About Eric

This author has not yet filled in any details.
So far Eric has created 5 blog entries.

Supernanny (Season 5, Ep. 2): the Porter Family – Summary and Critique of Therapeutic Methods

Supernanny (Season 5, Ep. 2): the Porter Family

Quick Summary and Critique of Therapeutic Methods

by Eric M. Fortier, B.A.

Case Summary
The focus of this Supernanny episode is the Porter family. Madison, their nine year old daughter is depicted crying, screaming, disobeying and hitting her mother Haley repeatedly for being asked to follow basic orders. We see Haley inconsistently giving into Madison’s protests, increasing distress and likely re-inforcing her behavior as a means to get what she wants. What’s more, Madison’s brother Harry has learned some of her behavior, serving to further normalize it. This sometimes becomes so intolerable that Haley and Merryl lose their temper. This reciprocal influence greatly exacerbates familial conflict. Jo suggests that, as a result of the death of Haley’s infant son, she was overbearing with her new daughter Madison, which prolonged Madison’s infantile attachment. By interviewing her separately from her parents, Jo confirms that Madison feels like she has no independence. Merryl also works full time, leaving the bereaved Haley at home to parent Madison and Harry alone for most of the day.

Critique

Diagnosis
Based on limited evidence of Madison’s externalizing, overt, and destructive behaviors (like destroying a vacuum cleaner), diagnosing Madison as having a Oppositional Defiant Disorder may provide a useful framework for treating her problem behaviors. Madison meets more than the minimum 4 diagnostic criteria for ODD, as she often i. loses her temper; ii. is angry and resentful; iii. argues with authority figures or adults; iv. actively defies or refuses to comply with requests from authority figures or with the rules; v. deliberately annoys others; vi. has been spiteful or vindictive at least twice within the past 6 months; and vii. is associated with distress in the individuals or those around them. Upon careful study, no evidence suggests that the behaviours do not occur exclusively during the course of a psychotic, substance use, depressive or bipolar episode. Madison does not appear to meet the criteria for the more serious diagnosis of Conduct Disorder. It may be worth screening Madison for ADHD or intellectual disabilities, since they are considered risk factors for conduct problems, and Madison appears not to be meeting developmental milestones (as exhibited by a behaviors more reminiscent of a toddler than a normally developing nine year old). Based on the premise that doctors said Haley was unlikely to give birth again after the premature death of her first-born, some neuro-developmental component may be worth investigating.

Treatment
Jo implements standardized contemporary treatment strategies for conduct disorders to help Madison and the Porter family, including parent management training and problem-solving skills training. Using one-on-one real-time coaching, and by way of example, Jo teaches Haley and Merryl to respond consistently with conditioning contingencies for improving Madison’s compliance, such as by revoking privileges and plans and enforcing a dedicated room for reflection time, but also by using affection, praise and congratulations. Once Jo has established herself as an authoritative and trustworthy figure, she clearly and sternly explains to Madison why her behavior is not acceptable. Jo further implements a list of self-care and basic life-skills that normally developing children of Madison’s age can perform, which Haley had previously been doing for her, aimed at improving her and Haley’s sense of independence. Next, Jo shows Haley a few ways to bond with her daughter. Finally, she teaches Haley and Merryl a three-step process for managing anger, improving their relationship and setting an example for Madison.

A two-week follow-up depicts the Porter family genuinely pleased with the results of Supernanny’s intervention, although this brief commentary might benefit from a supplemental standardized questionnaire. “Life was pretty awful before… and it feels happier… It’s terrific. [Madison] feels so much better, and it was well-needed.” Haley continues by noting that Madison’s tantrums are “over and done with very quickly,” when they do occur. The multi-pronged standardized treatment approach, the early intervention, the positive bond Jo developed with the family, and the promising follow-up commentary, suggests that the behavioral changes may last.

Note: According to some online sources, Haley and Merryl got divorced a few years after the airing of the episode.

Supernanny (Season 5, Ep. 2): the Porter Family – Summary and Critique of Therapeutic Methods 2019-04-14T01:33:58+00:00

5HT2A Receptor Agonists & Mood Disorders – Mood, Empathy & Social Pain

Psychedelic 5HT2A Receptor Agonists – Enhanced Mood and Empathy and Reduced Social Pain in Healthy Humans: Implications for Mood Disorders


Psychedelic Science Conference Oakland, April 19-24, 2017


Franz X. Vollenweider

Psychiatric University Hospital Zürich, Department of Psychiatry, Psychotherapy and Psychosomatics

Center for Psychiatric Research, Neuropsychopharmacology and Brain Imagining Unit, Heffter Research Center Zürich


Note:

This indent is used to highlight study results.

Some of the slides skipped in the lecture are included.

Feel free to link full texts for the citations, and I’ll add them to the post.

Please let me know if you find any mistakes. These are my personal notes shared to benefit the community


PART 1: Phenomenology – concepts of Depression

Emotional regulation & social interaction

Mechanisms of action – neuroplasticity


PART 2: Scientific approach to Consciousness and Psychedelic States 3:25

  Subject   Object Object Object
Platonic ideas Subj. experience     Observ., measure  
  1st person Explanatory gap   3rd person  
Dualism Introspection <======> Behavior <======> Brain-Body-Env.
    Functionalism?      
Monism Self   Body responses   Molecular PET
  Thought   Emotional responses   EEG-ERP/TMS
  Emotion   Cognitive performance   fMRT
  Qualia       MEG

Intro (History) 5:40

Psycholytic/psychedelic therapy 1956-72

in combination with psychodynamic-based psychotherapy

Landmark studies find improvements in:

Treatment-resistant depression – 64%

Chronic anxiety – 56%

Alcoholics 46%

Leuner 1972, ’94 several moderate doses of psilocybin

Neurotic depression – 68%

Anxiety – 70%

Mascher 1967 meta-analysis of 42 studies mostly psychodynamic-oriented psychotherapy N=1603

depression in terminal cancer patients

Pahnke 1968

First to show remarkable reductions in anxiety & depression in terminal cancer patients over 6 months

Grob 2011 single dose of psilocybin

Anxiety – HADS from 15 to 5, seven weeks after dose 5:55

Ross 2016

Depression/anxiety over 6 months – GRID-HAMD (Depression), HAM-A (Anxiety) scales

Quality of life improvements – McGill QOL scale

  • mediated by intensity of ASC

V. asks: what’s the neural basis? How come a single dose?

Griffiths 2016

Treatment-resistant depression – 70% of patients after 3 weeks

Carhart-Harris 2016 single dose p.o.


