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Long known as a party drug, ketamine now used for depression, but concerns remain

A decades-old anesthetic made notorious as a party drug in the 1980s is resurfacing as a potential “game-changing” treatment for severe depression, patients and psychiatrists say, but they remain wary about potential long-term problems.

The Food and Drug Administration earlier this month OKd use of Spravato for patients with depression who have not benefited from other currently available medications. Spravato, the brand name given to the drug esketamine, is a molecule derived from ketamine — known as Special K on the club scene.

Ketamine has been shown in some studies to be useful for treating a wide variety of neurological disorders including depression. Regular, longtime use of it isn’t well understood, psychiatrists say, but the need for a new drug to treat depression is so great that the FDA put Spravato on a fast-track course for approval.

The drug likely will be commercially available in a few weeks, and patients already are requesting it. Restrictions around its use, though — the drug must be administered in a doctor’s office by providers who are certified with the company making it — mean it may be months before it’s widely available, and longer than that before insurers start paying for it.

“I don’t think we know at this point how effective it’s going to be,” said Dr. Craig Nelson, a psychiatrist at the UCSF Depression Center. “There have been a number of studies of ketamine, sometimes showing effects in people who were resistant to other drugs. If we can treat a different group of people, it would be a great advantage.”

Ketamine was developed in the 1960s as a surgical anesthetic for people and animals. The drug can cause hallucinations and a feeling of “dissociation” or unreality, and in the 1980s it took off as a party drug among people seeking those effects. It remained a common anesthetic, though, and in the early 2000s doctors began to notice a connection between ketamine and relief from symptoms of depression and other mood disorders.

Spravato is delivered by nasal spray, which patients give themselves in a doctor’s office. Patients must be monitored while they get the drug and for two hours after to make sure they don’t suffer immediate complications. At the start, patients will get the nasal spray twice a week for four weeks, then taper to regular boosters every few weeks for an indefinite period of time.

Studies of ketamine — and specifically of Spravato — have produced encouraging but inconsistent results. Psychiatrists say that, like most other antidepressants, the drug probably won’t help everyone with difficult-to-treat depression. But there likely will be a subset of patients who get substantial benefits, and that alone may make it an incredible new tool.

About 16 million Americans experience depression every year, and roughly a quarter of them get no benefit from antidepressants on the market. Thought scientists haven’t determined exactly how ketamine works on the brains of people with depression or other mood disorders, it appears to take a different path of attack than any drug already available. That means that people who don’t respond to other antidepressants may find this one works for them.

But a concern among some psychiatrists is that studies have suggested that ketamine may affect the same receptors in the brain that respond to opioids. Ketamine and its derivations may then put patients at risk of addiction — but research so far hasn’t explored that kind of long-term effect.

“There might be some potential problems if you used it too aggressively,” said Dr. Alan Schatzberg, director of the Stanford Mood Disorders Center, who led the research that identified a connection with opioid receptors. “The issue is not so much the short-term use, it’s the repetitive use, and the use over time, as to whether there are going to be untoward consequences.

“It would be hard for me to recommend the use of this drug for chronically depressed people without knowing what the endgame is here,” he added.

Dr. Carolyn Rodriguez, a Stanford psychiatrist who was part of the studies of ketamine and opioid receptors, said she shares Schatzberg’s concerns. But she’s been studying the use of ketamine to treat obsessive-compulsive disorder, and for some patients the results have been so remarkable that the benefits may exceed the risks.

“When I gave ketamine to my first patient, I nearly fell off my chair. Somebody said it was like a vacation from their OCD, and I was just, ‘Wow, this is really possible,’” Rodriguez said. “I want to make sure patients have their eyes wide open. I hope (the FDA approval) spurs more research, so we can really inform consumers.”

Though the new nasal spray is the first formal FDA approval of a ketamine-derived drug, psychiatrists have been using the generic anesthetic for years to study its effect on depression and other mood disorders.

In recent years, clinics have opened around the country offering intravenous infusions of ketamine to people with hard-to-treat depression and other problems. These treatments aren’t specifically FDA-approved but are allowed as off-label use of ketamine. The clinics have faced skepticism from some traditional psychiatrists, but there’s a growing ream of anecdotal evidence that the ketamine IVs work — for some people.

Aptos resident Mary, who suffers from depression and other mood disorders and asked that her last name not be used to protect her privacy, said the already available antidepressants weren’t keeping her symptoms at bay, and she frequently felt “one step away from the abyss.” When she first heard about ketamine, from a support group for people with depression and other mood disorders, she was hesitant.

“I kind of hemmed and hawed, because I’d heard that K was a street drug,” Mary said. “But then I said, ‘What do I have to lose?’ So I went and did it.”

The results were quick: Within four days, “the cloud had lifted,” she said. More than a year later, she is still feeling good with regular infusions every three or four weeks. During the ketamine infusion, Mary said she’ll feel the dissociation, which she described as feeling like she’s viewing the world around her as though it were a movie and not her own life.

She said she’s pleased the FDA approved Spravato, though she hasn’t decided whether she’ll switch from the IV ketamine to the nasal spray. She hopes that the FDA approval will give some validation to ketamine and encourage others to try it.

Mary gets her infusions at Palo Alto Mind Body, where Dr. M Rameen Ghorieshi started offering ketamine two years ago. He’s certified with the maker of Spravato — Janssen Pharmaceuticals, a branch of Johnson and Johnson — to provide the drug, though he doesn’t know when he’ll actually start giving the nasal spray to patients.

Ghorieshi said that although he’s been offering IV ketamine for more than two years, he shares his colleagues’ wariness of the long-term effects of regular use of the drug. He hopes FDA approval will encourage further research.

“At this point we’ve done 1,000 infusions. The outcomes have exceeded my own expectations,” Ghorieshi said. “But anecdotes are not clinical trials. I approach this very cautiously. What I don’t want is 20 or 30 years from now to look back and say, ‘What did we do?’”

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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

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Ketamine has much support in the use of hard-to-treat depression and suicidal behaviors. Below are studies and their links, including a meta-analysis, which demonstrate the effect of Ketamine. Also a recent trial by Carlos Zarate shows the heterogenous nature of response to Ketamine . It is difficult to say who is going to be lifted from their depression completely or partially respond, but in the study, Dr. Zarate showed that patients with a long history of suicidal thinking and self-harm will have less of a response in some cases.

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Intravenous ketamine may rapidly reduce suicidal thinking in depressed patients << Article link 

Intravenous ketamine may rapidly reduce suicidal thinking in depressed patients

Repeat intravenous treatment with low doses of the anesthetic drug ketamine quickly reduced suicidal thoughts in a small group of patients with treatment-resistant depression. In their report receiving Online First publication in the Journal of Clinical Psychiatry, a team of Massachusetts General Hospital (MGH) investigators report the results of their study in depressed outpatients who had been experiencing suicidal thought for three months or longer.

“Our finding that low doses of ketamine, when added on to current antidepressant medications, quickly decreased suicidal thinking in depressed patients is critically important because we don’t have many safe, effective, and easily available treatments for these patients,” says Dawn Ionescu, MD, of the Depression Clinical and Research Program in the MGH Department of Psychiatry, lead and corresponding author of the paper. “While several previous studies have shown that ketamine quickly decreases symptoms of depression in patients with treatment-resistant depression, many of them excluded patients with current suicidal thinking.”

It is well known that having suicidal thoughts increases the risk that patients will attempt suicide, and the risk for suicide attempts is 20 times higher in patients with depression than the general population. The medications currently used to treat patients with suicidal thinking — including lithium and clozapine — can have serious side effects, requiring careful monitoring of blood levels; and while electroconvulsive therapy also can reduce suicidal thinking, its availability is limited and it can have significant side effects, including memory loss.

Primarily used as a general anesthetic, ketamine has been shown in several studies to provide rapid relief of symptoms of depression. In addition to excluding patients who reported current suicidal thinking, many of those studies involved only a single ketamine dose. The current study was designed not only to examine the antidepressant and antisuicidal effects of repeat, low-dose ketamine infusions in depressed outpatients with suicidal thinking that persisted in spite of antidepressant treatment, but also to examine the safety of increased ketamine dosage.

The study enrolled 14 patients with moderate to severe treatment-resistant depression who had suicidal thoughts for three months or longer. After meeting with the research team three times to insure that they met study criteria and were receiving stable antidepressant treatment, participants received two weekly ketamine infusions over a three-week period. The initial dosage administered was 0.5 mg/kg over a 45 minute period — about five times less than a typical anesthetic dose — and after the first three doses, it was increased to 0.75 mg/kg. During the three-month follow-up phase after the ketamine infusions, participants were assessed every other week.

The same assessment tools were used at each visit before, during and after the active treatment phase. At the treatment visits they were administered about 4 hours after the infusions were completed. The assessments included validated measures of suicidal thinking, in which patients were directly asked to rank whether they had specific suicide-related thoughts, their frequency and intensity.

While only 12 of the 14 enrolled participants completed all treatment visits — one dropped out because of ketamine side effects and one had a scheduling conflict — most of them experienced a decrease in suicidal thinking, and seven achieved complete remission of suicidal thoughts at the end of the treatment period. Of those seven participants, two maintained remission from both suicidal thinking and depression symptoms throughout the follow-up period. While there were no serious adverse events at either dose and no major differences in side effects between the two dosage levels, additional studies in larger groups of patients are required before any conclusions can be drawn.

“In order to qualify for this study, patients had to have suicidal thinking for at least three months, along with persistent depression, so the fact that they experienced any reduction in suicidal thinking, let alone remission, is very exciting,” says Ionescu, who is an instructor in Psychiatry at Harvard Medical School. “We only studied intravenous ketamine, but this result opens the possibility for studying oral and intranasal doses, which may ease administration for patients in suicidal crises.”

