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Ketamine and Psychedelic Drugs Change Structure of Neurons

ummary: A new study reveals psychedelics increase dendrites, dendritic spines and synapses, while ketamine may promote neuroplasticity. The findings could help develop new treatments for anxiety, depression and other related disorders.

Source: UC Davis.

A team of scientists at the University of California, Davis is exploring how hallucinogenic drugs impact the structure and function of neurons — research that could lead to new treatments for depression, anxiety, and related disorders. In a paper published on June 12 in the journal Cell Reports, they demonstrate that a wide range of psychedelic drugs, including well-known compounds such as LSD and MDMA, increase the number of neuronal branches (dendrites), the density of small protrusions on these branches (dendritic spines), and the number of connections between neurons (synapses). These structural changes suggest that psychedelics are capable of repairing the circuits that are malfunctioning in mood and anxiety disorders.

“People have long assumed that psychedelics are capable of altering neuronal structure, but this is the first study that clearly and unambiguously supports that hypothesis. What is really exciting is that psychedelics seem to mirror the effects produced by ketamine,” said David Olson, assistant professor in the Departments of Chemistry and of Biochemistry and Molecular Medicine, who leads the research team.

Ketamine, an anesthetic, has been receiving a lot of attention lately because it produces rapid antidepressant effects in treatment-resistant populations, leading the U.S. Food and Drug Administration to fast-track clinical trials of two antidepressant drugs based on ketamine. The antidepressant properties of ketamine may stem from its tendency to promote neural plasticity — the ability of neurons to rewire their connections.

“The rapid effects of ketamine on mood and plasticity are truly astounding. The big question we were trying to answer was whether or not other compounds are capable of doing what ketamine does,” Olson said.

Psychedelics show similar effects to ketamine

Olson’s group has demonstrated that psychedelics mimic the effects of ketamine on neurons grown in a dish, and that these results extend to structural and electrical properties of neurons in animals. Rats treated with a single dose of DMT — a psychedelic compound found in the Amazonian herbal tea known as ayahuasca — showed an increase in the number of dendritic spines, similar to that seen with ketamine treatment. DMT itself is very short-lived in the rat: Most of the drug is eliminated within an hour. But the “rewiring” effects on the brain could be seen 24 hours later, demonstrating that these effects last for some time.

Fairfax | NOVA Ketamine IV Ketamine for depression | Fairfax, Va 22306 | 703-844-0184
Fairfax | NOVA Ketamine IV Ketamine for depression | Fairfax, Va 22306 | 703-844-0184

Ketamine and Psychedelic Drugs Change Structure of Neurons

Summary: A new study reveals psychedelics increase dendrites, dendritic spines and synapses, while ketamine may promote neuroplasticity. The findings could help develop new treatments for anxiety, depression and other related disorders.

Source: UC Davis.

A team of scientists at the University of California, Davis is exploring how hallucinogenic drugs impact the structure and function of neurons — research that could lead to new treatments for depression, anxiety, and related disorders. In a paper published on June 12 in the journal Cell Reports, they demonstrate that a wide range of psychedelic drugs, including well-known compounds such as LSD and MDMA, increase the number of neuronal branches (dendrites), the density of small protrusions on these branches (dendritic spines), and the number of connections between neurons (synapses). These structural changes suggest that psychedelics are capable of repairing the circuits that are malfunctioning in mood and anxiety disorders.

“People have long assumed that psychedelics are capable of altering neuronal structure, but this is the first study that clearly and unambiguously supports that hypothesis. What is really exciting is that psychedelics seem to mirror the effects produced by ketamine,” said David Olson, assistant professor in the Departments of Chemistry and of Biochemistry and Molecular Medicine, who leads the research team.

Ketamine, an anesthetic, has been receiving a lot of attention lately because it produces rapid antidepressant effects in treatment-resistant populations, leading the U.S. Food and Drug Administration to fast-track clinical trials of two antidepressant drugs based on ketamine. The antidepressant properties of ketamine may stem from its tendency to promote neural plasticity — the ability of neurons to rewire their connections.

“The rapid effects of ketamine on mood and plasticity are truly astounding. The big question we were trying to answer was whether or not other compounds are capable of doing what ketamine does,” Olson said.

Psychedelics show similar effects to ketamine

Olson’s group has demonstrated that psychedelics mimic the effects of ketamine on neurons grown in a dish, and that these results extend to structural and electrical properties of neurons in animals. Rats treated with a single dose of DMT — a psychedelic compound found in the Amazonian herbal tea known as ayahuasca — showed an increase in the number of dendritic spines, similar to that seen with ketamine treatment. DMT itself is very short-lived in the rat: Most of the drug is eliminated within an hour. But the “rewiring” effects on the brain could be seen 24 hours later, demonstrating that these effects last for some time.

image shows neurons under psychedelics and ketamine

Psychedelic drugs such as LSD and ayahuasca change the structure of nerve cells, causing them to sprout more branches and spines, UC Davis researchers have found. This could help in “rewiring” the brain to treat depression and other disorders. In this false-colored image, the rainbow-colored cell was treated with LSD compared to a control cell in blue. NeuroscienceNews.com image is credited to Calvin and Joanne Ly.

Behavioral studies also hint at the similarities between psychedelics and ketamine. In another recent paper published in ACS Chemical Neuroscience, Olson’s group showed that DMT treatment enabled rats to overcome a “fear response” to the memory of a mild electric shock. This test is considered to be a model of post-traumatic stress disorder (PTSD), and interestingly, ketamine produces the same effect. Recent clinical trials have shown that like ketamine, DMT-containing ayahuasca might have fast-acting effects in people with recurrent depression, Olson said.

These discoveries potentially open doors for the development of novel drugs to treat mood and anxiety disorders, Olson said. His team has proposed the term “psychoplastogen” to describe this new class of “plasticity-promoting” compounds.

“Ketamine is no longer our only option. Our work demonstrates that there are a number of distinct chemical scaffolds capable of promoting plasticity like ketamine, providing additional opportunities for medicinal chemists to develop safer and more effective alternatives,” Olson said.

 

Psychedelic drugs, ketamine change structure of neurons

Psychedelic drugs, ketamine change structure of neurons

Psychedelics as Possible Treatments for Depression and PTSD

A team of scientists at the University of California, Davis, is exploring how hallucinogenic drugs impact the structure and function of neurons — research that could lead to new treatments for depression, anxiety and related disorders.