Effects of psilocybin/LSD in mood disorders 7:25

Leuner theorizes that results occur due to alterations in the sense of self – loss of boundaries, reduced defense mechanisms

  • regression of self (selflessness – reduced ego-functioning – reduction of cognitive control)
  • activation of personally relevant emotion schemas (autobiographic memory) – Vollenweider says this is the best observation to make concepts
  • shift from secondary to primary mode of thinking including symbolic imagery – activation of personally relevant memories – associated with imagery or symbolic optical phenomena based on personal experience, life, perhaps archetypal.
    • combination of emotional activation combined with recollection of memory is cornerstone in this process
  • integration of recollected emotions into the self

PART 1


Symptoms and processes in depression – Neurophenomenal and neurocognitive approach 8:55

Adapted from Northoff, 2014

Widely used depression model:

At the core: the self – phenomenological space

Described as:

  • ownership
  • nowness
  • agency

Lots of neuroimaging research on brain networks enabling experience of the self

What happens:

Self-reference – negative loop bias on a meta level – triggered inside, not from the outside

Increased self-centeredness hallmark of depression

Impoverished social interaction. (V.: Important to research people around other people. Bring them outside scanner.)

Increased self focus, decreased environmental focus (psychopathological symptoms)

Generally, negative emotions, hopelessness, diffuse bodily reactions, anhedonia, rumination, suicidal thought, enhanced stress sensitivity


Resting state – eyes closed (introspection). 11:25

  • phenomena/symptoms of resting state
  • studying specific cognitive psychological domains:
  • Regulation of affective, cognitive , social, sensorimotor functions

vs External stimuli

  • Neurocognitive task-evoked processes/functions
  • emotional face processing, social interactions
  • memory, emotional tasks, etc.
  • future: interaction with environment. Set & setting rarely examined in normal drug research. Emerging from psychedelic research

Goal: Towards a stratified medicine in psychedelic research 12:55

FDA 2013, Paving the way for the personalized medicine: FDA’s role in a new era of medical product development:

  • Stratified medicine: matching therapies with specific patient population characteristics using clinical biomarkers.
  • Precision medicine: integration of molecular research with clinical data from individual patients to develop a more accurate molecular taxonomy of diseases that enhances diagnosis and treatment and tailors disease management to the individual characteristic of each patient.
  • P4 medicine: clinical application of the tools and strategies o systems biology and medicine to quantify wellness and demystify disease for the well-being of an individual
  • Personalized medicine: genomics+medical information technology+patient empowerment

Simple depression model: negative processing bias in 13:45

  • attention
  • thought processing
  • memory

Quick overview of experimental process of looking at symptoms, biomarkers, etc. 14:10

[very brief, framing research for FDA regulations above]

Increased openness after 6 months

Griffiths, 2011


Typical model of emotional regulation in depression 15:10

After Disner et al., 2011 NNR and Dima et al., 2011)

Frontal cortex loses top-down control over negative stimuli (e.g. faces or words)

dlPFC-amygdala activity > connectivity

  • left dlPFC less active than controls
  • amygdala more active than controls

PART 2


Results: Conscious and non-conscious emotional face processing 16:10

0.175mg/kg psilocybin / 0.06mg/kg/min s-ketamin vs Placebo, N=20 healthy volunteers

Electrophysiological and behavioral experiment 16:30

[EEG?]

Psilocybin:

  • reduces response to fearful/anxiety inducing faces
  • does not affect response to neutral or positive/happy faces
  • reduced response to fear only occurs at conscious level (after long exposure, recognition)

vs Ketamine:

  • reduces response to fearful/anxious inducing faces
  • reduces response to positive/happy faces
  • maybe even reduce response to neutral faces
  • reduced response begins at non-conscious level (when presented very fast)
  • [anesthesia – reduced all around sensation]

Schmidt et al., 2012

N170 ERP signal – relative shift of emotional bias toward positive stimuli with psilocybin 17:45


Modulation of BOLD response during processing of emotional visual stimuli (IAPS) 17:55

Psilocybin (fMRT)

0.175mg/kg psilocybin (~15mg) vs Placebo, N= 25 healthy males

Found decreased amygdala activity with psilocybin paralleled with acute symptoms

V. asks: 2A receptor? or top-down control via PFC and Glu?


Fronto-Cingulate-Amygdala interaction in Depression 18:45

Less top-down dlPFC/dACC control over amygdala

See Pizzagalli NPP 2011

Resting state measures with psilocybin:

Increased dlPFC/dACC activity correlates with decreased amygdala activity

Vollenweider & Kometer, Nature Rev. Neurosci., 2010


Psilocybin: Role of 5HT2A in emotional face or word recognition 19:20

Reading mind through the eyes. Present faces: is it anxious, surprise, anger, hate, etc.?