She adds, “One main limitation of our study was that all participants knew they were receiving ketamine. We are now finishing up a placebo-controlled study that we hope to have results for soon. Looking towards the future, studies that aim to understand the mechanism by which ketamine and its metabolites work for people with suicidal thinking and depression may help us discover areas of the brain to target with new, even better therapeutic drugs.”

 

Rapid and Sustained Reductions in Current Suicidal Ideation Following Repeated Doses of Intravenous Ketamine: Secondary Analysis of an Open-Label Study  << Article in Clinical Psychiatry

Ketamine for Rapid Reduction of Suicidal Thoughts in Major Depression: A Midazolam-Controlled Randomized Clinical Trial Article link for below:

Ketamine was significantly more effective than a commonly used sedative in reducing suicidal thoughts in depressed patients, according to researchers at Columbia University Medical Center (CUMC). They also found that ketamine’s anti-suicidal effects occurred within hours after its administration.

The findings were published online last week in the American Journal of Psychiatry.

According to the Centers for Disease Control and Prevention, suicide rates in the U.S. increased by 26.5 percent between 1999 and 2015.

“There is a critical window in which depressed patients who are suicidal need rapid relief to prevent self-harm,” said Michael Grunebaum, MD, a research psychiatrist at CUMC, who led the study. “Currently available antidepressants can be effective in reducing suicidal thoughts in patients with depression, but they can take weeks to have an effect. Suicidal, depressed patients need treatments that are rapidly effective in reducing suicidal thoughts when they are at highest risk. Currently, there is no such treatment for rapid relief of suicidal thoughts in depressed patients.”

Most antidepressant trials have excluded patients with suicidal thoughts and behavior, limiting data on the effectiveness of antidepressants in this population. However, previous studies have shown that low doses of ketamine, an anesthetic drug, causes a rapid reduction in depression symptoms and may be accompanied by a decrease in suicidal thoughts.

The 80 depressed adults with clinically significant suicidal thoughts who enrolled in this study were randomly assigned to receive an infusion of low-dose ketamine or midazolam, a sedative. Within 24 hours, the ketamine group had a clinically significant reduction in suicidal thoughts that was greater than with the midazolam group. The improvement in suicidal thoughts and depression in the ketamine group appeared to persist for up to six weeks.

Those in the ketamine group also had greater improvement in overall mood, depression, and fatigue compared with the midazolam group. Ketamine’s effect on depression accounted for approximately one-third of its effect on suicidal thoughts, suggesting the treatment has a specific anti-suicidal effect.

Side effects, mainly dissociation (feeling spacey) and an increase in blood pressure during the infusion, were mild to moderate and typically resolved within minutes to hours after receiving ketamine.

“This study shows that ketamine offers promise as a rapidly acting treatment for reducing suicidal thoughts in patients with depression,” said Dr. Grunebaum. “Additional research to evaluate ketamine’s antidepressant and anti-suicidal effects may pave the way for the development of new antidepressant medications that are faster acting and have the potential to help individuals who do not respond to currently available treatments.”

Ketamine for Rapid Reduction of Suicidal Thoughts in major depression – A midazolam controlled trial PDF article

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______________________________________________________________________

Ketamine as a Potential Treatment for Suicidal Ideation A Systematic Review of the Literature 2015

Abstract
Objective To review the published literature on the efficacy
of ketamine for the treatment of suicidal ideation (SI).
Methods The PubMed and Cochrane databases were
searched up to January 2015 for clinical trials and case
reports describing therapeutic ketamine administration to
patients presenting with SI/suicidality. Searches were also
conducted for relevant background material regarding the
pharmacological function of ketamine.
Results Nine publications (six studies and three case
reports) met the search criteria for assessing SI after
administration of subanesthetic ketamine. There were no
studies examining the effect on suicide attempts or death
by suicide. Each study demonstrated a rapid and clinically
significant reduction in SI, with results similar to previously
described data on ketamine and treatment-resistant
depression. A total of 137 patients with SI have been
reported in the literature as receiving therapeutic ketamine.
Seven studies delivered a dose of 0.5 mg/kg intravenously
over 40 min, while one study administered a 0.2 mg/kg
intravenous bolus and another study administered a liquid
suspension. The earliest significant results were seen after
40 min, and the longest results were observed up to
10 days postinfusion.
Conclusion Consistent with clinical research on ketamine
as a rapid and effective treatment for depression, ketamine
has shown early preliminary evidence of a reduction in
depressive symptoms, as well as reducing SI, with minimal
short-term side effects. Additional studies are needed to
further investigate its mechanism of action, long-term
outcomes, and long-term adverse effects (including abuse)
and benefits. In addition, ketamine could potentially be
used as a prototype for further development of rapid-acting
antisuicidal medication with a practical route of administration
and the most favorable risk/benefit ratio.
Key Points
Preliminary data from randomized controlled trials
have demonstrated that ketamine may rapidly and
effectively control treatment-resistant depression,
though the effects are transient.
A small subset of studies has demonstrated similar
results in the effects of ketamine on suicidal ideation.
Ketamine has potential as a rapid treatment for
suicidal ideation and/or a possible model compound
for future drug development.

4 Discussion
With an estimated prevalence of mood disorders ranging
from 3.3 to 21.4 % and the substantially increased risk of
suicide among patients with mood disorders, treatment is
certainly warranted [19]. Current treatment options for
suicidality are limited. They include brain stimulation
therapeutics, such as ECT, and pharmacological intervention
(lithium, clozapine). The efficacy of lithium in treating
suicidality has been documented [20, 21] and has recently been reviewed and pooled in a recent meta-analysis of 48
studies [22]. Clozapine has also been shown to reduce
suicide risk in patients with schizophrenia [23, 24]. The
limitations of both lithium and clozapine include a longer
time to efficacy in this psychiatric emergency/urgency,
compared with the early response to ketamine [25]. Ketamine
seems to be gaining substantial evidence as a pharmacological
option for depression with a fast onset of
action, but its long-term effects need further investigation.
In addition, ketamine probably offers a faster onset of
action in terms of SI, but further work is certainly needed
in this area. Given the risk of suicide and even the
increasing rates of suicide in certain subgroups, such as
soldiers and veterans [26, 27], there is an urgent need for
faster therapeutics for SI and TRD. Importantly, suicidality
and suicide pose a high global burden of patient suffering
to families and society. Although several small-to-moderate
sized studies, in addition to several reviews, have been
published that have examined the efficacy of ketamine in
TRD, there are considerably fewer published data
specifically examining ketamine in patients presenting with
SI. Notably, only three studies have directly examined SI
as the primary outcome [11, 16, 17], while the rest
examined SI as the secondary outcome [4, 15, 18], not
including case reports. This review summarizes the current
published literature regarding ketamine as a treatment for
SI. The data so far show promising trends of ketamine
being an effective and rapid treatment with minimal side
effects.
Pharmacologically, ketamine is an N-methyl-D-aspartate
(NMDA) receptor antagonist. It has been used for anesthesia
in the USA since the 1970s. At subanesthetic doses,
ketamine has been shown to increase glutamate levels [3].
This mechanism is relevant, as glutamate regulation and
expression are altered in patients with major depressive
disorder (MDD). Studies have also demonstrated an
abnormal glutamate–glutamine–gamma-aminobutyric acid
cycle in patients with suicidality [28]. Furthermore, ketamine
has also been shown to work on nicotinic and opioid
receptors [29]. No other class of antidepressant medication
works to modulate the glutamatergic system, and research
continues into this, with the goal of characterizing the full
mechanism of action of ketamine and perhaps developing
other compounds that would have similar effects. Thus,
even if the approval and marketing of ketamine as a rapidacting
antisuicidal and antidepressant medication is not
realized, it could well be a prototype for development of
other medication(s) that retain the mechanism of action
with more favorable qualities and a lesser adverse effect
profile (such as a longer duration of action or less or no
addictive potential). Although the mechanisms explaining
the antisuicidal effect and the NMDA receptor antagonism
of ketamine are still unclear, some of the initial evidence
points to an anti-inflammatory action via the kynurenic
acid pathway. Strong suggestions as to the causal relationship
between inflammation and depression/suicidality
has come from studies demonstrating that cytokines [30,
31] and interferon-b [32] induce depression and suicidality.
Other recent studies have added to the notion of implicating
brain immune activation in the pathogenesis of suicidality.
For instance, one study showed microglial
activation of postmortem brain tissue in suicide victims
[33]. Another study found increased levels of the cytokine
interleukin-6 in cerebrospinal fluid from patients who had
attempted suicide [34]. Higher levels of inflammatory
markers have been shown in suicidal patients than in nonsuicidal
depressed patients [33, 35]. Inflammation leads to
production of both quinolinic acid (an NMDA agonist) and
kynurenic acid (a NMDA antagonist). An increased
quinolinic acid to kynurenic acid ratio leads to NMDA
receptor stimulation. The correlation between quinolinic
acid and Suicide Intent Scale scores indicates that changes
in glutamatergic neurotransmission could be specifically
linked to suicidality [36].
Small randomized controlled trials have demonstrated
the efficacy of ketamine in rapidly treating patients with
both TRD and/or bipolar depression [4, 8, 9, 11, 16–18].
Some studies have also examined suicide items as a secondary
measure in their depression rating scales [4, 7]. In
total, the studies examining ketamine and TRD have nearly
consistently demonstrated that ketamine provides relief
from depressive and suicidal symptoms, starting at 40 min
and lasting for as long as 5 days. Questions still remain as
to the long-term effects of this treatment, how much should
be administered and how often, any serious adverse effects,
and the mechanism of action.
Pharmacologically, ketamine has poor bioavailability
and is best administered via injection [37]. In their landmark
study, Berman et al. [4] found that a subanesthetic
dose (0.5 mg/kg) rapidly improved depressive symptoms.
Most of the subsequent studies have delivered ketamine as
a constant infusion for 40 min at a rate of 0.5 mg/kg.
Others have examined its efficacy after multiple infusions
and observed similar results [8, 13, 16, 38]. Currently, it is
recommended that ketamine be administered in a hospital
setting [39].