In a paper published on June 12 in the journal Cell Reports, they demonstrate that a wide range of psychedelic drugs, including well-known compounds such as LSD and MDMA, increase the number of neuronal branches (dendrites), the density of small protrusions on these branches (dendritic spines) and the number of connections between neurons (synapses). These structural changes could suggest that psychedelics are capable of repairing the circuits that are malfunctioning in mood and anxiety disorders.

“People have long assumed that psychedelics are capable of altering neuronal structure, but this is the first study that clearly and unambiguously supports that hypothesis. What is really exciting is that psychedelics seem to mirror the effects produced by ketamine,” said David Olson, assistant professor in the departments of Chemistry and of Biochemistry and Molecular Medicine, who leads the research team.

Ketamine, an anesthetic, has been receiving a lot of attention lately because it produces rapid antidepressant effects in treatment-resistant populations, leading the U.S. Food and Drug Administration to fast-track clinical trials of two antidepressant drugs based on ketamine. The antidepressant properties of ketamine may stem from its tendency to promote neural plasticity — the ability of neurons to rewire their connections.

“The rapid effects of ketamine on mood and plasticity are truly astounding. The big question we were trying to answer was whether or not other compounds are capable of doing what ketamine does,” Olson said.

Psychedelics show similar effects to ketamine

Olson’s group has demonstrated that psychedelics mimic the effects of ketamine on neurons grown in a dish, and that these results extend to structural and electrical properties of neurons in animals. Rats treated with a single dose of DMT — a psychedelic compound found in the Amazonian herbal tea known as ayahuasca — showed an increase in the number of dendritic spines, similar to that seen with ketamine treatment. DMT itself is very short-lived in the rat: Most of the drug is eliminated within an hour. But the “rewiring” effects on the brain could be seen 24 hours later, demonstrating that these effects last for some time.

Behavioral studies also hint at the similarities between psychedelics and ketamine. In another recent paper published in ACS Chemical Neuroscience, Olson’s group showed that DMT treatment enabled rats to overcome a “fear response” to the memory of a mild electric shock. This test is considered to be a model of post-traumatic stress disorder, or PTSD, and interestingly, ketamine produces the same effect. Recent clinical trials have shown that like ketamine, DMT-containing ayahuasca might have fast-acting effects in people with recurrent depression, Olson said.

These discoveries potentially open doors for the development of novel drugs to treat mood and anxiety disorders, Olson said. His team has proposed the term “psychoplastogen” to describe this new class of “plasticity-promoting” compounds.

“Ketamine is no longer our only option. Our work demonstrates that there are a number of distinct chemical scaffolds capable of promoting plasticity like ketamine, providing additional opportunities for medicinal chemists to develop safer and more effective alternatives,” Olson said.

Additional co-authors on the Cell Reports “Psychedelics Promote Structural and Functional Neural Plasticity.” study are Calvin Ly, Alexandra Greb, Sina Soltanzadeh Zarandi, Lindsay Cameron, Jonathon Wong, Eden Barragan, Paige Wilson, Michael Paddy, Kassandra Ori-McKinney, Kyle Burbach, Megan Dennis, Alexander Sood, Whitney Duim, Kimberley McAllister and John Gray.

Olson and Cameron were co-authors on the ACS Chemical Neuroscience paper along with Charlie Benson and Lee Dunlap.

The work was partly supported by grants from the National Institutes of Health.

Psychedelics Promote Structural and Functional
Neural Plasticity

Below is the Intro and Discussion for the article:

Psychedelics Promote Structural and Functional neural Plasticity

Authors:

Calvin Ly, Alexandra C. Greb,
Lindsay P. Cameron, …,
Kassandra M. Ori-McKenney,
John A. Gray, David E. Olson
Correspondence
deolson@ucdavis.edu

In Brief
Ly et al. demonstrate that psychedelic
compounds such as LSD, DMT, and DOI
increase dendritic arbor complexity,
promote dendritic spine growth, and
stimulate synapse formation. These
cellular effects are similar to those
produced by the fast-acting
antidepressant ketamine and highlight
the potential of psychedelics for treating
depression and related disorders.

  • Highlights
     Serotonergic psychedelics increase neuritogenesis,
    spinogenesis, and synaptogenesis
  •  Psychedelics promote plasticity via an evolutionarily
    conserved mechanism
  •  TrkB, mTOR, and 5-HT2A signaling underlie psychedelicinduced
    plasticity
  •  Noribogaine, but not ibogaine, is capable of promoting
    structural neural plasticity

SUMMARY
Atrophy of neurons in the prefrontal cortex (PFC)
plays a key role in the pathophysiology of depression
and related disorders. The ability to promote
both structural and functional plasticity in the PFC
has been hypothesized to underlie the fast-acting
antidepressant properties of the dissociative anesthetic
ketamine. Here, we report that, like ketamine,
serotonergic psychedelics are capable of robustly
increasing neuritogenesis and/or spinogenesis both
in vitro and in vivo. These changes in neuronal structure
are accompanied by increased synapse number
and function, as measured by fluorescence microscopy
and electrophysiology. The structural changes
induced by psychedelics appear to result from stimulation
of the TrkB, mTOR, and 5-HT2A signaling
pathways and could possibly explain the clinical
effectiveness of these compounds. Our results underscore
the therapeutic potential of psychedelics
and, importantly, identify several lead scaffolds for
medicinal chemistry efforts focused on developing
plasticity-promoting compounds as safe, effective,
and fast-acting treatments for depression and
related disorders.