Emotional word recognition (P300 ERP signal)

Psilocybin:

  • enhances recognition of positive emotions
  • reduces recognition of negative emotions

Kometer et al., Biol. Psych. 2013


Psilocybin and social interaction 20:20

Katherine Preller:

Psilocybin – good for examining 5-HT2A/1A system in social cognition

LSD incraeses glutamate release (PFC) in animals (Muschamp et al., 2004)

5-HT & Glu systems may be promising targets for pharmacological modulation of social cognition

e.g., Crockett et al., 2010

 

Study on social cognition 20:35

Psilocybin 0.22mg/kg, p.o.) vs Placebo

N=32 ~ages 22-32

ASL, fMRI – Social exclusion (cyberball game) – 60min post-dose

MRS – 90min

  • spectroscopy
  • glutamate release
  • aspartate
  • GABA release

in parallel with activation pattern

Questionnaires – 130min

Behavioral testing – Empathy (MET), Moral Decision Making (MDT) – 160min

Questionnaires – 300min

 

Social exclusion task – cyberball game 21:10

Social exclusion pain activation same as physical pain

dACC

  • social pain (Eisenberger, Science, 2003)
  • social distress, (Eisenberger SCAN 2015)
  • emotion appraisal, expression (Shackman 2011)

Borderline personality disorder patients – increased reaction to pain in mPFC/dACC, precuneus & occipital lobe

Domsalla, SCAN, 2013

Less social exclusion pain with psilocybin (neural response and subjective report) 21:50

Correlates with experience of unity and feeling of being connecting with others

fMRT: ACC BOLD activity reduced

MRSpectroscopy: ACC Aspartate increases correlates with BOLD activity change

(V.: GLU and aspartate are generally “coupled in a shunt biochemical function. We expected glutamate, but we found aspartate. Now we have to understand that a little better.”)

Preller et al., PNAS, 2016


Psilocybin: Multifaceted Empathy Task (MET) 23:00

Empathy-related processes thought to motivate prosocial behavior, caring for others, and to inhibit aggression

Depressed patients: decreased empathy

Psilocybin:

Increased explicit/implicit emotional empathy (EEE & EEI) correlates with changed meaning of percepts

  • e.g. going into someone, part of their feeling, and really interact

No effect on cognitive empathy (CE)

  • e.g. seeing picture, thinking “how does this person feel?”

Pokorny et al., Neuropsychopharmacology, in press


Impact of mindfulness expertise on acute psilocybin-induced states and long-term changes in quality of life measures 24:00

Core processes of mindfulness training:

  • emotional flexibility
  • attention
  • cognitive flexibility

leads to:

  • non-judgmental awareness

and finally:

  • acting with awareness, flexibility, and autonomy
  • physical & mental wellbeing

Tripping ZEN Buddhists fantastic 25:15

Mindfullness expertise and psilocybin: state and long-term changes 25:30

Psilocybin/placebo, n=30/30; 6 groups with 5/5 double-blind

Zen monks > 5000 hours meditation, 20 years, most from same Zen school

Trained in retreat, do not speak, do mantras according to teacher, practice in silence

Meditation depth measured every evening, state acquired over 8 hours meditation

Measures before:

  • Absorption (TAS)
  • lifetime mystical experience
  • cognitive control/emotional regulation (strategy):(dlPFC) “expressive suppression,” “cognitive reappraisal.”
  • Emotion regulation (FMI): (vmPFC, amy, hipp):Exposing to whatever is present in the field of awareness, letting oneself be affected by it, refraining from internal reactivityMindful presence, non-judgmental acceptance(vmPFC, amy, hipp)

Measures during:

  • fMRI/DTI (4 retreats – pre/post)
  • EEG (2 retreats)
  • 5D-ASC
  • Mystical Experience Scale
  • Mindfulness (TMS): curiosity (inner awareness), decentring (openness)
  • Meditation depth (MTF) TOT Score (relaxation, self transcendence)

Followup after 3 & 6 months, control with rating scales: Life Changes Inventory Revised and Persisting Effects Questionnaire by Griffiths

 

Tremendous effect on Unity, spiritual experience, blissful state, etc.


Predictors of acute ASC dimensions 26:50

  • absorption
  • lifetime mystical experience
  • emotion regulation (mindful presence, non-judgmental acceptance)
  • meditation depth (training over 3 days)
  • TOT score (relaxation, self transcendence)

Oceanic boundlessness/selflessness:

  • Meditation-depth over 3 years,
  • Life time mysticism

Visions:

  • Meditation-depth,
  • TAS

Anxious ego-dissolution:

  • acceptance

Placebo group could not achieve much oceanic boundlessness with their meditation.

29:10

Dramatic difference with psilocybin. Second best predictor was emotional acceptance.

 

Acute ASC predictors of long-term wellbeing 30:00

Hood’s Mystical rating scale with introvertive & extrovertive mysticism and interpretation

  • Sacredness (interpretation)
  • Positive affect (interpretation)
  • Unity (extrovertive mysticism)

The rest were not that related, like ineffability, ego loss, timelessness surprisingly it was mostly to do with the interpretive dimensions.

Very interesting because interpretation = meaning making.

So interpretive dimension tremendously important for long term wellbeing.

[see Validation of the revised Mystical Experience Questionnaire in experimental sessions with psilocybin (link) for new discussion]

Measures of wellbeing used:

  • autonomy
  • environmental mastery
  • personal growth
  • positive relations
  • purpose in life
  • self-acceptance

 

Predictors of ASC Dimensions 31:20

  OB AED VR
Emotional lability   +  
Rigid conventionality   +  
Optimistic extroversion +   +
High aesthetic sensibility +   +
Non-dogmatic religiosity +    
Optimistic naivety ?    
Desactivity +   +
Previous experience +    
Setting ? ?  
Dose + ++ +

OB=Oceanic boundlessness, AED=Anxious ego dissolution, VR=Visionary restructuralization

[Note: OB and AED are the same thing experienced positively vs negatively]

Dittrich, 1998; Studerus et al., 2010


Self dissolution – Oceanic Boundlessness and functional connectivity (H20-PET/MRT) 31:22

NCC Self/other & self referential processing:

Remembering, prospection, thoeory of mind, MTL network

  • Medial PFC – Post CC

Bruckner, 2008; Northoff, 2011

Vollenweider et al., 2016, in prep: [please PM me if you find this study]:

Decreased connectivity

  • ACC-PCC

Increased connectivity

  • midThal/glob. pallidus-fusiform Cx.-occipital Cx.-cuneus
  • caudate-amy-hipp-ACC-insula-orbitofront. Cx.