______________________________________

Characterizing the course of suicidal ideation response to ketamine

Characterizing the course of suicidal ideation response to ketamine PDF

2018 article from Carlos Zarate discussing the variable course outcomes with Ketamine for suicidality and correlations to serum markers and behavior and longevity of self-harm prior to treatment:

 

Background: : No pharmacological treatments exist for active suicidal ideation (SI), but the glutamatergic
modulator ketamine elicits rapid changes in SI. We developed data-driven subgroups of SI trajectories after
ketamine administration, then evaluated clinical, demographic, and neurobiological factors that might predict SI
response to ketamine.
Methods: : Data were pooled from five clinical ketamine trials. Treatment-resistant inpatients (n = 128) with
DSM-IV-TR-diagnosed major depressive disorder (MDD) or bipolar depression received one subanesthetic
(0.5 mg/kg) ketamine infusion over 40 min. Composite SI variable scores were analyzed using growth mixture
modeling to generate SI response classes, and class membership predictors were evaluated using multinomial
logistic regressions. Putative predictors included demographic variables and various peripheral plasma markers.
Results: : The best-fitting growth mixture model comprised three classes: Non-Responders (29%), Responders
(44%), and Remitters (27%). For Responders and Remitters, maximal improvements were achieved by Day 1.
Improvements in SI occurred independently of improvements in a composite Depressed Mood variable for
Responders, and partially independently for Remitters. Indicators of chronic SI and self-injury were associated
with belonging to the Non-Responder group. Higher levels of baseline plasma interleukin-5 (IL-5) were linked to
Remitters rather than Responders.
Limitations: : Subjects were not selected for active suicidal thoughts; findings only extend to Day 3; and plasma,
rather than CSF, markers were used.
Conclusion: : The results underscore the heterogeneity of SI response to ketamine and its potential independence
from changes in Depressed Mood. Individuals reporting symptoms suggesting a longstanding history of chronic
SI were less likely to respond or remit post-ketamine.

1. Introduction
Suicide poses a serious threat to public health. Worldwide, suicide
accounts for approximately 1 million deaths, and 10 million suicide
attempts are reported annually (World Health Organization, 2014). In
the United States, the national suicide rate has increased by approximately
28% over the last 15 years (Curtin et al., 2016). At the same
time, relatively few interventions for suicide risk exist. While treatments
such as clozapine and lithium have demonstrated effects on
suicidal behavior over weeks to months, these effects may be limited to
specific diagnoses (Cipriani et al., 2005; Griffiths et al., 2014). Currently,
no FDA-approved medications exist to treat suicidal ideation
(SI), leaving those who experience a suicidal crisis with limited options
for a reprieve of symptoms. Consequently, a critical need exists for
rapid-acting treatments that can be used in emergency settings.
A promising off-label agent for this purpose is the rapid-acting antidepressant
ketamine, which past studies have suggested reduces suicidal
thoughts (Diazgranados et al., 2010a; Murrough et al., 2015; Price
et al., 2009). A recent meta-analysis of 167 patients with a range of
mood disorder diagnoses found that ketamine reduced suicidal
thoughts compared to placebo as rapidly as within a few hours, with
effects lasting as long as seven days (Wilkinson et al., 2017). These
results are reinforced by newer findings of reduced active suicidal
ideation post-ketamine compared to a midazolam control(Grunebaum et al., 2018). As the efficacy literature develops in the era
of personalized medicine, two important issues must be addressed.
First, little is known about the acute course of SI following ketamine.
The speed with which antidepressant response occurs, and how much
improvement can be expected on average, has been documented for
single administrations of ketamine (Mathew et al., 2012; Sanacora
et al., 2017); in the limited available literature, researchers have
emulated previous studies examining antidepressant effect, where a
cutoff of 50% improvement demarcated response (Nierenberg and
DeCecco, 2001). Nevertheless, it remains unknown whether this categorization
accurately reflects the phenomenon of suicidal thoughts.
Empirically-derived approaches to the description of SI trajectory after
ketamine may be useful in operationalizing “response” in future clinical
trials.
Second, identifying demographic, clinical, or biological predictors
of SI response to ketamine would allow researchers and clinicians to
determine who is most likely to exhibit an SI response to ketamine. A
broad literature describes clinical and demographic predictors for suicide
risk (Franklin et al., 2017), and a smaller literature connects suicidal
thoughts and behaviors to plasma markers such as brain-derived
neurotrophic factor (BDNF) and cytokines (Bay-Richter et al., 2015;
Falcone et al., 2010; Isung et al., 2012; Serafini et al., 2017; Serafini
et al., 2013). However, no biomarkers have been shown to predict SI/
behavior response to intervention, a finding reinforced by the National
Action Alliance for Suicide Prevention’s Research Prioritization Task
Force’s Portfolio Analysis (National Action Alliance for Suicide
Prevention: Research Prioritization Task Force, 2015). Notably, predictor
analyses have the potential to reveal insights into personalized
treatments for suicidal individuals, as well as the neurobiology of SI
response. With respect to antidepressant response, for example, this
approach yielded the observation that individuals with a family history
of alcohol dependence may be more likely to exhibit an antidepressant
response to ketamine (Krystal et al., 2003; Niciu et al., 2014; PermodaOsip
et al., 2014).
The goals of this study were to elucidate trajectories of SI response
and identify predictors of that response, with the ultimate goal of
adding to the growing literature surrounding ketamine’s specific effects
on SI. In particular, we sought to determine whether the heterogeneous
patterns of change in SI after ketamine administration were better explained
by a model with two or more latent groups of trajectories rather
than a single average trajectory, using secondary analyses from previously
published clinical trials. These classes were then used to evaluate
potential clinical, demographic, and plasma biomarker predictors
of SI response to ketamine in order to generate hypotheses.. Discussion
This analysis used a data-driven approach to characterize SI response
to ketamine. The data were best explained by three trajectory
classes: one with severe average baseline SI and little to no response to
ketamine (Non-Responders), one with moderate average baseline levels
of SI and significant response to ketamine (Responders), and a third
with moderate average baseline levels of SI and complete remission of
SI by two days post-ketamine (Remitters). These findings suggest a
diversity of post-ketamine changes in SI that may not be captured under
traditional methods of categorizing response to treatment.
Furthermore, we found evidence that SI response and antidepressant
response could be distinguished from each other; one subset of participants
experienced improvement in SI that was partially explained by
improvements in Depressed Mood, while the other group’s improvements
in SI occurred independently of antidepressant response. With
regard to predictors of SI response trajectory, preliminary results suggest
the individuals least likely to experience improvement in SI postketamine
were those with the most severe SI and a history of self-injury.
Few plasma markers emerged as predictors of SI response in this study,
highlighting the limitations of connecting SI ratings of response with
biological markers.
The growth mixture modeling approach used here underscored the
heterogeneity of SI response to ketamine, which would not have been
captured by simply calculating the average trajectory. The class assignment
from this approach also differed from the definition of response
(50% reduction in symptoms) traditionally used in the antidepressant
literature, which often focuses on a specific timepoint rather
than the entire symptom trajectory. In comparing classification using a
50% response at Day 1 and Day 3 with the latent trajectory classes, we
found representation of almost every SI class across each responder
group, highlighting the potential limitations of the 50% response approach.
Further study is needed to determine which of these approaches
will prove more fruitful. Complete remission of SI has previously been
used as an outcome measure in clinical trials and in a meta-analysis of
ketamine’s efficacy (Grunebaum et al., 2017; Grunebaum et al., 2018;
Wilkinson et al., 2017), as well as in a study examining the relationship
between SI response to ketamine and changes in nocturnal wakefulness
(Vande Voort et al., 2017). One strength of the present study is that this
data-driven approach provides classifications that directly reflect the
phenomena under study as they are, as opposed to what they should be.
Especially when used in larger samples than the current study, this
approach is particularly promising in its ability to provide a more
nuanced understanding of the nature of SI response to ketamine.
Our results also support the idea that SI response in particular can target. First, it should be noted here that SI classes were not distinguishable
by baseline Depressed Mood scores; patients with the most
severe SI did not differ meaningfully in Depressed Mood scores from
those with the mildest SI. Second, while previous analyses of these data
documented that BMI and family history of alcohol dependence predicted
antidepressant response (Niciu et al., 2014), SI response was not
associated with these variables in the current analysis. Third, the antidepressant
response profiles of the SI classes suggest that SI response
and antidepressant response are not wholly redundant. This aligns with
previous clinical trials and meta-analytic reviews of the literature suggesting
that SI response to ketamine occurs partially independently of
antidepressant response (Grunebaum et al., 2018; Wilkinson et al.,
2017). Nevertheless, this independence did not hold true across both SI
response groups. Specifically, antidepressant and SI response were
clearly linked in Remitters, with depression accounting for half of the
changes in SI; however, in Responders, improvements in SI occurred
independently from improvements in Depressed Mood. These discrepancies
could be related to ketamine’s complex neurobiological
mechanisms or to the potentially low levels of clinical severity observed
in the Remitters.
Interestingly, the current analyses found no baseline demographic
variables that reliably distinguished Responders from Remitters. Some
phenotypic characteristics were uniquely associated with belonging to
the Non-Responder group, suggesting that a long-standing history of
self-injury or SI may indicate resistance to rapid changes in SI.
Relatedly, a recent, randomized clinical trial of repeat-dose ketamine
compared to placebo found that ketamine had no effect on SI in a
sample of patients selected for their longstanding, chronic history of SI
(Ionescu, 2017). These results highlight the importance of patient selection,
particularly for suicide risk. It should be stressed, however, that
SI does not necessarily translate to suicidal attempts or deaths; to our
knowledge, no study has yet linked ketamine with reduced risk of
suicidal behavior. Indeed, in the present study the SI Non-Responders
experienced limited antidepressant effects in response to ketamine, but
may nevertheless have improved on other, unmeasured symptoms that
could provide important benefit and relief. As the ketamine literature
develops, it will be important to identify which clinical symptom profiles
are most likely to have a robust anti-SI and anti-suicidal behavior
response to ketamine and which ones may benefit from other interventions.
While we evaluated a range of potential plasma markers previously
linked to suicidal ideation and behavior, in the present analysis only IL5
was associated with the SI Responder subgroup. Ketamine is known to
have anti-inflammatory effects (Zunszain et al., 2013), but the relationship
between antidepressant response and change in cytokine
levels remains unclear (Park et al., 2017). Cytokines have been linked
to suicidal behavior in the past; a recent meta-analysis found that lower
levels of IL-2 and IL-4, and higher levels of TGFbeta, were associated
with suicidal thoughts and behaviors (Serafini et al., 2013); however, toour knowledge IL-5 has not previously been linked to SI. Given the large
number of comparisons and lack of precedent in the literature, this
result may have been spurious and should be interpreted with caution.
A number of other results may reflect meaningful relationships, but the
high degree of variability—and the associated wide confidence intervals—suggests
that larger sample sizes are needed to better elucidate
the nature of any such relationships (e.g. baseline VEGF: χ2 = 6.13,
p = .05, but OR (95% CI) 13.33 (0.93–200.00)). Somewhat surprisingly,
plasma BDNF levels were not associated with responder class.
Previous studies of bipolar, but not MDD, samples found that plasma
BDNF levels were associated with SI response after ketamine
(Grunebaum, 2017; Grunebaum et al., 2017), suggesting that the mixed
diagnostic composition of this study may explain differences from
previous work. Studies exploring the relationship between BDNF and
antidepressant response to ketamine have also yielded mixed findings
(Haile et al., 2014; Machado-Vieira et al., 2009). Other data-driven
approaches have considered both biological and behavioral variables in
characterizing depression (Drysdale et al., 2017); a similar approach
might prove useful for predicting SI response.
The present study is associated with several strengths as well as
limitations. Strengths include the relatively large sample size of participants
who received ketamine, the use of composite SI scores from
previous exploratory factor analyses as opposed to individual items,
and the combination of clinical and biological markers as potential
predictors of class membership. Limitations include patient selection
methods, as these patients were part of an antidepressant trial and were
not selected for active suicidal thoughts, as well as the exploratory
nature of the analysis. As stated above, suicidal thoughts do not necessarily
equate to suicidal behavior, and class membership would thus
not necessarily correspond with an overall reduction in suicide risk.
Another limitation is that results were collapsed across several clinical
trials with slight variations in study design, and findings were thus only
extended to Day 3 rather than a week after ketamine administration. As
a result, only a subset of the sample could be used for predictive analyses.
In addition, plasma—rather than CSF—markers were used, and
the latter might better indicate underlying biology due to proximity to
the brain, though certain markers such as plasma BDNF may be related
to platelet storage, rather than the brain (Chacón-Fernández et al.,
2016). Comparison of results to trajectories of suicide-specific measures,
such as the Scale for Suicide Ideation (Beck et al., 1979), may also
give further insight into specific SI content. Finally, many clinical
predictors were collected upon hospital admission; future analyses
could use formal assessments, such as the Childhood Traumatic Questionnaire
(Bernstein et al., 1994), assessment of personality disorders,
or diagnoses such as post-traumatic stress disorder (PTSD) as potential
indicators of response.
Despite these limitations, the study demonstrates the utility of a
data-driven approach for characterizing the heterogeneity of SI response
to a rapid-acting intervention. This allows for a more finegrained
analysis of symptoms than would be permitted by traditionalapproaches, such as overall average response or dichotomization at
50% reduction in symptoms. This study identified several findings of
note. These included distinguishing at least three patterns of SI response
to ketamine and finding that subjects who exhibited more severe SI at
baseline were not likely to experience an SI response to ketamine.