INTRODUCTION
Neuropsychiatric diseases, including mood and anxiety disorders,
are some of the leading causes of disability worldwide
and place an enormous economic burden on society (Gustavsson
et al., 2011; Whiteford et al., 2013). Approximately
one-third of patients will not respond to current antidepressant
drugs, and those who do will usually require at least 2–4 weeks
of treatment before they experience any beneficial effects
(Rush et al., 2006). Depression, post-traumatic stress disorder
(PTSD), and addiction share common neural circuitry (Arnsten,
2009; Russo et al., 2009; Peters et al., 2010; Russo and
Nestler, 2013) and have high comorbidity (Kelly and Daley,
2013). A preponderance of evidence from a combination of
human imaging, postmortem studies, and animal models suggests
that atrophy of neurons in the prefrontal cortex (PFC)
plays a key role in the pathophysiology of depression and
related disorders and is precipitated and/or exacerbated by
stress (Arnsten, 2009; Autry and Monteggia, 2012; Christoffel
et al., 2011; Duman and Aghajanian, 2012; Duman et al.,
2016; Izquierdo et al., 2006; Pittenger and Duman, 2008;
Qiao et al., 2016; Russo and Nestler, 2013). These structural
changes, such as the retraction of neurites, loss of dendritic
spines, and elimination of synapses, can potentially be counteracted
by compounds capable of promoting structural and
functional neural plasticity in the PFC (Castre´ n and Antila,
2017; Cramer et al., 2011; Duman, 2002; Hayley and Litteljohn,
2013; Kolb and Muhammad, 2014; Krystal et al., 2009;
Mathew et al., 2008), providing a general solution to treating
all of these related diseases. However, only a relatively small
number of compounds capable of promoting plasticity in the
PFC have been identified so far, each with significant drawbacks
(Castre´ n and Antila, 2017). Of these, the dissociative
anesthetic ketamine has shown the most promise, revitalizing
the field of molecular psychiatry in recent years.
Ketamine has demonstrated remarkable clinical potential as a
fast-acting antidepressant (Berman et al., 2000; Ionescu et al.,
2016; Zarate et al., 2012), even exhibiting efficacy in treatmentresistant
populations (DiazGranados et al., 2010; Murrough
et al., 2013; Zarate et al., 2006). Additionally, it has shown promise
for treating PTSD (Feder et al., 2014) and heroin addiction
(Krupitsky et al., 2002). Animal models suggest that its therapeutic
effects stem from its ability to promote the growth of dendritic
spines, increase the synthesis of synaptic proteins, and
strengthen synaptic responses (Autry et al., 2011; Browne and
Lucki, 2013; Li et al., 2010).

Like ketamine, serotonergic psychedelics and entactogens
have demonstrated rapid and long-lasting antidepressant and
anxiolytic effects in the clinic after a single dose (Bouso et al.,
2008; Carhart-Harris and Goodwin, 2017; Grob et al., 2011;
Mithoefer et al., 2013, 2016; Nichols et al., 2017; Sanches
et al., 2016; Oso´ rio et al., 2015), including in treatment-resistant
populations (Carhart-Harris et al., 2016, 2017; Mithoefer et al.,
2011; Oehen et al., 2013; Rucker et al., 2016). In fact, there
have been numerous clinical trials in the past 30 years examining
the therapeutic effects of these drugs (Dos Santos et al., 2016),
with 3,4-methylenedioxymethamphetamine (MDMA) recently
receiving the ‘‘breakthrough therapy’’ designation by the Food
and Drug Administration for treating PTSD. Furthermore, classical
psychedelics and entactogens produce antidepressant
and anxiolytic responses in rodent behavioral tests, such as
the forced swim test (Cameron et al., 2018) and fear extinction
learning (Cameron et al., 2018; Catlow et al., 2013; Young
et al., 2015), paradigms for which ketamine has also been shown
to be effective (Autry et al., 2011; Girgenti et al., 2017; Li et al.,
2010). Despite the promising antidepressant, anxiolytic, and
anti-addictive properties of serotonergic psychedelics, their
therapeutic mechanism of action remains poorly understood,
and concerns about safety have severely limited their clinical
usefulness.
Because of the similarities between classical serotonergic
psychedelics and ketamine in both preclinical models and clinical
studies, we reasoned that their therapeutic effects might
result from a shared ability to promote structural and functional
neural plasticity in cortical neurons. Here, we report that serotonergic
psychedelics and entactogens from a variety of chemical
classes (e.g., amphetamine, tryptamine, and ergoline) display
plasticity-promoting properties comparable to or greater than
ketamine. Like ketamine, these compounds stimulate structural
plasticity by activating the mammalian target of rapamycin
(mTOR). To classify the growing number of compounds capable
of rapidly promoting induced plasticity (Castre´ n and Antila,
2017), we introduce the term ‘‘psychoplastogen,’’ from the
Greek roots psych- (mind), -plast (molded), and -gen (producing).
Our work strengthens the growing body of literature indicating
that psychoplastogens capable of promoting plasticity
in the PFC might have value as fast-acting antidepressants
and anxiolytics with efficacy in treatment-resistant populations
and suggests that it may be possible to use classical psychedelics
as lead structures for identifying safer alternatives.

DISCUSSION
Classical serotonergic psychedelics are known to cause
changes in mood (Griffiths et al., 2006, 2008, 2011) and brain
function (Carhart-Harris et al., 2017) that persist long after the
acute effects of the drugs have subsided. Moreover, several
psychedelics elevate glutamate levels in the cortex (Nichols,
2004, 2016) and increase gene expression in vivo of the neurotrophin
BDNF as well as immediate-early genes associated with
plasticity (Martin et al., 2014; Nichols and Sanders-Bush, 2002;
Vaidya et al., 1997). This indirect evidence has led to the
reasonable hypothesis that psychedelics promote structural
and functional neural plasticity, although this assumption had
never been rigorously tested (Bogenschutz and Pommy,
2012; Vollenweider and Kometer, 2010). The data presented
here provide direct evidence for this hypothesis, demonstrating
that psychedelics cause both structural and functional changes
in cortical neurons.

