Drugs of abuse and psychoplastogens Flashcards
(44 cards)
What are psychedelics, give examples?
A drug with mind manifesting/mind expanding effects.
They are 5-HT2A agonists
Examples include LSD and tryptamines such as psilocybin
What are hallucinogens, give examples?
A drug that makes you wander in the mind
They are 5-HT2A agonists and releasers
Examples include LSD and MDMA/ecstasy
What are dissassociatives, give examples?
A drug that causes detachment from one self and the enviroment
They are NMDA blockers
Examples include ketamine which is classically used as a dissociative anaesthetic
Describe the clinical use, side effects and MOA of ketamine
- Synthesised in 1962 from phencyclidine (PCP)
- Ketamine is used as a dissociative anaesthetic
- trance-like state - pain relief, sedation and amnesia.
- preserved breathing and airway reflexes, stimulated heart function with increased
blood pressure, and moderate bronchodilation - Side-effects: Psychotomimetic; emesis; urinary and liver toxicity (chronic consumption)
- MoA: NMDA receptor blocker
In a clinical trial, which was shown to be more effective in treating depression, Ketamine or midazolam?
Ketamine as a lower score was achieved on the montgomery depression rating scale after ketamine infusion compared to midazolam.
Response rate to the drug was also higher compared to midazolam because of this infusion
What is the importance of ketamine on dendrites for the treatment of depression?
prefrontal circuit spinogenesis is required for sustaining, but not inducing, ketamines effects on behaviour and circuit function.
Ketamine can help alleviate damage from chronic stress by causing clustered dendritic spine formation and restoration of lost spines, greater ensemble activity and less depression related behaviour.
Ketamine is a psychoplastogen
How does ketamine effect circuit function?
Ketamine increases (%) spine formation, immobility and multicellular ensemble event frequency (% per frame) compared to the vehicle
Does blue light have a positive or negative effect on spine growth
Negative - it causes disrupted maintanance of anti-depressant effects on circuit function and motivated escape behaviour.
What is the significance of restoration of synapse density in relation to ketamines anti-depressant action
A synaptic deficit group showed
increases in ligand binding to the
SV2A tracer suggestive of increases
in synaptic density and SV2A binding
increases that correlated with
improvement in depression
Are single ketamine injections or multiple ketamine injections more efficacious in treating depressive behaviour
Multiple ketamine injections
What is ketamines effect on hippocampal neurons
It increases adult hippocampal neurogenesis by increasing the number of immature hippocampal neurons but not increasing their neural activity.
How does single dose and multiple dose administration of ketamine cause different effects of hippocampal neurogenesis?
A single dose of ketamine increases the proportion of immature (CR +) neurons that express EGR1 without altering neuron numbers. By contrast, repeat doses increase the total number of immature neurons, and accordingly, the total number of active immature neurons, without changing the proportion of CR + cells that express EGR1. These findings suggest that the sustained behavioral effects of ketamine are mediated by a different mechanism than the rapid effects.
What is the significance of BMP on ketamines anti-depressant effects?
As BMP inhibits hippocampal neuronal growth, BMP also inhibits the anti-depressive behaviour of ketamine stopping its sustaining effects but not its rapid effects
Describe the dual action of ketamine
Dual action of ketamine – Both infer antidepressant effects
Acute action
– homeostatic plasticity (LTP-like effects)
Long-lasting action
– structural plasticity (synaptogenesis & Adult Hippocampal Neurogenesis
Describe the pharmacology of LSD
MOA, administration, S/E’s
Derived from ergoloids
5-HT2a agonist
Odourless, tasteless.
Effective in microgram doses – VERY potent
Orally Active
Tolerance over repeated doses – but short live
No direct toxicity
No dependence
Hallucinogen-persisting perception disorder
What are the effects if you increase doses of psychedelics
Increasing doses causes increased perceptual alterations, changes in the sense of time and emotions and increase in thought disorders and loss of self control
How do psychedelics influence brain activity
Psilocybin-induced brain activity patterns
in psychedelic states
Increase in Prefrontal cortex, Parietal cortex, Limbic system, Thalamus
Decreases in medial prefrontal cortex, anterior and posterior cingualate cortices.
5HT2A-mediated increase in glutamate-dependent
activity of pyramidal neuron
In a study, what was the result of psilocybin on depression after admin for 3 months
does it eventually plateau or dip?
1 week of administrations caused a significant decrease in depression compared to the baseline
The depression score slowly went up during the 3 month period but was still significantly lower compared to baseline.
How does the effects of SSRI’s and psychedelics compare in treating depression
Discuss in terms of pharmacology and emotional responses
Both of these drugs work on serotonergic pathways in the brain
SSRI’s increase post synaptic 5-HT1AR signalling but decreases limbic responsivity.
SSRI’s also decrease stress, impulsitivity, aggression and anxiety.
They also increase emotional blunting and resilience decreasing depression
On the other hand psychedelics increase 5-HT2AR signalling and cortical entropy.
They decrease rigid thinking.
They increase enviromental sensitivity and emotional release overal increasing well-being and treating depression.
What did phase 2 trials of psilocybin show?
Were there any adverse events?
Observations:
* There is significant reduction in MADRS score in 25 mg group.
* Less than 50% decrease in MADRS score from baseline to week 3
* We could observe sustained response in patients all the way from week 3 to week 12.
Adverse events
* 84%, 75% and 72% of participants from 25mg, 10mg, and 1mg experienced adverse events such as headache, nausea and
dizziness and fatigue.
* Severe suicidal events were seen in 9%, 7% and 1% of 25mg, 10mg, and 1mg groups, respective
What is psilocybin’s significance as an addiction therapy
One study showed psilocybin decreased cigarette usage significantly over a period of 6 months
Another study showed that this drug caused a massive decrease initially in alcohol consumption at weeks 5-8, while this level stayed steady after 6 months.
What is psilocybin’s significance as a psychoplastogen
What can inhibit this?
Psilocybin induces rapid and persistent growth of dendritic spines in the frontal cortex.
This increased spine width, density and formation rate.
However ketanserin which is a 5-HT2A antagonist inhibited the actions of psilocybin causing less synaptic plasticity.
Give 2 other examples of psychoplastogens as therapeutics
- Ketamine: treatment-resistant depression; PTSD; Addiction
- Psilocybin: smoking/alcohol dependence, end-of-life anxiety,
treatment-resistant depression - LSD: alcohol dependence, end-of-life anxiety
- DMT (Ayahuasca): MDD
- Ibogaine: substance use disorders
- MDMA: PTSD, treatment-resistant depression, anxiet
What is the MOA of opioids (heroin,morphine)
What brain areas are affected
MOR → GABA↓ → DA↑
Opioids, like morphine, heroin, or fentanyl, are agonists at MOR (214). Opioid stimulation of MOR in the VTA increases striatal DA release.