 

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Psychology Today Article: Ketamine: Old Drug, New Tricks

 

Ketamine has been used as an anesthetic for 50 years, and for decades the clinicians prescribing it have noticed sudden, appreciable anti-suicide and antidepressant effects in their patients. Case reports of desperate suicidal depressionrelieved within half an hour were discussed in the waning years of the 20th century, but actual research papers with small trials have only started trickling in within the last two decades.

Even after all this time, the research done thus far has not led to ketamine being mainstream FDA-approved as standard therapy for depression or suicidal ideation. For one thing, the kind of ketamine used in the US for most of the last 50 years is an IV drip requiring nursing and vital sign monitoring. In my neck of the woods, IV ketamine treatment is $3,000 (not covered by insurance or Medicare), usually completed in six treatments over two weeks. Not exactly within reach for many of my patients with resistant depression (who tend to decline in socioeconomic status over time).

In the case studies, folks’ depression rather notoriously rebounded back from ketamine therapy and then became resistant, though that didn’t happen to everyone. But how could we study how effective ketamine is? It’s generic, so there’s no pharmaceutical company with the millions to blow on state-of-the-art, beautiful randomized controlled trials to bring before the FDA. The patient population for ketamine is also a difficult one. Suicidal folks and depressed people with illness resistant to standard therapy or meds are more likely to give a drug company an expensive and public failure rather than profit, no matter that this is a population desperately in need of new ideas and new thinking. However, new formulations and the slow grind of publicly funded studies means new life for this elderly drug.

Before we talk about how ketamine works, let’s talk about how mental illness arises in terms of the actual pathology in the brain. (Note: This will necessarily be an oversimplification.) In short, most mental illness develops at the intersection of too much emotional or physical stress and genetic vulnerability leading to limitations in efficient brain functioning. This happens when brain becomes overwhelmed with excitatory signals: too much stress, too much activation of the fight-or-flight nervous system leading to specific over-activation of certain brain areas (like the left prefrontal cortex, the hippocampus, or the amygdala) without compensatory time or resources for recovery and repair.

The emotional and physical stressors could be, for example, a death in the family, extended work stress, viral illness that affects the brain, medications that affect the brain, or traumatic brain injury. The genetic vulnerability could be an increased inefficiency in being able to make specific neurotransmitters or brain fertilizers that help in recovery and repair, or an increased genetic ability to send excitatory ions through cell membranes, or many more complex issues we haven’t yet figured out.

Under this theory, almost any intervention could decrease symptoms of mental illness if it increases general neuron recovery and repair—or the efficiency of neurotransmitter use in the recovery and repair pathway—or reduces neurotoxic activation of the excitatory pathway (or “excitotoxicity“). Interventions such as regular exercise, meditationpsychotherapy, selective serotonin reuptake inhibitors (SSRIs), antipsychotics, lithium, magnesium, anti-seizure meds and many other treatment paradigms can be at least partially effective to decrease symptoms. Keep in mind, sometimes the disease is a tank, and the spear in your arsenal (regular exercise, for example) is never going to be enough to take out that tank. Sometimes you need anti-tank missiles (such as low dose antipsychotics for severe resistant depression).

Ketamine is, among many other things, an NMDA receptor antagonist(though even this characterization is complicated). This means that ketamine blocks the action at the NMDA receptor, normally turned on by the major excitatory neurotransmitter in the nervous system, glutamate. NMDA receptor over-activation is ground zero for excitotoxiticy, kind of like a gas pedal that is stuck in the downward position. So far, though, not a single FDA-approved psychiatric medication in general practice specifically unsticks that gas pedal. But ketamine does. (So will, to a much lesser extent, magnesium* and the supplement NAC, which decreases glutamate concentrations). This gas pedal unsticking is how ketamine can seemingly do the impossible: take a dangerously suicidal patient and make them feel much, much better in less than an hour.

Wikimedia Commons
Source: Wikimedia Commons

In 2016, a new formulation of ketamine, esketamine, was granted FDA “breakthrough therapy” designation for major depressive disorder with imminent risk of suicide. It’s a nasal spray used in Europe for anesthesia, but never used in the US before. It has three to four times the affinity for the NMDA receptor as ketamine and fewer intolerable side effects (such as hallucinations, dissociation, and dangerous fluctuations of vital signs). A phase two study of esketamine was published in April 2018, a randomized controlled trial of suicidal depressed patients. They agreed to be monitored on an inpatient unit for five days after the first administration of the medicine, followed by twice-a-week administration for four weeks in addition to standard antidepressant treatment. To empathize how ill the population in this study was, three (placebo) patients out of 68 made suicide attempts during the follow up period, and half needed additional suicide precautions during their inpatient stay (usually decreased time between nursing checks which is, at the low end, every 15 minutes on a standard inpatient unit). Esketamine results separated from those of placebo treatment by four hours and at 24 hours, with rapid relief from suicidal thoughts and depressive symptoms, but there seemed to be no difference with esketamine and placebo at 25 days.