Prior to this study, two reports suggested
that psychedelics might be able
to produce changes in neuronal structure.
Jones et al. (2009) demonstrated that DOI
was capable of transiently increasing the
size of dendritic spines on cortical neurons,
but no change in spine density was
observed. The second study showed
that DOI promoted neurite extension in a
cell line of neuronal lineage (Marinova
et al., 2017). Both of these reports utilized
DOI, a psychedelic of the amphetamine
class. Here we demonstrate that the ability
to change neuronal structure is not a
unique property of amphetamines like
DOI because psychedelics from the ergoline,
tryptamine, and iboga classes of compounds also promote
structural plasticity. Additionally, D-amphetamine does not increase
the complexity of cortical dendritic arbors in culture,
and therefore, these morphological changes cannot be simply
attributed to an increase in monoamine neurotransmission.
The identification of psychoplastogens belonging to distinct
chemical families is an important aspect of this work because
it suggests that ketamine is not unique in its ability to promote
structural and functional plasticity. In addition to ketamine, the
prototypical psychoplastogen, only a relatively small number of
plasticity-promoting small molecules have been identified previously.
Such compounds include the N-methyl-D-aspartate
(NMDA) receptor ligand GLYX-13 (i.e., rapastinel), the mGlu2/3
antagonist LY341495, the TrkB agonist 7,8-DHF, and the muscarinic
receptor antagonist scopolamine (Lepack et al., 2016; Castello
et al., 2014; Zeng et al., 2012; Voleti et al., 2013). We
observe that hallucinogens from four distinct structural classes
(i.e., tryptamine, amphetamine, ergoline, and iboga) are also
potent psychoplastogens, providing additional lead scaffolds
for medicinal chemistry efforts aimed at identifying neurotherapeutics.
Furthermore, our cellular assays revealed that several
of these compounds were more efficacious (e.g., MDMA) or more potent (e.g., LSD) than ketamine. In fact, the plasticity-promoting
properties of psychedelics and entactogens rivaled that
of BDNF (Figures 3A–3C and S3). The extreme potency of LSD
in particular might be due to slow off kinetics, as recently proposed
following the disclosure of the LSD-bound 5-HT2B crystal
structure (Wacker et al., 2017).
Importantly, the psychoplastogenic effects of psychedelics in
cortical cultures were also observed in vivo using both vertebrate
and invertebrate models, demonstrating that they act through an
evolutionarily conserved mechanism. Furthermore, the concentrations
of psychedelics utilized in our in vitro cell culture assays
were consistent with those reached in the brain following systemic
administration of therapeutic doses in rodents (Yang
et al., 2018; Cohen and Vogel, 1972). This suggests that neuritogenesis,
spinogenesis, and/or synaptogenesis assays performed
using cortical cultures might have value for identifying
psychoplastogens and fast-acting antidepressants. It should
be noted that our structural plasticity studies performed in vitro
utilized neurons exposed to psychedelics for extended periods
of time. Because brain exposure to these compounds is often
of short duration due to rapid metabolism, it will be interesting
to assess the kinetics of psychedelic-induced plasticity.
A key question in the field of psychedelic medicine has been
whether or not psychedelics promote changes in the density of
dendritic spines (Kyzar et al., 2017). Using super-resolution
SIM, we clearly demonstrate that psychedelics do, in fact, increase
the density of dendritic spines on cortical neurons, an effect
that is not restricted to a particular structural class of compounds.
Using DMT, we verified that cortical neuron spine
density increases in vivo and that these changes in structural
plasticity are accompanied by functional effects such as
increased amplitude and frequency of spontaneous EPSCs.

We specifically designed these experiments
to mimic previous studies of ketamine
(Li et al., 2010) so that we might
directly compare these two compounds,
and, to a first approximation, they appear
to be remarkably similar. Not only do they
both increase spine density and neuronal
excitability in the cortex, they seem to
have similar behavioral effects. We have
shown previously that, like ketamine,
DMT promotes fear extinction learning
and has antidepressant effects in the
forced swim test (Cameron et al., 2018). These results, coupled
with the fact that ayahuasca, a DMT-containing concoction, has
potent antidepressant effects in humans (Oso´ rio et al., 2015;
Sanches et al., 2016; Santos et al., 2007), suggests that classical
psychedelics and ketamine might share a related therapeutic
mechanism.
Although the molecular targets of ketamine and psychedelics
are different (NMDA and 5-HT2A receptors, respectively), they
appear to cause similar downstream effects on structural plasticity
by activating mTOR. This finding is significant because ketamine is
known to be addictive whereas many classical psychedelics are
not (Nutt et al., 2007, 2010). The exact mechanisms by which these
compounds stimulate mTOR is still not entirely understood, but
our data suggest that, at least for classical psychedelics, TrkB
and 5-HT2A receptors are involved. Although most classical psychedelics
are not considered to be addictive, there are still significant
safety concerns with their use in medicine because they
cause profound perceptual disturbances and still have the potential
to be abused. Therefore, the identification of non-hallucinogenic
analogs capable of promoting plasticity in the PFC could
facilitate a paradigm shift in our approach to treating neuropsychiatric
diseases. Moreover, such compounds could be critical to
resolving the long-standing debate in the field concerning whether
the subjective effects of psychedelics are necessary for their therapeutic
effects (Majic et al., 2015  ). Although our group is actively
investigating the psychoplastogenic properties of non-hallucinogenic
analogs of psychedelics, others have reported the therapeutic
potential of safer structural and functional analogs of ketamine
(Moskal et al., 2017; Yang et al., 2015; Zanos et al., 2016).
Our data demonstrate that classical psychedelics from several
distinct chemical classes are capable of robustly promoting the
growth of both neurites and dendritic spines in vitro, in vivo, and across species. Importantly, our studies highlight the similarities
between the effects of ketamine and those of classical serotonergic
psychedelics, supporting the hypothesis that the clinical
antidepressant and anxiolytic effects of these molecules might
result from their ability to promote structural and functional plasticity
in prefrontal cortical neurons. We have demonstrated that
the plasticity-promoting properties of psychedelics require
TrkB, mTOR, and 5-HT2A signaling, suggesting that these key
signaling hubs may serve as potential targets for the development
of psychoplastogens, fast-acting antidepressants, and anxiolytics.
Taken together, our results suggest that psychedelics
may be used as lead structures to identify next-generation neurotherapeutics
with improved efficacy and safety profiles.

Also below is a great article on DMT and neuroplasticity:

 

Dark Classics in Chemical Neuroscience N,N-Dimethyltryptamine DMT

New Psychoactive Substances

New Psychoactive substances (NPS) are creating a nightmare for physicians, law-enforcement, and public safety. A variety of new synthetic agents, many with opioid-drug similarities have been leeching into the public domain, wreaking havoc and death  among naive users who are not even aware of what drug they are taking

Named examples include AH-7921, U-47700, MT-45, Butyrfentanyl, 4F-butyrfentanyl, acetylfentanyl, 4-MeO butyrfentantl, Furanylfentanyl, and acrylfentanyl.  These have been labeled as ‘not for human consumption’ or ‘research chemical’ thereby circumventing legislative control. Even after illegality is established, other countries may still allow their use and even internet trade. Problems with these chemicals include poor quality control, debasement with other chemicals, and unknown or unintended secondary medical consequences from unknown pharmacodynamics. Fatalities have been documented form unintended or intentional use.