Carhart-Harris, 2015 (rsMRT Conn.):

Decreased connectivity

  • ACC-PCC,
  • ACC-pariet. Cx,

Increased entropy

  • hipp

Tagliazuchi et al., 2014::

Increased BOLD variability

  • hipp
  • ACC

 

Effective connectivity between CSTC-regions of interest 31:23

Resting state -DCM (dynamic causal modelling)

LSD vs LSD+ketanserin vs placebo, n=30 healthy subjects

Sensory information processing – gating

  • thalamus (Thal; gate to consciousness)
  • ventral striatum (VS)
  • posterior cingulate cortext (PCC; self)
  • temporal cortex (Temp Cx.; self)

LSD

Overall:

Increases connectivity from Thal to cortical areas via 5-HT2AR

Decreases connectivity from VS to Thal likely through D2R.

Increased (Specific):

  • effective connectivity from Thalamus to PCC (2A)
  • effective connectivity from PCC to VS (D2)
  • increased inhibition of temporal cortex (2A)

Decreased Specific (Specific):

  • reciprocal connectivity between PCC to Thalamus (2A)
  • effective connectivity from VS to Thal and PCC (D2)
  • effective connectivity from Thal to Temp Cx. (D2)
  • reduced inhibition of PCC (D2)

2A: Serotonin-2A mediated blocked by ketanserin, D2: Dopamine-D2 mediated not blocked by ketanserin

First evidence LSD alters CSTC connectivity in sensory and sensorimotor info. gating to the cortex.

Preller, Friston, Zeidman, Vollenweider, 2017, in press


See Dynamic causal modelling revisited for an approach to resolve complications between hemodynamic and neuronal activity by fusing fMRI and EEG

Related: Enhanced repertoire of brain dynamical states during the psychedelic state


Mechanisms of action and novel Analogs 31:25

Psilocybin, DMT, LSD

Mostly 5-HT2A, which also leads to

Glu release —

-> 5-HT2A-mGluR2 —> modulatory effects of mGluR2 activity? [note: Nichols doesn’t think so according to Q&A]

-> AMPA —> BDNF —> triggers neuroplasticity (may be responsible for changes after 6 months)

-> NMDA —> Learning, memory

5-HT2A —

-> increased pyramidal cell activity

-> increased GABAergic activity

-> increased Dopaminergic activity

 

Possible mechanism of neuroplastic effects of Psilocybin/Psilocin 32:18

1 – Psilocybin

  • increases Glu in PFC (e.g. ACC)
  • LSD and Psilocybin increase BDNF in rat pyramidal neurons

Vollenweider & Kometer, Nature Rev. Neurosci., 2010

2 – 5-HT2A agonists, e.g. Psilocybin,

  • facilitate extinction of fear memory (indexed as freezing)
  • and activate neurogenesis in hippocampus

Zhang et al., 2015

3 – 5-HT2A agonists (e.g. DOI)

  • facilitates NMDA mediated thalamocortical associative learning
    • associative memory
    • thalamofrontal connectivity
    • increase of AMPA mediated mEPSCs

Barre et al., PNAS, 2016

V.: “with associative learning, new experiences in psychedelic state get processed by brain systems responsible for making connections between the experience and your memory, so it’s not just lost.”


Summary: 33:45

  • Participants felt less excluded in psilocybin condition vs placebo
  • other behavioral parameters were not affected
  • psilocybin reduced social pain signal in ACC
  • psilocybin significantly increase explicit and implicit emotional empathy

2A/1A receptors

  • may play an important role in the modulation of socio-cognitive functioning
  • may be relevant for the treatment of disturbances in social cognition in psychiatric disorders
  • may be important for the normalization of empathy deficits and increased negative reaction to social exclusion in patients

Citations needed

Leuner 1972, ’94 – several moderate doses of psilocybin
Mascher 1967 – meta-analysis of 42 studies – mostly psychodynamic-oriented psychotherapy – N=1603
Pahnke 1968
Northoff, 2014
After Disner et al., 2011 NNR and Dima et al., 2011)
See Pizzagalli NPP 2011
Kometer et al., Biol. Psych. 2013
Crockett et al., 2010
Domsalla, SCAN, 2013
Preller et al., PNAS, 2016
Bruckner, 2008; Northoff, 2011
Dittrich, 1998; Studerus et al., 2010
Pokorny et al., Neuropsychopharmacology, in press
Barre et al., PNAS, 2016

References

5HT2A Receptor Agonists & Mood Disorders – Mood, Empathy & Social Pain 2019-03-25T20:23:16+00:00

Varieties of Fear and Loathing

A little while ago in /r/AskDrugNerds, I made a post, Looking for a humorous quote that involved an impressively long list of the effects of psychedelics:

It may have been the beginning of a chapter.

It’s one big paragraph, talks about how it’s difficult to characterize its effects, and uses the ridiculously long list as an example of why it’s not an easy thing to do. It had a combined counterculture and scholarly feel. Alan Watts comes to mind, but I don’t think it’s him.

… Anyone?

At first, /u/MusicPsychFitness quoted the timeless Fear and Loathing suitcase inventory check, and /u/schizorobo

added a gem from the same book:

“Look outside,” I said. “Why?” “There’s a big… machine in the sky,… some kind of electric snake… coming straight at us.” “Shoot it,” said my attorney. “Not yet,” I said. “I want to study its habits.”

Out of love, I searched this quotation and found the shimmering lines that preceded it:

“The only problem now was a gigantic neon sign outside the window, blocking our view of the mountains — millions of colored balls running around a very complicated track, strange symbols & filigree, giving off a loud hum….”

Fantastic. But not the words I’m looking for.

This morning I was reading my copy of The Varieties of Psychedelic Experience by Masters and Houston, and found it:

Even the briefest summation of the psychological effects of these drugs would have to include the following: Changes in visual, auditory, tactile, olfactory, gustatory, and kinesthetic perception; changes in experiencing time and space; changes in the rate and content of thought; body image changes; hallucinations; vivid images eidetic images seen with the eyes closed; greatly heightened awareness of color; abrupt and frequent mood and affect changes; heightened suggestibility; enhanced recall or memory; depersonalization and ego dissolution; dual, multiple, and fragmentized consciousness; seeming awareness of internal organs and processes of the body; upsurge of unconscious materials; enhanced awareness of linguistic nuances; increased sensitivity to nonverbal cues; sense of capacity to communicate much better by nonverbal means, sometimes including the telepathic; feelings of empathy; regression and “primitivization”; apparently heightened capacity for concentration; magnification of character traits and psychodynamic processes; an apparent nakedness of psycho-dynamic processes that makes evident the interaction of ideation, emotion, and perception with one another and with inferred unconscious processes; concern with philosophical, cosmological, and religious questions; and, in general, apprehension of a world that has slipped the chains of normal categorical ordering, leading to an intensified interest in self and world and also to a range of responses moving from extremes of anxiety to extremes of pleasure. These are not the only effects of the psychedelic drugs, but the listing should suffice to convey some idea of the potency of the drugs and the range of the experiences they afford.