This study seems to support the old case study observations, that ketamine can be amazingly helpful short term, but is not really a long-term intervention. But it’s hard to tell, and we need more data. No one really knows why there’s such a rapid ketamine poop-out, but from a clinical perspective, who cares? A fast intervention that decreases suicidal ideation could save lives while our other, proof-tested, slower interventions take their time to work. This could also shorten inpatient hospital stays for depression, freeing up precious resources and getting people back to their families, work, and communities. While the use in observed settings such as inpatient units and emergency rooms is likely to accelerate, we need way more-real world data before we start prescribing nasal spray in outpatient treatment, especially for dangerously suicidal patients.

Ketamine studies have also opened the doors for other NMDA receptor antagonist interventions. Some drugs in development include new formulations of dextromethorphan and rapastinel. Given that psychiatric drugs have been endless renditions of the same tricyclic antidepressants,  SSRIs, dopamine blockers, and dopamine partial agonists for decades, we could use a new approach.

And remember, there are plenty of ways to unstick that gas pedal early in the game, with proper self care and healthy living. Modern life, in America at least, doesn’t much incentivize vacation or sleep, both of which help that recovery and repair cycle. As a psychiatrist I’ll use whatever evidence-based intervention I can at any stage to treat the patient where he or she is to make them start getting better in the moment. As a health writer I can suggest eating a (mostly) home-cooked whole foods diet, avoiding a lot of alcohol and smoking, and getting enough physical movement, rest, and recharging time. In the brain, it’s all about reducing that excitotoxicity. In life, it’s all about a clear head, good energy, and serenity.

*Magnesium is also felt to work, in some respects, by antagonizing NMDA receptors “

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Traditional antidepressants may take weeks to work on individuals. There have been associations with increased suicidality in some studies. The need for a more rapidly acting antidepressant is important. The study below investigated the antidepressant effect of Ketamine by looking through an FDA database and observing associations of pain and depression reduction with the use of Ketamine. They were clearly present. Of note, minocycline and Diclofenac also seemed to be associated with improved depression parameters.

Ketamine provides both pain relief and anti-depression effects in refractory patients, who by definition, have failed multiple therapies.   ::

 

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Ketamine for Pain Management, Treatment of Depression << Article Link

Article below:

Ketamine may alleviate depression, pain, and adverse effects associated with opioid treatment, and may thus represent an attractive adjunct therapy for pain management, according to a novel population analysis recently published in Scientific Reports.1

Nearly half of all patients with depression taking conventional antidepressants discontinue their treatment prematurely.2 Researchers have sought alternatives to standard antidepressants, for which therapeutic effects are delayed by 2 to 10 weeks.3

Ketamine, an N-methyl-D-aspartate antagonist, was shown to provide acute benefits for treatment-resistant depression, bipolar depression, and major depressive disorder with suicidal ideation, when administered intravenously, however, those studies were conducted on limited samples (20 to 57 participants).4-7

The history of ketamine as an illicit drug favored for its hallucinogenic effects presents ethical obstacles to its use in large clinical trials. Researchers from the University of California San Diego in La Jolla, therefore employed an Inverse-Frequency Analysis approach to investigate whether ketamine, when administered in addition to other therapeutics, has antidepressant properties.

The team applied the inverse frequency analysis method, which looks for negative statistical patterns in the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) post-marketing database of more than 8 million patient records. They observed reductions in depression and pain in patients receiving ketamine, as indicated by negative log odds ratio (logOR) values (logOR, -0.67 ± 0.034 and logOR, -0.41 ± 0.019, respectively). “The data we analyzed are indirect and skewed by cases of bad or lethal adverse effects. Nevertheless the statistics were sufficient to notice the trends,” explained study co-author, Ruben Abagyan, PhD, in an interview with Clinical Pain Advisor.

According to Dr Abagyan, a study recently published by a British team indicates that ketamine might be effective in nearly 40% of patients with severe, treatment-resistant depression, results that are concordant with those from the current study.8

The IFA method was also used to evaluate ketamine efficacy and associated side effects reported in the FAERS database. The investigators found significant reductions in a number of side effects associated with opioid therapies, including constipation (LogOR −0.17 ± 0.023), vomiting (LogOR −0.16 ± 0.025), and nausea (LogOR −0.45 ± 0.034) compared with other drug combinations used for pain management.

The authors concluded that their findings are in line with those from smaller studies, indicating beneficial effects for ketamine as a monotherapy or adjunctive therapy for depression, particularly treatment-resistant depression, with particular indication for patients with suicide ideation, because of its rapid onset of action. “The results should serve as a motivation to conduct a proper clinical trial for the rapid onset treatment of severe depression,” Dr Abagyan noted.

The novel analysis employed in this study may help investigate off-label indications for other drugs. “Ideally the method we proposed should be applied to the actual clinical data rather than the somewhat biased set of un-normalized FAERS reports,” Dr Abagyan added. “The method [can be used] to observe unexpected effects of a treatment by looking at the reduction of the baseline of this effect upon treatment. It can be applied to any effect that is being recorded including cancer, viral diseases mortality, longevity.” he concluded.

 

References

  1. Cohen IV, Makunts T, Atayee R, Abagyan R. Population scale data reveals the antidepressant effects of ketamine and other therapeutics approved for non-psychiatric indicationsSci Rep 2017;7:1450.
  2. Sansone RA, Sansone LA. Antidepressant adherence: are patients taking their medications?. Innov Clin Neurosci. 2012;9(5-6):41-46.
  3. Frazer A, Benmansour S. Mol Psychiatry. Delayed pharmacological effects of antidepressantsMol Psychiatry 2002;7:S23-8.
  4. Price RB, Iosifescu DV, Murrough JW,  et al. Effects of ketamine on explicit and implicit suicidal cognition: a randomized controlled trial in treatment-resistant depressionDepress Anxiety 2014;31:335-343.
  5. DiazGranados N, Ibrahim LA, Brutsche NE, et al. Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorderJ Clin Psychiatry 2010;71:1605-1611.
  6. Alberich S, Martínez-Cengotitabengoa M, López P,et al. Efficacy and safety of ketamine in bipolar depression: A systematic reviewRev Psiquiatr Salud Ment 2017;10:104-112.
  7. Larkin, G. L. & Beautrais, A. L. A preliminary naturalistic study of low-dose ketamine for depression and suicide ideation in the emergency departmentInt J Neuropsychopharmacol 2011;8:1127-31.
  8. Singh I, Morgan C, Curran V, et al. Ketamine treatment for depression: opportunities for clinical innovation and ethical foresightLancet Psychiatry 2017;4:419-42

 

Population scale data reveals the antidepressant effects of Ketamine  ::  << Article below

Population scale data reveals the
antidepressant effects of ketamine
and other therapeutics approved
for non-psychiatric indications

Isaac V. Cohen, Tigran Makunts, Rabia Atayee & Ruben Abagyan

Current therapeutic approaches to depression fail for millions of patients due to lag in clinical response
and non-adherence. Here we provide new support for the antidepressant efect of an anesthetic
drug, ketamine, by Inverse-Frequency Analysis of eight million reports from the FDA Adverse Efect
Reporting System. The results of the examination of population scale data revealed that patients who
received ketamine had signifcantly lower frequency of reports of depression than patients who took
any other combination of drugs for pain. The analysis also revealed that patients who took ketamine
had signifcantly lower frequency of reports of pain and opioid induced side efects, implying ketamine’s
potential to act as a benefcial adjunct agent in pain management pharmacotherapy. Further, the
Inverse-Frequency Analysis methodology provides robust statistical support for the antidepressant
action of other currently approved therapeutics including diclofenac and minocycline.

We found that patients listed in the FAERS database who received ketamine in addition to other therapeutics
had signifcantly lower frequency of reports of depression than patients who took any other combination of drugs
for pain (LogOR−0.67±0.034)

Te analysis of the whole FAERS database revealed several other unintentional depression reducing drugs
among antibiotics, cosmeceuticals and NSAIDS.Our data supported previous studies that observed the
psychiatric polypharmacology of minocycline, a tetracycline antibiotic.The NSAID, diclofenac, was also
observed to have some antidepressant properties.It is theorized that both of these drugs may accomplish
antidepressant effects through an anti-inflammatory mechanism.Because of the antidepressant activity of several
NSAIDs, we further separated the non-ketamine pain cohort. Ketamine patients were then compared to
patients who received any other combination of drugs for pain excluding NSAIDs. It was observed that depression
event rates remained low (LogOR−0.56±0.035).As an important side note, we also evaluated efcacy and side efects with the use of ketamine for pain management.
We found that patients who were on ketamine had reduced opioid induced side effects including constipation, vomiting, and nausea. Our data supports ketamine’s
opioid-sparing properties and alludes to the fact that patients may receive benefts of improved pain, reduced
requirement of opioids, and ultimately less opioid reduced side effects.

References
1. Murray, C. J. & Lopez, A. D. Evidence-based health policy–lessons from the Global Burden of Disease Study. Science 274, 740–743,
doi:10.1126/science.274.5288.740 (1996).
2. Kessler, R. C. et al. Te epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication
(NCS-R). JAMA 289, 3095–3105, doi:10.1001/jama.289.23.3095 (2003).
3. Bromet, E. et al. Cross-national epidemiology of DSM-IV major depressive episode. BMC Med 9, 90, doi:10.1186/1741-7015-9-90
(2011).
4. Andrade, L. et al. The epidemiology of major depressive episodes: results from the International Consortium of Psychiatric
Epidemiology (ICPE) Surveys. Int J Methods Psychiatr Res 12, 3–21, doi:10.1002/(ISSN)1557-0657 (2003).
5. Sansone, R. A. & Sansone, L. A. Antidepressant adherence: are patients taking their medications? Innov Clin Neurosci 9, 41–46
(2012).
6. Frazer, A. & Benmansour, S. Delayed pharmacological effects of antidepressants. Mol Psychiatry 7, S23–28, doi:10.1038/
sj.mp.4001015 (2002). Suppl 1.
7. Braun, C., Bschor, T., Franklin, J. & Baethge, C. Suicides and Suicide Attempts during Long-Term Treatment with Antidepressants:
A Meta-Analysis of 29 Placebo-Controlled Studies Including 6,934 Patients with Major Depressive Disorder. Psychother Psychosom
85, 171–179, doi:10.1159/000442293 (2016).
8. Seemüller, F. et al. Te controversial link between antidepressants and suicidality risks in adults: data from a naturalistic study on a
large sample of in-patients with a major depressive episode. Int J Neuropsychopharmacol 12, 181–189, doi:10.1017/
S1461145708009139 (2009).
9. Rush, A. J. et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D
report. Am J Psychiatry 163, 1905–1917, doi:10.1176/ajp.2006.163.11.1905 (2006).
10. Price, R. B. et al. Efects of ketamine on explicit and implicit suicidal cognition: a randomized controlled trial in treatment-resistant
depression. Depress Anxiety 31, 335–343, doi:10.1002/da.22253 (2014).