The Swedish STRIDA project, initiated in 2010 by the Karolinska Institute and University Laboratory monitors the occurrence and health hazards of NPS in Sweden, and has documented structurally diverse agents, such as MT-45, which have resulted in a number of unintended toxic effects such as hearing loss, cataracts, and sever skin problems due to use of NPS. Of note, many individuals will mix drugs and create even more risk for side effects or death. Even in spite of public knowledge of medical complications of NPS use, including death, the use of NPS has continued to rise quickly in numerous countries.  NPS distribution has largely been driven by the internet, with countries such as China and India playing significant roles in their manufacture. The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) identified over 650 diff erent websites selling so-called legal highs on the surface web in 2013; European monitoring center for drugs and drug addiction  More recently, “cryptomarkets”, which are anonymous marketplaces operating on the so-called darknet, and accessible only via specially configured browsers, have played an increasing role in NPS distribution. Multiple agents of varying classes are sold, including hallucinogens and amphetamine-type stimulants. For example, the 2C-x class of empathogens (substances in the 2C-x class, despite often being sold as substitutes for MDMA have other hallucinogenic qualities) , the psychedelic tryptamine DMT, and substituted 2C-x variants of the NBOMe class are sold by the highest number of vendors across markets. α-PVP is also available on cryptomarkets and is sold by around 5% of NPS vendors. In these communities, online vendors depend on consumer feedback to maintain trust with the community, and are thus accountable for the products they sell. People using cryptomarkets to obtain drugs report fewer concerns about drug purity, lower levels of exposure to physical violence, and fewer law enforcement consequences compared with obtaining drugs from other sources.

Death from NPS has been documented throughly: For eample, the fentanyl analogue acetylfentanyl, for example, has been associated with multiple cases of life-threatening intoxication and death.  http://www.emcdda.europa.eu/publications/insights/internet-drug-markets

The internet and Drug Markets – PDF

Drugs and the Internet – Australia

DRUGS AND THE INTERNET – Australia 2016 PDF

https://www.cryptocoinsnews.com/%20%20darknet-marketplace-issues-complete-ban-drug/

Hidden wholesale The drug diffusing capacity of online drug cryptomarkets   The cryptomarket: an ‘anonymous open’ drug market that transcends locale

Novel Synthetic Opioids An Opioid Epidemic Within an Opioid Epidemic   Prescriptions for opioid analgesics paralleled an
increase in opioid abuse and fatalities between 2002 and
2010, leveling off from 2011 to 2013.3 However, drug
overdose deaths involving natural and semisynthetic opioids,
including the most commonly prescribed opioid pain
relievers, oxycodone and hydrocodone, increased by 9%
between 2013 and 2014. However, as
the availability of prescription opioids has decreased, the use
and availability of other opioids has increased. Heroin overdose death rates increased 26% from 2013 and 2014 and have more than tripled since 2010. Even more concerning, between 2013 and 2014
the death rates for synthetic opioids, excluding methadone
(eg, fentanyl), increased by 80%, largely because of increased
use and abuse of nonpharmaceutical fentanyl. There have been spikes in overdose deaths related to fentanyl and its analog, acetylfentanyl.  National Heroin Threat Assessment Summary

Heroin Trafficking in the United States 2016

Concepts of illicit drug quality among darknet market users Purity, embodied experience, craft and chemical knowledge

The internet and Drug Markets

Trends in new psychoactive substances from surface and “dark” net monitoring

New psychoactive substances in prisons high and getting higher

Who sells what Country specific differences in substance availability on the Agora cryptomarket

Everything you always wanted to know about drug cryptomarkets

Safer scoring Cryptomarkets, social supply and drug market violence

Going international Risk taking by cryptomarket drug vendors

The transparency paradox. Building trust, resolving disputes and optimising logistics on conventional and online drugs markets

Results of an international drug testing service for cryptomarket users

Drug use harm trajectories before, during and after the emergence of Silk Road§

In addition to nonpharmaceutical fentanyl, there are myriad other novel synthetic opioids that continue to emerge on the illicit drug market.1 Many of these drugs were initially developed in research laboratories as opioid agonists for analgesic use but were never brought to market for use in human beings. As such, most of the novel synthetic opioids do not have any human pharmacokinetic or pharmacodynamic data available. One such example is the W-series research opioids (W1 to W32), specifically, W-18, developed in 1981 at a Canadian university. Although early reports suggest that W-18 has 100 times the potency of fentanyl, true pharmacologic and potency data are lacking. Recently, in Ohio, multiple overdoses and deaths of patients who believed they were purchasing heroin were attributed to the ultrapotent fentanyl derivative carfentanil.  (elephant-sedative-carfentanil-threat) The synthetic opioids MT-45 and AH-7921 were first reported to the National Forensic Laboratory Information System in 2013. Opiates and Related Drugs 2009-2014 NFLS MT-45 has been associated with 28 deaths reported to the European Monitoring Centre for Drugs and Drug Addiction since 2013 and 2 reported deaths in the United States. MT-45 – opioid dataset  The abuse potential of AH-7921 was identified in 2012, when it was isolated in a seized sample purchased on the Internet, and it has been increasingly used in Japan, the United States, and Europe. Lethal poisonings with AH-7921 in combination with other substances [

Abstract 

J Anal Toxicol. 2014 Oct;38(8):599-604. doi: 10.1093/jat/bku057.

Fatal intoxications associated with the designer opioid AH-7921

AH-7921 (3,4-dichloro-N-[(1-dimethylamino)cyclohexylmethyl]benzamide) is a designer opioid with ∼80% of morphine’s µ-agonist activity. Over a 6-month period, we encountered nine deaths where AH-7921 was involved and detected in blood from the deceased. Shortly after the last death, on August 1 2013, AH-7921 was scheduled as a narcotic and largely disappeared from the illicit market in Sweden. AH-7921 was measured by a selective liquid chromatography-MS-MS method and the concentrations of AH-7921 ranged from 0.03 to 0.99 µg/g blood. Six of our cases had other drugs of abuse on board and most had other medications such as benzodiazepines, antidepressants and analgesics. However, the other medicinal drugs encountered were present in postmortem therapeutic concentrations and unlikely to have contributed to death. In addition to the parent compound, we identified six possible metabolites where two N-demethylated dominated and four mono-hydroxylated were found in trace amounts in the blood. In conclusion, deaths with AH-7921 seem to occur both at low and high concentrations, probably a result of different tolerance to the drug. Hence, it is reasonable to assume that no sharp dividing line exists between lethal and non-lethal concentrations. Further, poly-drug use did not seem to be a major contributing factor for the fatal outcome.]