-Ch.1, p.5 in Park Street Press softcover (2000 edition)

I’ve been looking for this quotation because it illustrates in empirical terms how difficult it is to talk about the psychedelic eye in five or ten seconds. It can’t be done in two minutes; it can’t be done in an hour. That is the feeling, the burden, the tragic severance with all those lost to the restless temptation of insta-gramification. Without sustained attention most people will never know the beauty of it all–there is no easy way to talk about the brilliant breadth, experiential richness and spectacular meaning that characterize the use of these drugs–particularly in the vile face of hysteria they excite in people today.

Just wanted to share this and update for those left wondering what it is I was looking for.

-syn

Varieties of Fear and Loathing 2019-04-09T19:50:19+00:00

D. W. Woolley, the Serotonin Hypothesis and the Genesis of Psychopharmacology

D. W. Woolley, the Serotonin Hypothesis and the Genesis of Psychopharmacology

by Eric M. Fortier, B.A. | 2018

D. W. Woolley (source: Whitaker-Azmitia, 1999)

Dilworth Wayne Woolley was a Canadian-born biochemist with an impressive interdisciplinary expertise in chemistry, psychiatry and pharmacology (Hewitt, 2016). Woolley was an outstanding student. He graduated high school at the age of thirteen, published his first paper at seventeen, and graduated with honors from the University of Alberta, where he obtained an undergraduate degree in chemistry, by age nineteen. He completed his PhD at the University of Wisconsin in 1939 (Miller, 1941). He then joined the Rockefeller institute for Medical research, which according to Wild and Hildebrand (2014) was “a unique gathering place for elite biochemical and medical researchers, who are free to pursue virtually any avenue of inquiry they wish.” Woolley was a proficient writer with a serious dedication to biochemistry research, handing in twenty of his own peer-reviewed papers instead of a traditional thesis. He published 232 articles in his career, over 80 percent of which he is the sole or senior author (Wild and Hildebrand, 2014).

During his stay at the University of Wisconsin, he worked with Conrad Elvehjem, studying nicotinic acid for canine black-tongue with implications for human pellagra. While investigating cases of pellagra, he recognized that a staple food of Southern United States at the time was corn, and he found that an ingredient in corn was preventing absorption of niacin. That is, something was acting as an antimetabolite—work out of which was born A Study of Antimetabolites (1952). This research was soon investigated by two Canadian psychiatrists, Humphrey Osmond and Abraham Hoffer, who found that niacin (vitamin B3) could cure symptoms of pellagra-induced psychosis, which at the time accounted for the majority of psychiatric hospitalizations. The influence of biochemistry on mental illness and altered states of consciousness intrigued Woolley; he was becoming increasingly interested in the link between psychology and biology, and strove to integrate the two. So with the help of his understanding of antimetabolites, he eventually developed the serotonin hypothesis of schizophrenia.

Origins
It is important to root Woolley’s contributions in the somewhat mysterious historical context from which they emerged. The term schizophrenia (Greek for ‘split mind.’) was initially coined by Swiss Psychiatrist Eugene Bleuler in 1911, who was the first to conceptualize it as a metabolic disorder. This was much to the opposition of Freud’s theories at the time (who he closely studied) which he felt were too dogmatic in their focus on the impact of childhood experience and psychodynamics, and were inadequate for understanding mental illness.

Modern research on mental illness based in biochemistry largely emerged from observations involving exogenous psychoactive substances, with a special interest in hallucinogens around the turn of the 20th century. One of the first systematic studies with hashish (a concentrated form of cannabis) on normal and mentally ill individuals was conducted and published in 1845 by French Psychiatrist Jacques-Joseph Moreau. Also known as Moreau de Tours, he was member of the Club des Hashischins: a Paris club of scientists, artists, and writers who were keen on exploring strange, exalting, and often hidden realms of the mind with the help of drug-induced altered states of consciousness. The results of Moreau’s controlled experiments on patients, and on himself and colleagues, led him to believe orally ingested hashish may simulate mental illness, yet paradoxically treat it by revealing its origins through introspection and observation. This work was published as Du hachisch et de l’aliénation mentale: études psychologiques. Moreau was the first psychiatrist with an interest in psychopharmacology (Holmstedt, 1973), and this was the first book about a drug written by a scientist.

Shortly after the publication of Du hachisch et de l’alienation mentale, mescaline (the psychoactive ingredient of the south-American sacrament, peyote) entered the Western world and began to make its way through elite intellectual circles, somewhat also popularized by the Hashischins and their contemporaries. The effects were sometimes compared to mental and behavioral aspects of the acute schizophrenic state, and physicians and psychiatrists began to use it as a working model for psychosis.

In 1952, Osmond and Smythies discovered that compounds structurally similar to mescaline (putative endogenous compounds they called ‘Substance M’) could be produced by altering the human catecholamine metabolism, and proposed the transmethylation/catecholamine hypothesis of schizophrenia. This was presented as evidence that hallucination and psychosis were a result of faulty biochemistry.

Osmond and Smythies’ research emphasized that fantastical or otherwise hallucinatory accounts described by mental patients were not merely stories of make-believe as was often thought at the time, but appeared to the patient as real, undeniable, somatic and visceral experiences which could be elicited on demand using a hallucinogen. ‘Substance M’ was never found (Gillin et al., 1978). But this hypothesis served as a foundation for understanding the involvement of biochemistry in mental disease.