11. DiazGranados, N. et al. Rapid resolution of suicidal ideation afer a single infusion of an N-methyl-D-aspartate antagonist in
patients with treatment-resistant major depressive disorder. J Clin Psychiatry 71, 1605–1611, doi:10.4088/JCP.09m05327blu (2010).
12. Alberich, S. et al. Efcacy and safety of ketamine in bipolar depression: A systematic review. Rev Psiquiatr Salud Ment (2016).
13. Larkin, G. L. & Beautrais, A. L. A preliminary naturalistic study of low-dose ketamine for depression and suicide ideation in the
emergency department. Int J Neuropsychopharmacol 14, 1127–1131, doi:10.1017/S1461145711000629 (2011).
14. Miyaoka, T. et al. Minocycline as adjunctive therapy for patients with unipolar psychotic depression: an open-label study. Prog
Neuropsychopharmacol Biol Psychiatry 37, 222–226, doi:10.1016/j.pnpbp.2012.02.002 (2012).
15. Rosenblat, J. D. et al. Anti-infammatory agents in the treatment of bipolar depression: a systematic review and meta-analysis.
Bipolar Disord 18, 89–101, doi:10.1111/bdi.2016.18.issue-2 (2016).
16. FDA Adverse Event Reporting System (FAERS): Latest Quarterly Data Files. http://www.fda.gov/Drugs/
GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEfects/ucm082193.htm (Accessed 2016).
17. The Adverse Event Reporting System (AERS): Older Quarterly Data Files. http://www.fda.gov/Drugs/
GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEfects/ucm083765.htm (Accessed 2016).
18. Questions and Answers on FDA’s Adverse Event Reporting System (FAERS) http://www.fda.gov/Drugs/
GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEfects/default.htm (Acessed 2016).

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Call 703-844-0184 if you are interested in options for Ketamine treatment for Depression, Anxiety, PTSD, fibromyalgia, Lyme disease, CRPS, or other disorders.

 

The articles below link to research and mainstream media demonstrating the efficacy of Ketamine infusions and intranasal Ketamine approaches for depression. The IV formulation is very effective for immediate relief of depression and even suicidality. The effects are almost immediate in some of our cases.

 

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Ketamine Relieves Depression By Restoring Brain Connections

Chris Stephens, 28, has been battling depression all of his life. At times he wouldn’t get out of bed for weeks. In January, he said his depression hadn’t returned since he started taking ketamine.

Lianne Milton/For NPR

Scientists say they have figured out how an experimental drug called ketamine is able to relieve major depression in hours instead of weeks.

Researchers from Yale and the National Institute of Mental Health say ketamine seems to cause a burst of new connections to form between nerve cells in parts of the brain involved in emotion and mood.

The discovery, described in Science, should speed development of the first truly new depression drugs since the 1970s, the researchers say.

“It’s exciting,” says Ron Duman, a a psychiatarist and neurobiologist at Yale University. “The hope is that this new information about ketamine is really going to provide a whole array of new targets that can be developed that ultimately provide a much better way of treating depression.”

Ketamine is an FDA-approved anesthetic. It’s also a popular club drug that can produce out-of-body experiences. Not exactly the resume you’d expect for a depression drug.

But a few years ago, researchers discovered that ketamine could help people with major depression who hadn’t responded to other treatments. What’s more, the relief came almost instantly.

The discovery “represents maybe one of the biggest findings in the field over the last 50 years,” Duman says.

A rat neuron before (top) and after (bottom) ketamine treatment. The increased number of orange nodes are restored connections in the rat’s brain.

Ronald Duman/Yale University

Depression is associated with a loss of so-called synaptic connections between nerve cells, Duman says. So he and other scientists began to study mice exposed to stresses that produce symptoms a lot like those of human depression.

The stressed mice lost connections in certain parts of the brain. But a dose of ketamine was able to “rapidly increase these connections and also to rapidly reverse the deficits that are caused by stress,” Duman says.

A team at the National Institute of Mental Health also has found evidence that ketamine works by encouraging synaptic connections.

It’s possible to see the change just by studying rodent brain cells with a microscope, says Carlos Zarate from the Mood and Anxiety Disorders Program at NIMH.

A healthy neuron looks like a tree in spring, he says, with lots of branches and leaves extending toward synaptic connections with other neurons. “What happens in depression is there’s a shriveling of these branches and these leaves and It looks like a tree in winter. And a drug like ketamine does make the tree look like one back in spring.”

And there’s also indirect evidence that ketamine is restoring synaptic connections in people, Zarate says.

His team studied 30 depressed patients who got ketamine. And they found changes in brainwave activity that indicated the drug had strengthened connections between neurons in areas of the brain involved in depression.

All of this research is intended to produce drugs that will work like ketamine, but without the hallucinations. And several of these alternative drugs are already being tried in people.

Preliminary results suggest that “some of these compounds do have rapid antidepressant effects without the side effects that occur with ketamine,” Zarate says.

One of these drugs, called GLYX-13, has already been tested in two large groups of people — a key step toward FDA approval. The company that makes the drug, Naurex, says it will tell scientists how well GLYX-13 works at a meeting in December.

From Chaos To Calm: A Life Changed By Ketamine

 

Clinical experience using intranasal ketamine in the longitudinal treatment of juvenile bipolar disorder with fear of harm phenotype.

Clinical experience using intranasal ketamine in the longitudinal treatment of juvenile bipolar disorder with fear of harm phenotype.

 2018 Jan 1;225:545-551. doi: 10.1016/j.jad.2017.08.081. Epub 2017 Aug 30.

Clinical experience using intranasal ketamine in the longitudinal treatment of juvenile bipolar disorder with fear of harm phenotype.

Abstract

OBJECTIVES:

Fear of Harm (FOH) is a pediatric onset phenotype of bipolar disorder (BD) characterized by BD plus treatment resistance, separation anxiety, aggressive obsessions, parasomnias, and thermal dysregulation. Intranasal ketamine (InK) in 12 youths with BD-FOH produced marked improvement during a two-week trial. Here we report on the open effectiveness and safety of InK in maintenance treatment of BD-FOH from the private practice of one author.

METHODS:

As part of a chart review, patients 18 years or older and parents of younger children responded to a clinical effectiveness and safety survey. Effectiveness was assessed from analysis of responses to 49 questions on symptomatology plus qualitative content analyses of written reports and chart review. Adverse events (AEs) were analyzed by frequency, duration and severity. Peak InK doses ranged from 20 to 360mg per administration.

RESULTS:

Surveys were completed on 45 patients treated with InK for 3 months to 6.5 years. Almost all patients were “much” to “very much” improved clinically and in ratings of social function and academic performance. Significant reductions were reported in all symptom categories. There were 13 reports of persistent AEs, none of which resulted in discontinuation. Acute emergence reactions were sporadically observed in up to 75%, but were mild and of brief duration.

LIMITATIONS:

Retrospective review from a single practice without placebo control with potential for response and recall bias.

CONCLUSIONS:

InK every 3-4 days at sub-anesthetic doses appeared to be a beneficial and well-tolerated treatment. Use of InK may be considered as a tertiary alternative in treatment refractory cases. Randomized control trials are warranted.

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Low-dose ketamine for treatment resistant depression in an academic clinical practice setting. <<< ARTICLE link

BACKGROUND:

Recent studies demonstrating a rapid, robust improvement in treatment resistant depression (TRD) following a single sub-anesthetic infusion of ketamine have generated much excitement. However, these studies are limited in their generalizability to the broader TRD population due to their subject exclusion criteria which typically limit psychiatric comorbidity, concurrent medication, and level of suicide risk. This paper describes the safety and efficacy of sub-anesthetic ketamine infusions in a naturalistic TRD patient sample participating in a real-world TRD treatment program within a major university health system.

METHODS:

The effects of a sub-anesthetic dose (0.5mg/kg) of ketamine infused IV over forty minutes on TRD patients participating in a treatment program at the University of California, San Diego was investigated by retrospectively analyzing the medical charts of 41 adult TRD patients with a diagnosis of Major Depressive Disorder (MDD) or Bipolar Disorder (BD).

RESULTS:

Subjects were aged 48.6, 78% white, 36.6% female, and 82.9% had MDD. Significant psychiatric comorbidity existed in 73%. Average pre-infusion BDI score was 32.6 ± 8.4 (S.D) and dropped to 16.8 ± 3.1 at 24-h post-infusion (p < 0.001). The 24-h response (≥ 50% reduction from pre-infusion) and remission (BDI <13) rates were 53.7% and 41.5%, respectively. Three quarters of responders maintained responder status at 7-days. Ketamine infusions were well tolerated with occasional nausea or anxiety and mild hemodynamic effects during the infusion.

