Sub(acute) Neuropsychopharmacological Profiling of 2C-B vs Psilocybin

Novel psychoactive substances (NPS) are emerging at a fast pace (EMCDDA 2018,
UNODC 2019) These are psychotropic drugs that are not controlled by the 1961
United Nations Single Convention on Narcotic Drugs or the 1971 United Nations
Convention on Psychotropic Substances, but which are liable to abuse and
dependence, producing similar effects on the central nervous system compared to
scheduled compounds (Schifano, Orsolini et al. 2015). The risk they pose is
indicated by their prevalence across 94 countries/territories and recreational
drug users, with some 5% of 19-24 years old Europeans having already
experimented with some forms of an NPS (UNODC 2014).

Information on their clinical pharmacology and toxicity is in most cases very
limited. Given the large number of new compounds released on the market each
year a timely evaluation of NPS by current standards in ex-vivo and in-vivo
animal models or expert evaluations is unfeasible. Here we we intend for a
targeted imaging-metabolomics approach in humans that provides fast
classifications of NPS and their effects on brain function. In order to do so,
we will conduct placebo-controlled clinical trials to assess acute effects of
on resting state brain networks, neurocognition and metabolomics. A predictive
model based on machine learning algorithms will use the quantification of
neurotransmitters, endocannabinoids, steroid hormones and their metabolites in
blood, functional connectivity in resting state brain networks and
neurocognitive function to predict the similarity of a new drug to classical
drugs of abuse. This initiative is based on previous preclinical work in rodent
models (Olesti, De Toma et al. 2019). In order to collect the necessary
parameters for the algorithm, a series of clinical trials employing NPS (2C-B,
4-fluoroamphetamine, JWH-018 and mephedrone) in healthy volunteers are to be
carried out.

The present study marks the first of this series and will investigate the
effects of 2C-B which shows substantial effect overlaps with classical
stimulants and psychedelic drug classes. 2C-B belongs to the 2C class of
phenylethylamine derivatives and is a hallucinogenic substituted phenethylamine
NPS and since its development in the 1970s, has spawned a number of NPS
phenylethlamines with a significantly higher risk profile.
These developments are the result of its similarities with popular recreational
psychedelics, which generate similar changes to consciousness and have a
long-lasting impact on behaviour and mood.

As a result, 2C-B is an optimal template compound for distinction of NPS harms
from classical psychedelics such as psilocybin which show low to modest risk.
Further due to its equivalent popularity and the absence of data on its
neuropsychopharmacology, it may represent a potentially high level of societal
risk, which requires investigation.

Methods and results produced by the outcome of this research project can be
implemented in NPS risk assessment procedures at European and national levels
and can be adopted by emergency departments in any hospital. Metabolomics
screenings at emergency departments would allow a fast classification of
unknown NPS relative to a reference NPS and/or classical drugs of abuse and
inform clinicians on which treatment protocol to select. The current research
will therefore improve identification and classification of NPS, improve
knowledge on health risks associated with NPS, and advance evidence-based
policy making..In addition, public knowledge about the hazards of NPS will also
contribute to a better weighted opinion about these substances by drug users
and can result in use reduction or harm reduction in the future and may
therefore prevent serious health consequences.

Primary Objective: Idenitfying 2C-B*s effects in relation to the commonly
used psychedelic psilocybin and placebo on neurocognition by using the Digit
Symbol Substitution Task.

Secondary Objective(s): Probing different aspects of the acute changes to
neurocognition, phenomenology and the underlying neural correlates of 2C-B by
using neurocognitive tests, subjective effect questionnaires and fMRI. Further,
to map out 2C-B*s pharmacokinetics and metabolomics using blood samples and
MRS investigations. Specific to psychedelic experiences, drug-induced changes
in emotional regulation and self-embodiment will be investigated by employing
an fMRI emotional regulation task and a VR scenario. Lastly, to investigate
subacute effects of psychedelic drugs on neurocognition, social cognition,
aggression and impulsivity.

The overarching goal is to use this data to provide a complete
neuropsychopharmacological mapping of 2C-B's effects as to incorporate the data
in a predictive algorithm which can aid in judicial drug classification and
harm-reduction.

The present study will employ double-blind, randomized, placebo controlled,
within-subject crossover design. Participants will receive on three separate
occasions either placebo, 20 mg 2C-B or 15 mg psilocybin. One day and five days
following each acute dosing session, participants will be evaluated for
subacute behavioural effects. Each drug condition will be subject to a
fourteen-day washout period, commencing upon completion of each five-day
follow-up. A 14-day washout has been decided on the basis of minimising
carryover effects that may arise from persisting psychedelic drug effects,
which are found to be absent in previous studies when employing a similar
timeframe (Kraehenmann 2015).

20mg 2C-B, 15 mg Psilocybin, placebo (bitter lemon soft drink )
Each to be administered orally, dissolved as a solution in bitter lemon soft
drink.

During acute dosing days participants will need to stay for 6 hours at the unit
and have blood, earwax and urine samples taken. They will need to partake in an
fMRI scanning session in which they will need to stay still for over 55
minutes, complete a series of computer/tablet neurocognitive tasks, subjective
effect questionnaires and a virtual reality paradigm.
The morning after they will need to return for 3 hours to complete further
computer-based behavioural tasks and persisting effect questionnaires. They
will also need to email a patient diary 5 days after each dosing visit 1h to
provide a patient diary in which they noted all side effects they may have
experienced, along with the completion of persisting effect questionnaires
online via Qualtrics.
Including the medical screening and training day, the total participation time
is 33 hours over the course of 9 weeks (including washouts and training).
Participants must also refrain from drug-use, alcohol and pregnancy throughout
the trial and cannot smoke during dosing days.
They must also provide demographic data.

The acute effects of the stated dose of 20mg 2C-B indicated in the literature
include; pro-sociability, euphoria, stimulation, changes in perception,
hallucinations, internal narratives, introspection, emotionality
The acute common risks of the stated 20mg 2C-B indicated in the literature
include; nausea, tremors, difficulty focusing gaze, hypertension, tachycardia,
sweating. Survey data has indicated insomnia, headaches, involuntary
reoccurrences of the psychoactive effects and hallucinations ("flashbacks") as
common potential subacute effects (+48h). An indirect case of persistent
psychosis has been reported in the literature.

For 15mg psilocybin, the main effects include; hallucinations, introspection,
changes in perception, disembodiment, emotionality and the main side effects
are anxiety, paranoia and tachycardia.

For both of these drugs, the principal concern is long lasting adverse
psychological reactions which may manifest as panic attacks, anxiety and
paranoia.