For the first half of the 20th century, much of mental illness was blamed on bad parenting–things like “refrigerator mothers” who were emotionally unavailable to their children (Nichols, 2013). Freudian theories and psychodynamics were often used to explain mental illness and split-mind phenomena, and handling severe cases mostly involved relatively dangerous approaches including insulin treatment, electro-convulsive therapy, lobotomy, and eventually tranquilizers and Thorazine (Hewitt, 2016). However, it was not well understood why these treatments worked and they were not based on empirical theories of the origins of mental illness. At the time, most scientists believed that biochemistry only affected the peripheral, and not the central, nervous system (Whitaker-Azmitia, 1999).

But the view that biochemistry had no stake in the brain was soon to change after a series of discoveries about serotonin in the early 1950s. Prior to this, serotonin was thought only to be involved in the periphery, acting on smooth muscle in the gastrointestinal tract and vascular systems. Once Maurice Rapport identified serotonin’s chemical structure as an indole in 1949, and Betty Twarog and Irvin Page discovered serotonin in the brain in 1953, it was proposed as a neurotransmitter. But neurochemistry was still considered a fringe discipline at the time.

It was around this time that Woolley recognized LSD’s indole structure, and imagined it could act as an antimetabolite of serotonin. He synthesized structural intermediaries between LSD and 5HT and demonstrated that all of them acted as antimetabolites of serotonin, and found behavioral effects in animals. Adding to this Twarog and Page’s discovery of serotonin in the brain along with the fact that these compounds produced mental disturbances similar to those of mescaline, Woolley proposed that low brain serotonin might play a role in the origins of schizophrenia (Woolley and Shaw, 1954).

The Biochemical Bases of Psychoses (1962), Ch. 6, p.133.

A New Era
The serotonin hypothesis of mental disease was the first scientific application of the antimetabolite hypothesis in psychopharmacology and psychiatry, and most importantly, was the first formal hypothesis involving brain chemistry in mental illness and behavior (Nichols, 2013). David Nichols, pharmacologist and medical chemist from Purdue University states, “The idea that disturbances in brain chemistry might be important to behavior was profound, and began to revolutionize thinking about the brain, and neuroscience in general.” The same hypothesis was simultaneously put forward independently by Gaddum (1953), but Woolley’s work was meticulously detailed and explained the involvement of  serotonin specifically in schizophrenia, so he received most of the credit (Cozzi, 2013; Nichols, 2013; Wild and Hildebrand, 2014; Hewitt, 2016).

However, soon after this initial hypothesis, Woolley and Shaw began to see the complexity of the serotonin problem. Studies showed mixed results and it was now uncertain whether LSD inhibited or stimulated the serotonergic system (Shaw and Woolley, 1956; Baumeiseter and Hawkins, 2004). It was later found that serotonin produced a combination of inhibition and excitation of the system at various parts in the body and brain.

Finally, based on the findings that antipsychotics (like reserpine and chlorpromazine) and monoamine-oxidase inhibitors (MAOIs) decreased serotonin levels, combined with the finding that psychotomimetic substances were antimetabolites of serotonin, Woolley proposed his hypothesis in further detail–namely, that bipolar psychosis could be explained by high serotonin levels being associated with psychotic excitement and low levels with symptoms of depression–in his 1962 book, The Biochemical Bases of Psychoses–or the Serotonin Hypothesis of Mental Disease.

He further believed serotonin played a role in brain development because of its resemblance to auxin (a plant hormone that orients and stimulates its growth toward sources of energy) and was the first to propose that serotonin dysfunctions interfered with learning and memory.

Woolley’s work contributed to the shift from a view of the brain and central nervous system as primarily electrical to a brain deeply controlled by chemistry (Hewitt, 2016). This contributed significantly to the credibility of neurochemistry. His theories about serotonin, along with his pioneering research in antimetabolites, greatly demystified the function of metabolic mechanisms, paving new avenues for drug development.

Perhaps the most impressive thing about Woolley is that he acted as the head of the biochemistry department at Rockefeller, conducted and published his research (including his two monographs on antimetabolites and serotonin), and delivered university lectures, after going entirely blind from diabetes-related complications.

He stayed up to date on research by having others read it aloud to him, and was able to lecture and write on the blackboard clearly–taking pride in knowing that most people could not even tell he was blind. He had keen spatial abilities—demonstrated when he calmly led colleagues at Rockefeller out of the building after a power-outage. Naturally, he worked with the lights off late into the night—to the astonishment of colleagues who found him working in complete darkness. Despite his blindness, Woolley’s colleagues often credited his brilliance to his knack for “seeing things” with his mind, and finding meaning in isolated and diverse facts (Whitaker-Azmitia, 1999).

Joel Elkes and Avrid Carlsson used Woolley’s research to further popularize the idea that the brain did in fact have neurotransmitters that influenced mental states and behavior, and this lead to the development of antipsychotics and new drugs that control neurotransmitters. Biochemist Bernard Brodie’s discovery that reserpine (a tranquilizer) decreased serotonin levels in the animal brain further confirmed Woolley’s hypothesis, and led to the dopamine hypothesis of schizophrenia, and the development of tricyclic antidepressants (Baumeister and Hawkins, 2004; Hewitt, 2016). Eventually Prozac (fluoxetine, a selective serotonin reuptake inhibitor) was developed and praised as a wonder drug for relieving symptoms of depression and marketed as an agent of personality change. This set the stage for the development of modern SSRIs. Nicholas Cozzi, director of Neuropharmacology Lab at the University of Wisconsin, states, “[p]resent-day research into neurotransmitters and drugs that affect their function in the brain is directly traceable to the experiments and writings of scientists investigating the mechanisms of action of LSD, DMT, and other psychedelic compounds” (Cozzi, 2013). He further emphasizes how these discoveries were among the most lucrative to the pharmaceutical industry, adding that despite the controversy, they have indeed helped out countless people.

The neurochemical paradigm played a large role in disintegrating stigma associated with mental illness–relieving parents of blame–but is often itself blamed for robbing the patient of dignified agency and dismissing important personal history and context (Hewitt, 2016).