LIMITATIONS:

Retrospective nature of this study, lack of control group and use of self-report depression ratings scales.

CONCLUSIONS:

This is the first published study of sub-anesthetic ketamine infusions in a real-world TRD population. The results suggest that this treatment is effective and well tolerated in this population.

 

BACKGROUND:

Recent studies demonstrating a rapid, robust improvement in treatment resistant depression (TRD) following a single sub-anesthetic infusion of ketamine have generated much excitement. However, these studies are limited in their generalizability to the broader TRD population due to their subject exclusion criteria which typically limit psychiatric comorbidity, concurrent medication, and level of suicide risk. This paper describes the safety and efficacy of sub-anesthetic ketamine infusions in a naturalistic TRD patient sample participating in a real-world TRD treatment program within a major university health system.

METHODS:

The effects of a sub-anesthetic dose (0.5mg/kg) of ketamine infused IV over forty minutes on TRD patients participating in a treatment program at the University of California, San Diego was investigated by retrospectively analyzing the medical charts of 41 adult TRD patients with a diagnosis of Major Depressive Disorder (MDD) or Bipolar Disorder (BD).

RESULTS:

Subjects were aged 48.6, 78% white, 36.6% female, and 82.9% had MDD. Significant psychiatric comorbidity existed in 73%. Average pre-infusion BDI score was 32.6 ± 8.4 (S.D) and dropped to 16.8 ± 3.1 at 24-h post-infusion (p < 0.001). The 24-h response (≥ 50% reduction from pre-infusion) and remission (BDI <13) rates were 53.7% and 41.5%, respectively. Three quarters of responders maintained responder status at 7-days. Ketamine infusions were well tolerated with occasional nausea or anxiety and mild hemodynamic effects during the infusion.

LIMITATIONS:

Retrospective nature of this study, lack of control group and use of self-report depression ratings scales.

CONCLUSIONS:

This is the first published study of sub-anesthetic ketamine infusions in a real-world TRD population. The results suggest that this treatment is effective and well tolerated in this population.

 

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Washington Post Kratom article Scan Feb 16, 2018, 4.42 AM

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EROWID -KRATOM

From Erowid:

Mitragyna speciosa is a leafy tree that grows from 3-20 meters tall. Its leaves contain 7-Hydroxymitragynine and mitragynine. The leaves are chewed as an opiate substitute and stimulant in Thailand and South-East Asia, primarily among the working class. It has a relatively long history of human use.Kratom (Mitragyna speciosa) is a tropical tree growing from 15-50 feet tall (5-15 meters) that is native to Thailand and Malaysia. It has broad, oval leaves that taper to points, yellow flowers that grow in clusters, and winged seeds. The primary active chemicals are mitragynine, mitraphylline, and 7-hydroxymitragynine, all found in the leaves. Kratom leaves have been chewed for stimulant, sedative, and euphoric effects by people in Thailand and South Asia for centuries. They can also be smoked, brewed as a tea, or made into an extract. Kratom use is relatively uncommon in the US and Europe, though it is available in raw and extract-enhanced forms from ethnobotanical vendors.

Kratom leaves differ greatly in potency, depending on the type, grade, and freshness. Leaves with green veins are often claimed to be more potent than those with red veins, but there is contradictory evidence. Low doses are around 2-4 g of plain dried leaf, moderate doses are 3-6 g, and strong doses are 5 g or more. When chewed fresh, half of a large leaf (8-10″) is often enough to produce noticeable effects.

 

We spoke about Kratom at the end of 2016 when Congress was considering banning it. Again it is in the news as more deaths have been linked to it’s use. The FDA has determined that 23/25 substances located within it are opioid in effect and that there was one death of 38 that was linked ONLY to Kratom. Obviously detoxing from opioids leaves people open to overdosing if they go back and use…and they most probably will since they will be using Kratom on their own without medical advice. That is one problem. But the FDA also noticed that as in many other overdoses, there are also confounding use of other medications such as benzodiazepines. See below:

FDA announcement regarding Kratom

 

Over the past several months, there have been many questions raised about the botanical substance known as kratom. Our concerns related to this product, and the actions we’ve taken, are rooted in sound science and are in the interest of protecting public health. However, we recognize that there is still much that is unknown about kratom, which is why we’ve taken some significant steps to advance the scientific understanding of this product and how it works in the body. Today, we’re providing details of some of the important scientific tools, data and research that have contributed to the FDA’s concerns about kratom’s potential for abuse, addiction, and serious health consequences; including death.

Notably, we recently conducted a novel scientific analysis using a computational model developed by agency scientists, which provided even stronger evidence of kratom compounds’ opioid properties. These kinds of models have become an advanced, common and reliable tool for understanding the behavior of drugs in the body. We also have learned more about deaths that involved kratom use, and have identified additional adverse events related to this product. This new data adds to our body of substantial scientific evidence supporting our concerns about the safety and abuse potential of kratom.

We have been especially concerned about the use of kratom to treat opioid withdrawal symptoms, as there is no reliable evidence to support the use of kratom as a treatment for opioid use disorder and significant safety issues exist. We recognize the need and desire for alternative treatments for both the treatment of opioid addiction, as well as the treatment of chronic pain. The FDA stands ready to evaluate evidence that could demonstrate a medicinal purpose for kratom. However, to date, we have received no such submissions and are not aware of any evidence that would meet the agency’s standard for approval.

The FDA’s PHASE model used to assess kratom

Federal agencies need to act quickly to evaluate the abuse potential of newly identified designer street drugs for which limited or no pharmacological data are yet available. This is why the FDA developed the Public Health Assessment via Structural Evaluation (PHASE) methodology – a tool to help us simulate, using 3-D computer technology, how the chemical constituents of a substance (such as the compounds/alkaloids found in kratom) are structured at a molecular level, how they may behave inside the body, and how they can potentially affect the brain. In effect, PHASE uses the molecular structure of a substance to predict its biological function in the body. For example, the modelling platform can simulate how a substance will affect various receptors in the brain based on a product’s chemical structure and its similarity to controlled substances for which data are already available.

Using this computational model, scientists at the FDA first analyzed the chemical structures of the 25 most prevalent compounds in kratom. From this analysis, the agency concluded that all of the compounds share the most structural similarities with controlled opioid analgesics, such as morphine derivatives.

Next, our scientists analyzed the chemical structure of these kratom compounds against the software to determine its likely biologic targets. The model predicted that 22 (including mitragynine) of the 25 compounds in kratom bind to mu-opioid receptors. This model, together with previously available experimental data, confirmed that two of the top five most prevalent compounds (including mitragynine) are known to activate opioid receptors (“opioid agonists”).

The new data provides even stronger evidence of kratom compounds’ opioid properties.

The computational model also predicted that some of the kratom compounds may bind to the receptors in the brain that may contribute to stress responses that impact neurologic and cardiovascular function. The agency has previously warned of the serious side effects associated with kratom including seizures and respiratory depression.

The third aspect of the model is the 3-D image we generate to look at not just where these compounds bind, but how strongly they bind to their biological targets. We found that kratom has a strong bind to mu-opioid receptors, comparable to scheduled opioid drugs.

So what does this body of scientific evidence mean? The FDA relies on this kind of sophisticated model and simulation to supplement its data on how patients react to drugs; often as a way to fully elucidate the biological activity of a new substance. The data from the PHASE model shows us that kratom compounds are predicted to affect the body just like opioids. Based on the scientific information in the literature and further supported by our computational modeling and the reports of its adverse effects in humans, we feel confident in calling compounds found in kratom, opioids.

Furthermore, this highlights the power of our computational model-based approach to rapidly assess any newly identified natural or synthetic opioids to respond to a public health emergency.

Learnings from reports of death associated with kratom

We’ve been carefully monitoring the use of kratom for several years, and have placed kratom products on import alert to prevent them from entering the country illegally. We have also conducted several product seizures. These actions were based, in part, on a body of academic research, as well as reports we have received, suggesting harm associated with its use. And we are not alone in our evaluation and our public health concerns. Numerous countries, states and cities have banned kratom from entering their jurisdictions. We described some of this information in a public health advisory in November 2017, in which we urged consumers not to use kratom or any compounds found in the plant.

Now, I’d like to share more information about the tragic reports we have received of additional deaths involving the use of kratom. Looking at the information we have received – including academic research, poison control data, medical examiner reports, social science research and adverse event reports – we now have 44 reported deaths associated with the use of kratom. This is an increase since our November advisory, which noted 36 deaths associated with these products. We’re continuing to review the newly received reports and will release those soon. But it’s important to note that these new reports include information consistent with the previous reports.

Today, we’re releasing the reports of the 36 deaths we referenced in November. These reports underscore the serious and sometimes deadly risks of using kratom and the potential interactions associated with this drug. Overall, many of the cases received could not be fully assessed because of limited information provided; however, one new report of death was of particular concern. This individual had no known historical or toxicologic evidence of opioid use, except for kratom. We’re continuing to investigate this report, but the information we have so far reinforces our concerns about the use of kratom. In addition, a few assessable cases with fatal outcomes raise concern that kratom is being used in combination with other drugs that affect the brain, including illicit drugs, prescription opioids, benzodiazepines and over-the-counter medications, like the anti-diarrheal medicine, loperamide. Cases of mixing kratom, other opioids, and other types of medication is extremely troubling because the activity of kratom at opioid receptors indicates there may be similar risks of combining kratom with certain drugs, just as there are with FDA-approved opioids.