Abuse of AH-7921 has accounted for at least 16 deaths between 2012 and 2013,16 including one in the United States. AH-7921 PDF  and AH-7921 the list of new psychoactive opioids is expanded An isomer of AH-7921, U-47700, is the new compound reported and is now present in the illicit drug marketplace; it already has one recent report of death related to its use. Legislators are seeking to gain control over the spread of this dangerous drug, and recently the Kansas Bureau of Investigation released a public health warning after a number of unintentional drug overdose deaths in Kansas during the past month related to the use of U-47700.  Several states, including Ohio, Wyoming, Georgia, and Kansas, are taking steps to have U-47700 placed under emergency scheduling to make consumption, possession, and distribution illegal. In addition, anecdotally, many medical toxicology program directors from across Canada and the United States have reported presumed cases of U-47700 exposures and deaths; analytical studies are sorely missing. < Of note as of January 2017 the drug is schedule 1::

AH-7921 is a structurally unique synthetic opioid analgesic that has recently entered the drug arena in Europe, the USA, and Japan. Although it was synthesized and patented in the mid-1970s, it was first identified in a seized sample purchased via the Internet in July 2012 and formally brought to the attention of the European Union early warning system in August 2012 by the United Kingdom. Several in vitro experiments and animal model studies established the morphine-like analgesic action of AH-7921 as a l-opioid receptor agonist that has been found to be several times more potent than codeine and at least as potent as morphine. This novel psychoactive substance has already led to eight non-fatal intoxications and 16 deaths in Sweden, the United Kingdom, Norway, and the USA. AH-7921 is a new, structurally atypical synthetic opioid analgesic that appears to be sold as a ‘‘research chemical’’ or ‘‘legal opioid’’ on the Internet since 2012. It was synthesized in the 1970s by Allen and Hanburys Ltd. as a potential analgesic medicine; however, its development was abandoned due to its addictive properties. It has never been marketed as a medicine, nor used as pharmaceutical or medicinal product; it has also no industrial use [6]. There are very few references available on this compound [7]. In vivo studies in animals indicated its l-opioid receptor agonistic activities, although no studies have evaluated its pharmacological and toxicological properties in humans. Its activities are similar to those of morphine and include analgesia, hypothermia, respiratory depression, and addictive behavior [7–9]. The abuse of AH-7921 has been reported in eight member states of the European Union as well as in Norway, leading to severe toxicity (non-fatal) cases and 16 reported deaths within a limited period of time (December 2012–September 2013).

U-47700:

https://psychonautwiki.org/wiki/U-47700

 

U-47700 (3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]- N-methylbenzamide) is a novel compound with opioid properties, developed by Upjohn in the 1970s and derived from the earlier opioid analgesic AH-7921 (3,4-dichloro-N- {[1-(dimethylamino)-cyclohexyl]methyl}benzamide) . U-47700 is a structural isomer of AH-7921. AH-7921, which possesses the same potency as morphine, was first identified in 2012 in a seizure purchased over the internet and recently entered the recreational and illicit drug market as new psychotropic substance in Japan, the USA, and Europe . U-47700 was never studied in humans and is not registered for medical use in humans. Very little, if any, information on it is available in scientific literature. U-47700 is an opioid analgesic drug, considered to have a potency of approximately 7.5 times that of morphine.

Tolerance and addiction potential -psychwiki

As with other opioids, the chronic use of U-47700 can be considered moderately addictive with a high potential for abuse and is capable of causing psychological dependence among certain users. When addiction has developed, cravings and withdrawal symptoms may occur if a person suddenly stops their usage.

Tolerance to many of the effects of U-47700 develops with prolonged and repeated use. The rate at which this occurs develops at different rates for different effects, with tolerance to the constipation-inducing effects developing particularly slowly for instance. This results in users having to administer increasingly large doses to achieve the same effects. After that, it takes about 3 – 7 days for the tolerance to be reduced to half and 1 – 2 weeks to be back at baseline (in the absence of further consumption). U-47700 presents cross-tolerance with all other opioids, meaning that after the consumption of U-47700 all opioids will have a reduced effect.

The risk of fatal opioid overdoses rise sharply after a period of cessation and relapse, largely because of reduced tolerance.[21] To account for this lack of tolerance, it is safer to only dose a fraction of one’s usual dosage if relapsing. It has also been found that the environment one is in can play a role in opioid tolerance. In one scientific study, rats with the same history of heroin administration were significantly more likely to die after receiving their dose in an environment not associated with the drug in contrast to a familiar environment

U-47700 has a high toxicity relative to its dose due to its extreme potency. As with all opioids, long-term effects can vary but can include diminished libido, apathy and memory loss. It is also potentially lethal when mixed with depressants like alcohol or benzodiazepines.

It is worth noting that U-47700 crystals are particularly corrosive and somewhat caustic to mucous membranes. Careless use may deteriorate the chosen routes of administration so it is important to practice routine maintenance such as soaking the sinus cavity with water prior to and following insufflation. It is unwise to vaporise the substance as it can damage the lungs. Sublingual administration is likely to damage the skin in the mouth.

Combined consumption of U-47700 and fentanyl caused one fatality in Belgium.[19] At least 17 opioid overdoses and several deaths in the USA have also been connected with the use of U-47700.[20]

It is strongly recommended that one use harm reduction practices, and take extreme caution when using this substance.