Experimental psychosis?
The role of classical psychedelics as providing model psychoses was questioned as time went on. Experiences varied so widely that it was becoming increasingly difficult to characterize its effects, let alone use it as a model psychosis. With time, it became apparent that experiences under the effects of hallucinogens were heavily influenced by the set and setting.

For example, Walter Pahnke’s 1962 Good Friday Experiment found that Harvard divinity graduates given psilocybin (another serotonergic psychedelic) for a sermon at Marsh Chapel had mystical/religious experiences of unity rather than psychotic-type experiences of frightening mental splitting. The spiritual mind set of the participants and the religious setting heavily influenced the experience to be positive and valued among the single, or top five most meaningful events of their lives. It was eventually found that anxiety and distress experienced prior to and during psychedelic sessions predict difficult and frightening experiences (Carbonaro, 2016), and produce what is called anxious ego dissolution comparable to splitting of the mind, as opposed to oceanic boundlessness, comparable to religious experience.

Marsch Chapel (image credit www.hiddensacredspaces.org)

The often sterile, clinical environment under the scrutiny of researchers imposed by the experiment and the intensification of emotions caused by the drug would greatly amplify the emotional and psychological impact of every minute interaction between subject and researcher. In these strict clinical conditions, this often resulted in a paranoia, distrust in experimenters and an intense sense of dehumanization due to their treatment as simple “subjects” rather than fully living, breathing humans with rich mental worlds often impossible to verbalize, experiencing frightening visual and mental experiences–while others in less clinical contexts often experienced wonderful sense of meaning, mental unity, and dissolution of boundaries between the self and the world, accompanied by lavish, beautiful imagery, and dubbed them invigorating, life-saving blessings. The profound effect of set and setting on positive and negative acute and enduring effects of psychedelics is now much better understood using environmental predictors and psychometric scales such as the Altered States of Consciousness rating scale (Studerus et al., 2010). With such a scale, researchers can predict the degree and likelihood of positive and enduring outcomes depending the degree of ego dissolution experienced positively (oceanic boundlessness) or negatively (anxious ego dissolution).

Hartogsohn (2017) explains that the idea of set and setting can be traced back as far as ancient religion, in which the (loosely defined) shaman set up a specific set of rituals, chants, symbols and acts for a particular purpose and individual in their sociocultural context. Furthermore, Moreau actually made explicit note of the importance of set and setting in his experiments, in which for the hachisch eater, “a word, a gesture, a look, a sound or the slightest noise, by demanding his attention, will confer a special character on his illusions.”

Holy, holy, all–the irony
So as with Moreau’s insights on mental illness, gleamed from his studies in hashish and mental alienation, serotonergic psychedelics—once thought to produce mental illness–are now being used to treat it. New research on terminally-ill cancer patients with existential distress shows great promise for psychedelics with concomitant psychotherapy as one-time treatments for alleviating depression and anxiety, re-introducing a sense of meaning, and improving quality of life and personal relationships (Griffiths et al., 2016). This research has also been conducted on healthy participants with similar benefits. Recent research identifies one of the main effects of psychedelics as an amplification of meaningful thought content, which accordingly has become one of the core focuses of NYU’s psilocybin-assisted psychotherapy trials.

Psychosis and mania are characterized in part by an over-ascription of meaning, and depression with a lack of meaning, consistent with Woolley’s work on the hyper- and hypo-serotonergic effects on bipolar psychosis. The importance of set and setting in defining the character and content of the experience emphasizes the need for a more comprehensive understanding of the personal mind set, history, environment, and therapeutic paradigm which are being used to treat mental illness. This is in line with the modern humanistic approach to mental illness.

The new understanding of serotonin in the brain and the mental effects of psychedelics led to a resurgence of interest in questions of consciousness and the relationship between the mind and body (Hewitt, 2016). The current standard of treatment for depression and anxiety involving (especially serotonergic) medication recommends concomitant therapy such as psychodynamic psychotherapy. Prior to 1964 psychotherapists had used psychedelics as catalytic tools, by combining them with psychotherapy they could accomplish in an afternoon what otherwise could have taken years. Despite these findings, many are prescribed SSRIs and similar medication without psychotherapeutic treatment. This mis-prescription has been considered a symptom of the over-medicalization of mental illness, ironically, with too great a focus on the promise of the biochemical paradigm in academic research (Hewitt, 2016).

The surprising discoveries of LSD’s activity on the central nervous system and mind fostered interest in the neurochemical paradigm, and greatly amplified the field of neuropsychopharmacology. At once unveiling a biological piece of the puzzle in mental illness, and later reinforcing the need for a holistic approach to mental illness that considers the mental and environmental elements of set and setting, Woolley’s ideas exemplify “a broader paradigm shift in cultural studies toward a biopsychosocial model that acknowledges the intersections between biology and culture” (Hewitt, 2016).

Untimely end
Throughout his career, Woolley was a member of a number of scientific organizations, including the Federation of American Societies for Experimental Biology, American Society for Nutrition, American Society for Pharmacology and Experimental Therapeutics, and American Society of biological chemists. For his contributions, he received the Eli Lilly award twice—once in 1940 by the Society of American Bacteriologists for outstanding contributions to bacteriology, and again in 1948 by the American Chemical Society for his work on vitamins and antimetabolites. He won a Mead Johnson prize for his work on vitamins in 1945, and a research award in 1947 from the American Pharmaceutical Manufacturers Association. He was later given an honorary medical degree by the University of Alberta in 1949. In 1959 he became president of the Institute of Nutrition. He was also nominated for the Nobel Prize for his work on antimetabolites (Wild and Hildebrand, 2014; Hewitt, 2016). Woolley died in 1966 at the age of 54 during a hike through the Andes Mountains on his way to a pharmacological conference in Brazil, only three years after the publication of The Biochemical Bases of Psychoses (Whitaker-Azmitia, 1999).

Enter your email to receive an update when something new is posted.

