in capsules, or by the pill
-Pills containing hugely varying amounts of MDMA
-Ecstasy Pills - MDMA sometimes, often not alone

Typical doses range between 50 – 150 mg
-CYP2D6 metabolism influence
-Isomers may matter, S- for Stimulant, R- for wieRd

Question 45

MDMA – Neurophysiology

Answer 45

-MDMA is an indirect serotonergic agonist – blocks serotonin transporter and therefore stops reuptake

-Also increases the release of NE and DA

Question 46

Other hormones invovled in MDMA effects

Answer 46

-Oxytocin – relevant, but importance debated (Bershad et al., 2016)

-Some suggest prolactin also important (Passie et al., 2005)

-Cortisol, ADH changes too (perhaps not so good)

Question 47

MDMA – Physiological Effects

Answer 47

-Increases in;
Wakefulness
Energy
Heart rate
Body temperature

-Pupil Dilation
-Vasoconstriction
-Jaw tightness

Question 48

MDMA – Subjective Effects

Answer 48

-MDMA produces intense feelings of physical and mental euphoria

-A standout effect of MDMA compared to other amphetamines – closeness to others, empathy, “love and connection”

-Effects are context dependent

Question 49

MDMA – Tolerance

Answer 49

MDMA induces rapid tolerance
-Therefore, it is not taken chronically*
-Some report “losing the magic”

Question 50

MDMA- withdrawal

Answer 50

-No physical dependence – no classical withdrawal

-May produce a post-use crash* – Comedown/Blue Monday/ Suicide Tuesday. Comedowns are real, but debated– potentially related to individual, behavioural and contextual factors

Question 51

MDMA – The Bad

Answer 51

-Famous experiment linked MDMA and neurotoxicity – redacted, researchers used methamphetamine instead of MDMA

-Some animal experiments that show significant neurotoxicity, have animals exposed to very large doses – in number and frequency

-Heavy users of MDMA have lower serotonin neuron markers in the brain:
-> Unclear if this observation is clinically relevant
-> Neurotoxicity/deficit literature is muddy and controversial

-May increase risk of serotonin-related damage in certain contexts (e.g., poorly ventilated club, summer festivals)

Question 52

Chronic use of MDMA associated with…

Answer 52

-Sleep issues

-Anxiety

-Impairments in attention and working memory – also observed in ex-users

Question 53

Chronic use of MDMA linked to depression? Issues with this?

Answer 53

-MDMA use associated with lower odds of lifetime major depressive episode (Jones and Nock, 2022)

-With all research on MDMA use – very rarely used in isolation; difficult to analyse factors involved in polydrug use/abuse

Question 54

Deaths associated with MDMA use

Answer 54

-Some deaths are associated with MDMA use:
-> Hyperthermia
-> Hyponatremia
-> Heart complications
-> Seizures

-A major contributor to “MDMA-related” deaths – other substances! Often, other drugs are in place of MDMA that are much more dangerous
-> Cathinones (“bath salts”)
-> PMA – results from processing of aniseed instead of sassafras – uptick linked to worldwide sassafras seizure
-> Alcohol = Increases risk of MDMA (physiological risk) and inhibits harm reduction behaviour (cognitive risk)

Question 55

MDMA effect on social behaviour (animals + humans)

Answer 55

-Increases prosocial behaviour and reduces aggression in lab animals =
Rats under influence of MDMA in cage with free animal. Free animal (sober) interacts more with the animal that is under the influence.

-Increases prosocial mood states and affiliative feelings in humans – also blunts responses to negative social stimuli (Kamilar-Britt & Bedi, 2015)

Question 56

What stage of clinical trials is MDMA use in for PTSD? What might be the possible mechanism for this?

Answer 56

-Currently in Stage III of clinical trials for severe PTSD
-> Breakthrough medicine classification
->Used as an adjunct to psychotherapy
-> Promising results for veterans and first responders

-Memory consolidation and fear extinction may underlie the benefits:
->Monoamine modulation of emotional memory
-> Also enhanced therapeutic alliance

Question 57

Mitchell et al., 2021

Answer 57

-Taking MDMA 3 times a month. First dose max= 120g. Then half for second dose. Can take up to 180g a month

-Two therapists alongside (male + female team)

-Large effect size in reducing PTSD symptoms/ remissions

Question 58

MDMA use in NZ

Answer 58

-MDMA social cost ~$139,000/kg (NZ Illicit Drug Harm Index; McFadden et al., 2022)

-Global annual prevalence = 0.4%

-NZ Health Survey (15+ y/o)
= 2020/21, 4.8%
= 2021/22, 4.3%

Question 59

Whelan et al, unpublished

Answer 59

-Survey of all people that used MDMA in last 5 years

-Interested in the consequences of use: both the positive and negative
–> positive consequences are clear for users (why they engage in the drug) but sometimes not always known by researchers/ wider society.

-Results = most disagreed that MDMA penalties should be harsher. Agreed that MDMA use could be done safely and know about drug checking organisations e.g. know your stuff (probs best to check the slide with the diagram as this is just some of the question responses).

Question 60

MDMA harm reduction

Answer 60

-Check your substance! – either yourself or KYSNZ

-Dose carefully – more is not better!

Look after your body:
-Only dose if feeling well
-Eat well before and after
-Rest/recuperate
-Magnesium and antioxidants may help

-Stay hydrated, but don’t drink too much (avoid excess alcohol)

-Take breaks to remain cool when in party settings