Erowid links for U47700

Why relapse ends in death

Comparing fatal cases involving U-47700

Fentanyl and a Novel Synthetic Opioid U-47700 masquerading as street Norco in Central California

A case of acute intoxication due to combined use of fentanyl and U-47700

Use of synthetic opioid “U-47700” poses risk to Kansas citizens

Ocfentanil overdose fatality in the recreational drug scene

The hidden web and the fentanyl problem Detection of ocfentanil as an adulterant in heroin

The interest in eight new psychoactive substances before and after scheduling

Next generation of novel psychoactive substances on the horizon – A complex problem to face

The introduction of novel synthetic compounds poses several issues, including limited analytical methods for detecting and monitoring these substances. As shown in the related case report,2 suspicion for the presence of a novel drug is often initiated by experienced recreational drug users who concede that their drug experience was somehow different from normal. Additionally, a significant increase in opioid overdoses, particularly in patients with routine urine drug screens that are negative for opioids, suggests that fentanyl or another novel synthetic opioid is present. Unique toxicities have indeed been reported, including alveolar hemorrhage with butyrfentanyl and ototoxicity with MT-45.  Opioid intoxications involving butyrfentanyl, 4-fluorobutyrfentanyl, and fentanyl from the Swedish STRIDA project b

Tightrope or SlacklineThe Neuroscience of Psychoactive Substances

25B-NBOMe

Case series toxicity from 25B-NBOMe – a cluster of N-bomb cases

SYNTHETIC CANNABINOIDS

A systematic review of adverse events arising from the use of synthetic cannabinoids and their associated treatment

How toxic is ibogaine

METHOXETAMINE

A polydrug intoxication involving methoxetamine in a drugs and driving case.

Methoxetamine (MXE) – A Phenomenological Study of Experiences Induced by a Legal High from the Internet

Acute toxicity associated with the recreational use of the ketamine derivative methoxetamine

MDPV  BATH SALTS

Intoxications involving MDPV in Sweden during 2010–2014

Death following recreational use of designer drug bath salts containing 3,4-Methylenedioxypyrovalerone (MDPV)

NATURE: The Psychoactive Designer Drug and Bath Salt Constituent MDPV Causes Widespread Disruption of Brain Functional Connectivity.

PCP derivatives

Phencyclidine analog use in Sweden—intoxication cases involving 3-MeO-PCP and 4-MeO-PCP from the STRIDA project

FENTANYL-LIKE drugs

Opioid intoxications involving butyrfentanyl, 4-fluorobutyrfentanyl, and fentanyl from the Swedish STRIDA project

Death following intentional ingestion of e-liquid

I like the old stuff better than the new stuff – Subjective experiences of new psychoactive substances

Flubromazolam – A new life-threatening designer benzodiazepine

TRYPTAMINES

Recreational use, analysis and toxicity of tryptamines.

There are many categories of NPS, such as synthetic cannabinoids, synthetic cathinones, phenylethylamines, piperazines, ketamine derivatives and tryptamines. Tryptamines are naturally occurring compounds, which can derive from the amino acid tryptophan by several biosynthetic pathways: their structure is a combination of a benzene ring and a pyrrole ring, with the addition of a 2-carbon side chain. Tryptamines include serotonin and melatonin as well as other compounds known for their hallucinogenic properties, such as psilocybin in ‘Magic mushrooms’ and dimethyltryptamine (DMT) in Ayahuasca brews.

Neuropharmacology of New Psychoactive Substances (NPS) Focus on the Rewarding and Reinforcing Properties of Cannabimimetics and Amphetamine-Like Stimulants.

http://www.fsijournal.org/article/S0379-0738(14)00157-1/pdf::

Abstract

Following the initial popularity of mephedrone (4-methylmethcathinone) there has been a stream of new “recreational drugs” entering the global market. The lack of clinical studies on the effects and toxicity of these drugs has made interpretation of toxicological findings difficult. In an attempt to assist in a better understanding of the extent of their use and the fatalities that have been linked to these compounds we present our collated findings in post-mortem and criminal casework where these have been detected and/or implicated. Between January 2010 and December 2012 we have detected new psychoactive substances (NPS) in 203 cases, with 120 cases in 2012 alone. The drugs detected in in life or post-mortem blood and urine are, in order of decreasing frequency; mephedrone, 4-methylethcathinone, BZP, MDPV, TFMPP, methoxetamine, 4-fluoromethcathinone, 4-methylamphetamine, PMA, methylone, PMMA, naphyrone, alpha-methyltryptamine, butylone, MDAI, desoxypipradrol, D2PM, MPA, synthetic cannabinoids, 2-AI, 5-IAI, 5-MeODALT, MDPBP, 5/6-APB, pentedrone and pentylone. Other drugs or alcohol were detected in 84% of the cases including other NPS and in fatalities it should be noted that alternative causes of death (including mechanical suicide, accidental death and non-psychoactive drug overdose) accounted for the majority. Related to this was that of all fatalities involving cathinones, 41% of these were hangings or other mechanical suicides, this was a higher proportion than seen with other drugs found in such cases. The presence of multiple NPS and/or other stimulants was a particular feature in various cases, however, of the drug deaths only 7% solely involved NPS. Across all case types and including some cases investigated in 2013, NPS concentrations showed a wide range but these and selected cases are presented to assist toxicological interpretation in future cases.

Trifluoromethylphenylpiperazine (TFMPP) is a recreational drug of the piperazine chemical class. Usually in combination with its analogue benzylpiperazine (BZP), it is sold as an alternative to the illicit drug MDMA (“Ecstasy”) under the name “Legal X

α-Methyltryptamine (abbreviated as αMT, AMT) is a psychedelic, stimulant, and entactogen drug of the tryptamine class.[2][3] It was originally developed as an antidepressant by workers at Upjohn in the 1960s,[4] and was used briefly as an antidepressant in Russia under the trade name Indopan before being discontinued

https://psychonautwiki.org/wiki/5-MeO-DALT   << Psychonaut WIKI

5-MeO-DALT, or N,N-diallyl-5-methoxytryptamine, is a psychedelic tryptamine first synthesized by Alexander Shulgin. It is chemically related to the compounds 5-MeO-DPT and DALT. It is described as having rapid, intense and short-acting entheogenic effects.

Alexander Shulgin sent the first material regarding the synthesis and effects of 5-MeO-DALT to a researcher in May 2004; afterwards, it soon circulated online. In June 2004, it became available through the use of online research chemical vendors. In August 2004, the synthesis and effects of 5-MeO-DALT were published by Erowid.