References

Baumeister, A. A., & Hawkins, M. F. (2004). The Serotonin Hypothesis of Schizophrenia: A Historical Case Study on the Heuristic Value of Theory in Clinical NeuroscienceJournal of the History of the Neurosciences,13(3), 277-291. doi:10.1080/09647040490510560

Carbonaro, T. M., Bradstreet, M. P., Barrett, F. S., Maclean, K. A., Jesse, R., Johnson, M. W., & Griffiths, R. R. (2016). Survey study of challenging experiences after ingesting psilocybin mushrooms: Acute and enduring positive and negative consequences. Journal of Psychopharmacology, 30(12), 1268-1278. doi:10.1177/0269881116662634

Cozzi, N. V. (2013). Psychedelic Breakthroughs in Neuroscience: How Psychedelic Drugs Influenced the Growth and Development of Psychopharmacology. Multidisciplinary Association for Psychedelic Studies, 23(1), 16-19

Gaddum, J. H. (1953) Antagonism between lysergic acid diethylamide and 5-hydroxytryptamineJ. Physiol. 121, 15.

Griffiths, R. R., Johnson, M. W., Carducci, M. A., Umbricht, A., Richards, W. A., Richards, B. D., … Klinedinst, M. A. (2016). Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. Journal of Psychopharmacology, 30(12), 1181-1197. doi:10.1177/0269881116675513

Hartogsohn, I. (2017). Constructing drug effects: A history of set and setting. Drug Science, Policy and Law, 3, 205032451668332. doi:10.1177/2050324516683325

Hewitt, K (1999). A Biochemical Bridge to the Embodied Psyche: LSD Research 1945-1965. Bulletin of the Multidisciplinary Association for Psychedelic Studies, 9(1), 30-34

Hewitt, K. (2016). Rehabilitating LSD history in postwar America: Dilworth Wayne Woolley and the serotonin hypothesis of mental illnessHistory of Science, 54(3), 307-330. doi:10.1177/0073275316674724

Miller, V. (1941). A Tribute to Dr. Wayne Woolley. Lethbridge Herald (February 25, 1941): 11. via Newspapers.com 

Nichols, D. E. (2013). Serotonin, and the Past and Future of LSD. Bulletin of the Multidisciplinary Association for Psychedelic Studies, 23(1), 20-23

Shaw, E., & Woolley, D. W. (1956). Some Serotoninlike Activities of Lysergic Acid Diethylamide. Science, 124(3212), 121-122. doi:10.1126/science.124.3212.121

Smythies, J. R. (1963). Biochemistry of Schizophrenia. Postgraduate Medical Journal, 39(447), 26-33. doi:10.1136/pgmj.39.447.26

Studerus, E., Kometer, M., Hasler, F., & Vollenweider, F. X. (2010). Acute, subacute and long-term subjective effects of psilocybin in healthy humans: a pooled analysis of experimental studies. Journal of Psychopharmacology, 25(11), 1434-1452. doi:10.1177/0269881110382466

Whitaker-Azmitia, P. (1999). The Discovery of Serotonin and its Role in Neuroscience. Neuropsychopharmacology, 21(2). doi:10.1016/s0893-133x(99)00031-7

Wild, G. C., & Hildebrand, J. G. (2014). Dilworth W. Woolley, 1914-1966: A Biographical MemoirNational Academy of Sciences. Retrieved November, 2017, from http://www.nasonline.org/publications/biographical-memoirs/memoir-pdfs/woolley-dilworth.pdf

Woolley, D. W. (1952). A Study of Antimetabolites. Wiley.

Woolley, D. W. (1962). The Biochemical Bases of Psychoses. Print. Wiley.

D. W. Woolley, the Serotonin Hypothesis and the Genesis of Psychopharmacology 2019-12-08T03:18:06+00:00

Spiders on Drugs

 

Is the classic Hinterland Who’s Who parody “Spiders on Drugs” a cover-up for the fact that LSD and psilocybin were found non-toxic in 1950s spider research?

HM. Peters, Zoologist at University of Tubingen in Germany was researching Orb-web spiders that only spin their webs early in the morning in 1948. He asked Peter N Witt, Swiss pharmacologist to help him find a solution to making them spin webs at a more convenient time of day. Witt tried to do this by feeding them with sugar water mixed with either caffeine, mescaline, amphetamine, LSD or strychnine; but it didn’t work. Instead Witt found that drugged spiders generally spun smaller and more irregular webs. Caffeinated spiders, for example, made smaller but wider webs, but small LSD doses made spiders spin more webs with regular patterns.

Witt’s analysis found a genetic component to web structures, with each spider having unique (though similar to to other orb spiders) webs and their offspring having similar webs. He could even identify those that escaped by what their webs looked like.

Spiders on drugs reveal LSD is non-toxic.

spiders on drugs - LSD

Web from a spider on LSD

spiders on drugs psilocybin

Web from a spider on psilocybin

 

 

 

 

 

 

 

 

 

 

NASA replicated the study, but this time with either caffeine, speed, marijuana or chloral hydrate on house spiders (aka European garden spiders aka Araneus diadematus), and concluded that drug toxicity was responsible for the deformity seen in their webs, with less sides of each web cell completed occurring as a function of toxicity.

(Further animal and human studies confirming LSD is non-toxic support this idea).

They suggested spiders could be used to screen drugs for toxicity before giving them to animals to save time and money (and mammalian lives), and contribute to research with restrictive ethics laws on animal testing, which have become increasingly stringent over the past 40 years.

But the findings that LSD and psilocybin were found not to affect the spiders’ webs is hardly emphasized, as if tossed aside for the more telling toxicity of amphetamines and sleeping pills.

A credit appears at the very the end of the video: “First Church of Christ, Ottawa” which is a Christian Science church here in Ottawa.

Could “Spiders on Drugs” be a skilled piece of anti-drug propaganda?

An inquiry was sent to the Youtube account owner that posted this video, but I received no response. The reference to the First Church of Christ is more likely part of the parody.

More on Witt’s research: SPIDERS SEDUCED INTO YIELDING SECRETS OF WEB


References:

http://www.sciencealert.com/spider-on-drugs

NASA’s paper

Wikipedia with section on this research

more on spiders and drugs:

What Does Marijuana Do to Spiders?

 

Spiders on Drugs 2019-04-09T12:21:59+00:00