However, unlike kratom, FDA-approved drugs have undergone extensive review for safety and efficacy, and the agency continuously tracks safety data for emerging safety risks that were previously unknown. So we have better information about the risks associated with these products; and can better inform the public of new safety concerns. For example, in August 2016, the FDA required a class-wide change to drug labeling to help inform health care providers and patients of the serious risks (including respiratory depression, coma and death) associated with the combined use of certain opioid medications and benzodiazepines. In June 2016, the agency also issued a warning that taking significantly high doses of loperamide, including through abuse or misuse of the product to achieve euphoria or self-treat opioid withdrawal, can cause serious heart problems that can lead to death. We also recently took steps to help reduce abuse of loperamide by requesting packaging restrictions for these products sold “over-the-counter.”

Taken in total, the scientific evidence we’ve evaluated about kratom provides a clear picture of the biologic effect of this substance. Kratom should not be used to treat medical conditions, nor should it be used as an alternative to prescription opioids. There is no evidence to indicate that kratom is safe or effective for any medical use. And claiming that kratom is benign because it’s “just a plant” is shortsighted and dangerous. After all, heroin is an illegal, dangerous, and highly-addictive substance containing the opioid morphine, derived from the seed pod of the various opium poppy plants.

Further, as the scientific data and adverse event reports have clearly revealed, compounds in kratom make it so it isn’t just a plant – it’s an opioid. And it’s an opioid that’s associated with novel risks because of the variability in how it’s being formulated, sold and used recreationally and by those who are seeking to self-medicate for pain or who use kratom to treat opioid withdrawal symptoms. We recognize that many people have unmet needs when it comes to treating pain or addiction disorders. For individuals seeking treatment for opioid addiction who are being told that kratom can be an effective treatment, I urge you to seek help from a health care provider. There are safe and effective, FDA-approved medical therapies available for the treatment of opioid addiction. Combined with psychosocial support, these treatments are effective. Importantly, there are three drugs (buprenorphine, methadone, and naltrexone) approved by the FDA for the treatment of opioid addiction, and the agency is committed to promoting more widespread innovation and access to these treatments to help those suffering from an opioid use disorder transition to lives of sobriety. There are also safer, non-opioid options to treat pain. We recognize that some patients have tried available therapies, and still have unmet medical needs. We’re deeply committed to these patients, and to advancing new, safe and effective options for those suffering from these conditions.

The U.S. Food and Drug Administration is warning consumers not to use Mitragyna speciosa, commonly known as kratom, a plant which grows naturally in Thailand, Malaysia, Indonesia, and Papua New Guinea. FDA is concerned that kratom, which affects the same opioid brain receptors as morphine, appears to have properties that expose users to the risks of addiction, abuse, and dependence.

There are no FDA-approved uses for kratom, and the agency has received concerning reports about the safety of kratom. FDA is actively evaluating all available scientific information on this issue and continues to warn consumers not to use any products labeled as containing the botanical substance kratom or its psychoactive compounds, mitragynine and 7-hydroxymitragynine. FDA encourages more research to better understand kratom’s safety profile, including the use of kratom combined with other drugs.

Since identifying kratom on an import alert for unapproved drugs in 2012 and on a second import alert in February 2014 regarding kratom-containing dietary supplements and bulk dietary ingredients, FDA has taken a number of additional actions, including:

  • In September 2014, U.S. Marshals, at the FDA’s request, seized more than 25,000 pounds of raw kratom material worth more than $5 million from Rosefield Management, Inc. in Van Nuys, California.
  • In January 2016, U.S. Marshals, at the FDA’s request, seized nearly 90,000 bottles of dietary supplements labeled as containing kratom and worth more than $400,000. The product, manufactured for and held by Dordoniz Natural Products LLC, located in South Beloit, Illinois, is marketed under the brand name RelaKzpro.
  • In August 2016, U.S. Marshals, at the FDA’s request, seized more than 100 cases of products labeled as containing kratom and worth more than $150,000. The products are distributed by Nature Therapeutics LLC, which does business as Kratom Therapy and is located in Grover Beach, California. The seized products are marketed under the brand name Kratom Therapy.

While FDA evaluates the available safety information about the effects of kratom, the agency encourages health care professionals and consumers to report any adverse reactions to the FDA’s MedWatch program:

kratom deaths PDF

Statement from FDA Commissioner Scott Gottlieb, M.D. on FDA advisory about deadly risks associated with kratom

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm584970.htm

November 14, 2017

Summary

The FDA has issued a public health advisory related to mounting concerns regarding risks associated with the use of kratom.

Statement

The FDA is concerned about harmful unapproved products that have been crossing our borders in increasing numbers. The agency has a public health obligation to act when we see people being harmed by unapproved products passed off as treatments and cures for serious conditions.

Over the past several years, a botanical substance known as kratom has raised significant concerns given its increasing prevalence and potential safety risks. Today, the agency issued a public health advisory related to the FDA’s mounting concerns regarding risks associated with the use of kratom.

Kratom is a plant that grows naturally in Thailand, Malaysia, Indonesia and Papua New Guinea. It has gained popularity in the U.S., with some marketers touting it as a “safe” treatment with broad healing properties. Proponents argue that it’s a safe substance largely because it’s a plant-based product. The FDA knows people are using kratom to treat conditions like pain, anxiety and depression, which are serious medical conditions that require proper diagnosis and oversight from a licensed health care provider. We also know that this substance is being actively marketed and distributed for these purposes. Importantly, evidence shows that kratom has similar effects to narcotics like opioids, and carries similar risks of abuse, addiction and in some cases, death. Thus, it’s not surprising that often kratom is taken recreationally by users for its euphoric effects. At a time when we have hit a critical point in the opioid epidemic, the increasing use of kratom as an alternative or adjunct to opioid use is extremely concerning.

It’s very troubling to the FDA that patients believe they can use kratom to treat opioid withdrawal symptoms. The FDA is devoted to expanding the development and use of medical therapy to assist in the treatment of opioid use disorder. However, an important part of our commitment to this effort means making sure patients have access to treatments that are proven to be safe and effective. There is no reliable evidence to support the use of kratom as a treatment for opioid use disorder. Patients addicted to opioids are using kratom without dependable instructions for use and more importantly, without consultation with a licensed health care provider about the product’s dangers, potential side effects or interactions with other drugs.

There’s clear data on the increasing harms associated with kratom. Calls to U.S. poison control centers regarding kratom have increased 10-fold from 2010 to 2015, with hundreds of calls made each year. The FDA is aware of reports of 36 deaths associated with the use of kratom-containing products. There have been reports of kratom being laced with other opioids like hydrocodone. The use of kratom is also associated with serious side effects like seizures, liver damage and withdrawal symptoms.

Given all these considerations, we must ask ourselves whether the use of kratom – for recreation, pain or other reasons – could expand the opioid epidemic. Alternatively, if proponents are right and kratom can be used to help treat opioid addiction, patients deserve to have clear, reliable evidence of these benefits.

I understand that there’s a lot of interest in the possibility for kratom to be used as a potential therapy for a range of disorders. But the FDA has a science-based obligation that supersedes popular trends and relies on evidence. The FDA has a well-developed process for evaluating botanical drug products where parties seek to make therapeutic claims and is committed to facilitating development of botanical products than can help improve people’s health. We have issued guidance on the proper development of botanical drug products. The agency also has a team of medical reviewers in the FDA’s Center for Drug Evaluation and Research that’s dedicated to the proper development of drug applications for botanicals. To date, no marketer has sought to properly develop a drug that includes kratom.

We believe using the FDA’s proven drug review process would provide for a much-needed discussion among all stakeholders. Until then, I want to be clear on one fact: there are currently no FDA-approved therapeutic uses of kratom. Moreover, the FDA has evidence to show that there are significant safety issues associated with its use. Before it can be legally marketed for therapeutic uses in the U.S., kratom’s risks and benefits must be evaluated as part of the regulatory process for drugs that Congress has entrusted the FDA with. Moreover, Congress has also established a specific set of review protocols for scheduling decisions concerning substances like kratom. This is especially relevant given the public’s perception that it can be a safe alternative to prescription opioids.

The FDA has exercised jurisdiction over kratom as an unapproved drug, and has also taken action against kratom-containing dietary supplements. To fulfill our public health obligations, we have identified kratom products on two import alerts and we are working to actively prevent shipments of kratom from entering the U.S. At international mail facilities, the FDA has detained hundreds of shipments of kratom. We’ve used our authority to conduct seizures and to oversee the voluntary destruction of kratom products. We’re also working with our federal partners to address the risks posed by these imports. In response to a request from the Drug Enforcement Administration (DEA), the FDA has conducted a comprehensive scientific and medical evaluation of two compounds found in kratom. Kratom is already a controlled substance in 16 countries, including two of its native countries of origin, Thailand and Malaysia, as well as Australia, Sweden and Germany. Kratom is also banned in several states, specifically Alabama, Arkansas, Indiana, Tennessee and Wisconsin and several others have pending legislation to ban it.

We’ve learned a tragic lesson from the opioid crisis: that we must pay early attention to the potential for new products to cause addiction and we must take strong, decisive measures to intervene. From the outset, the FDA must use its authority to protect the public from addictive substances like kratom, both as part of our commitment to stemming the opioid epidemic and preventing another from taking hold.

As a physician and FDA Commissioner, I stand committed to doing my part to prevent illegal substances that pose a threat to public health from taking their grip on Americans. While we remain open to the potential medicinal uses of kratom, those uses must be backed by sound-science and weighed appropriately against the potential for abuse. They must be put through a proper evaluative process that involves the DEA and the FDA. To those who believe in the proposed medicinal uses of kratom, I encourage you to conduct the research that will help us better understand kratom’s risk and benefit profile, so that well studied and potentially beneficial products can be considered. In the meantime, based on the weight of the evidence, the FDA will continue to take action on these products in order to protect public health.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.