Ephenidine_ A new psychoactive agent with ketamine-like NMDA receptor antagonist properties

Legal Highs– novel and emerging psychoactive drugs a chemical overview for the toxicologist

Spice Kryptonite Black Mamba An Overview of Brand Names and Marketing Strategies of Novel Psychoactive Substances on the Web

An Internet Study of User s Experiences of the Synthetic Cathinone 4 Methylethcathinone 4 MEC

Investigation of Bath Salts Use Patterns Within an Online Sample of Users in the United States

Exploring the Attractiveness of New Psychoactive Substances NPS among Experienced Drug Users

New psychoactive substances and British drug policy A view from the cyber psychonauts

 

https://psychonautwiki.org/wiki/Main_Page

Self-Reported Use of Novel Psychoactive Substances in a US survey

Psychinfo

Web of KNowledge

Who database

Lilacs database

https://health.ebsco.com/products/the-cinahl-database

In chronic fentanyl users, such as those patients who use fentanyl therapeutically for their chronic pain, a ratio of postmortem blood fentanyl to norfentanyl concentrations of less than 2.5 probably indicate chronic fentanyl usage rather than acute fentanyl toxicity, while that of greater than 8 is consistent with acute fentanyl toxicity

Ayahuasca – herbal hallucinogenic medicine in the news again

Ayahuasca in the United States

Erowid and Arahuasca

From Wikipedia: (https://en.wikipedia.org/wiki/Ayahuasca)

Ayahuasca (UK /ˌjəˈwæskə/; US /ˌjəˈwɑːskə/), also commonly called yagé (/jɑːˈh/ or /jæˈh/) or iowaska, is an entheogenic brew made out of Banisteriopsis caapi vine and the Psychotria viridis leaf.[1] The brew is used as a traditional spiritual medicine in ceremonies among the Indigenous peoples of Amazonia.

It can be mixed with the leaves of chacruna or chagropanga, dimethyltryptamine (DMT)-containing plant species. It has been reported that some effects can be felt from consuming the caapi vine alone, but that DMT-containing plants (such as Psychotria viridis) remain inactive when drunk as a brew without a source of monoamine oxidase inhibitor (MAOI) such as B. caapi.[2] The resulting brew is known by a number of different names.

Recent studies have put the substance back in the news, including research regarding Alzheimers disease:

-ayahuasca-alzheimers-down-syndrome-study in the news ::

Harmine stimulates proliferation of human neural progenitors

Harmine is the β-carboline alkaloid with the highest concentration in the psychotropic plant decoction Ayahuasca. In rodents, classical antidepressants reverse the symptoms of depression by stimulating neuronal proliferation. It has been shown that Ayahuasca presents antidepressant effects in patients with depressive disorder. In the present study, we investigated the effects of harmine in cell cultures containing human neural progenitor cells (hNPCs, 97% nestin-positive) derived from pluripotent stem cells. After 4 days of treatment, the pool of proliferating hNPCs increased by 71.5%. Harmine has been reported as a potent inhibitor of the dual specificity tyrosine-phosphorylation-regulated kinase (DYRK1A), which regulates cell proliferation and brain development. We tested the effect of analogs of harmine, an inhibitor of DYRK1A (INDY), and an irreversible selective inhibitor of monoamine oxidase (MAO) but not DYRK1A (pargyline). INDY but not pargyline induced proliferation of hNPCs similarly to harmine, suggesting that inhibition of DYRK1A is a possible mechanism to explain harmine effects upon the proliferation of hNPCs. Our findings show that harmine enhances proliferation of hNPCs and suggest that inhibition of DYRK1A may explain its effects upon proliferation in vitro and antidepressant effects in vivo.

Classical antidepressants can reverse or block stress-induced hippocampal atrophy in rodents, mostly by stimulating neuronal proliferation (Malberg et al., 2000). Fluoxetine, one of the most used selective serotonin reuptake inhibitors, induces proliferation of rat hypothalamic (Chen et al., 2007; Sachs & Caron, 2015; Sousa-Ferreira et al., 2014) and How to cite this article Dakic et al. (2016), Harmine stimulates proliferation of human neural progenitors. PeerJ 4:e2727; DOI 10.7717/peerj.2727 hippocampal neural progenitors in vitro and in vivo (Chen et al., 2007; Sachs & Caron, 2015). Unfortunately, treatment with classic antidepressants leads to full remission in only 50% of patients (Nestler et al., 2002), causes side effects and the time required for achieving therapeutic response is usually measured in weeks. Thus, the demand for novel psychopharmacological agents able to revert depression remains significant. Beta-carbolines, a large group of indole alkaloids are widely distributed in plants. Two members of this group, harmine and harmaline, have been found in human plasma after ingestion of Ayahuasca (Callaway et al., 1996), a psychotropic beverage traditionally used in the Amazonian region of South America as part of local religious ceremonies (Labate & Feeney, 2012). Evaluation of the effects of a single dose of Ayahuasca in six volunteers with a current depressive episode suggested that this plant decoction has fast-acting anxiolytic and antidepressant effects (Osorio Fde et al., 2015). Moreover, in rodents, the use of harmine leads to the reduction of symptoms associated with depression (Farzin & Mansouri, 2006) and re-establishment of normal levels of hippocampal brain-derived neurotrophic factor (BDNF) (Fortunato et al., 2009). Apart of these initial studies, there are no data available regarding the neurogenic effects of harmine in humans. Here we examine the effects of harmine on the proliferation of human neural progenitor cells derived from pluripotent stem cells. We show that harmine increased the pool of neural progenitor cells .  < Abstract

http://ayahuascahealings.com/ < Retreats even offered as medical tourism or spiritual tourism

But yet, bad things happen sometimes when using the Ayahuasca – click here:

A British citizen was stabbed to death in Peru after taking a hallucinogenic plant brew known as ayahusca, police have confirmed.

Unais Gomes, 26, was allegedly killed by 29-year-old Joshua Freeman Stevens during a shamanic ceremony, which involved drinking the plant brew, near the city of Iquitos on Wednesday. 

The incident is said to have taken place at Phoenix Ayahuasca, an alternative health center in the Amazonian jungle.

Witnesses at the scene claim Gomes tried to stab Stevens with a kitchen knife during a bad trip, according to a police source in Iquitos. 

More on the Dark side of Ayahuasca

Ayahuasca can have extreme negative health effects if taken with some presciptions drugs, especially antidepressants such as Prozac and other selective serotonin reuptake inhibitors. A few deaths have been attributed to the use of ayahuacsa, although the causes of the deaths have not all been conclusively determined. In at least some cases ayahuasca use might have directly resulted in the fatality.

Even TedX has something to say:

 

 

DMT