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From Popular Anesthetic to Antidepressant, Ketamine Isn’t the Drug You Think It Is

An hour before we spoke, Darragh O’Carroll, an emergency room physician from Hawaii, had just given an elderly patient a sedating shot of ketamine. The man had pneumonia and was acting confused and fidgety, making him hard to treat.

“Not only it was a pain control for him when I was putting needles into his neck, but it also kept him still,” O’Carroll says. “And with very minimal risk of lowering his blood pressure.”

Ketamine’s use as an anesthetic — and not as a party drug — is widespread, though not commonly known. In fact, the World Health Organizationestimates ketamine is the most widely used anesthetic in the world and keeps it on their list of essential medicines, a category of drugs that all developed countries should have on hand.

O’Carroll has described ketamine as his “favorite medicine of all time” in an article for Tonic, not only because the anesthetic is incredibly safe and effective, but also because of its versatility. It’s most widely used in surgery, but could also help treat severe asthma, chronic pain, and may even possess anti-tumor properties. In the last two decades, ketamine has also emerged as a potent antidepressant, able to treat symptoms of some mental illnesses in less than 72 hours.

“I think the more research that goes into ketamine, the more uses that we find for it,” O’Carroll says.

From PCP to Painkiller

Ketamine’s story begins with a drug called PCP. Yes, that PCP — phencyclidine or so-called “angel dust,” a drug that when smoked can cause a trance-like state, agitation and out-of-body hallucinations. After it was first synthesized by medicinal chemist Victor Maddox in 1956, the drug was briefly approved as an anesthetic by the FDA for its sedative properties. In tests with a wild rhesus monkey, for example, researchers put their fingers in the previously aggressive animal’s mouth and watched its jaw remain slack.

But while it was safe and effective for pain relief, the side effects of PCP soon became too obvious to ignore.

Some patients under the influence of PCP would feel like they lost their arms or legs or that they were floating in space. It could also cause seizures and delirium. Scientists began seeking a shorter-acting anesthetic without convulsant properties. In 1962, chemistry professor Calvin Stevens discovered a PCP analogue that fit the bill: ketamine.

Ketamine is a potent, sedating painkiller that can cause amnesia and is mostly used in surgery and veterinary medicine. During the Vietnam Invasion, ketamine saw widespread use in the U.S. military because it has several advantages over opioids. First, unlike morphine, ketamine doesn’t suppress blood pressure or breathing. It also doesn’t need to be refrigerated, making it useful in the field or in rural areas that don’t have access to electricity.

Ketamine’s benefits extend beyond use as an anesthetic, though — in some cases it can serve as a balm for the mind as well. A 2008 analysis found that burn victims who were given ketamine were less likely to develop symptoms of post-traumatic stress disorder, even if their injuries were more severe. Those findings have been replicated, such as a 2014 clinical trial of 41 patients, who saw their PTSD symptoms diminish within 24 hours, an effect that lasted for two weeks.

“When somebody gets one of their limbs dramatically blown off or is shot in the face, it’s a very traumatic event,” O’Carroll says. In such a situation, giving ketamine not only provides instant pain relief, it could prevent long-lasting trauma.

Because its chemical structure is so similar to PCP, ketamine can still give lucid hallucinations, such as feeling that your mind has separated from the body — a dissociative state users sometimes call a “K-hole.” One recent study based on users’ written reports even indicated that this kind of experience might be a close analogue to a near-death experience. However, these dissociative states only happen at high doses — the amount of ketamine used to for surgery and to treat depression is typically much lower.

But ketamine’s side effects are less common and easier to manage than PCP. In fact, ketamine is one of the safest drugs used in medicine today and can even be given to young children. For example, ketamine was used to sedatethe boys’ soccer team trapped in a cave in Thailand last year. Putting the kids in a tranquilized state made it easier to rescue them, and ketamine is safer than the opioids or benzodiazepines that are also commonly used as sedatives.  

Ketamine as Antidepressant

But it wasn’t until the 1990s that what could turn out to be ketamine’s most important function was discovered. A team from Yale University School of Medicine was examining the role of glutamate, a common neurotransmitter, in depression, and discovered something remarkable: ketamine could rapidly relieve depression symptoms.

“To our surprise, the patients started saying, they were better in a few hours,” Dennis Charney, one of the researchers, told Bloomberg. This rapid relief was unheard of in psychiatry.

Glutamate is associated with neural plasticity, our brain’s ability to adapt and change at the level of the neuron. Ketamine blocks certain glutamate receptors, but not others, and the end effect could be to promote the growth of new neurons while protecting old ones. This could explain how ketamine can help reset the brain, though the theory hasn’t yet been definitively proven.

The prescription meds currently on the market for depression have some major drawbacks. Drugs like Prozac or Wellbutrin can take a few weeks or months to kick in while worsening symptoms in the short term — not a good combination, especially for someone who is extremely depressed, or even suicidal.

It took around a decade for mainstream science to take notice of these early ketamine-depression studies. But once it did, ketamine clinics began popping up all across North America, offering fast relief for depression, anxiety and other mental illnesses. Patients are given an infusion — an IV drip that lasts about an hour — and many people, but not everyone, have seen rapid relief of their symptoms.

Suddenly, ketamine infusions became trendy, though the science to back up some of the medical claims is still inconclusive, according to STAT. However, ketamine infusions are rarely covered by insurance, although that is changing. A typical session can run $700, with many patients taking six sessions or more. But many of these patients have so-called treatment-resistant depression. They’ve tried other medications or therapies without success and some see ketamine as a last resort.

Steven Mandel, a clinical psychologist and anesthesiologist, has used ketamine on patients since it first came on the market around 50 years ago. In 2014, he began using it for patients with depression and opened Ketamine Clinics of Los Angeles, one of the oldest and largest clinics in the country. They’ve done over 8,000 infusions so far.

“Our success rate is better than 83 percent,” Mandel says. For his clinic, success means a 50 percent improvement of depression symptoms for longer than three months.

Ketamine’s success as an antidepressant couldn’t help but attract the attention of major pharmaceutical companies as well. In 2009, Johnson & Johnson began developing their own version of the drug they called esketamine. Rather than an infusion through a vein, it’s dispensed through a nasal spray. The FDA approved their formulation in early March. It was thefirst drug in 35 years to fight depression using a different approach than traditional drugs.

“Esketamine is a giant step forward,” Mandel says. “It means we’re not going to be demonizing mind-altering substances used for therapeutic purposes. It opens the door to research on LSD, on psilocybin, on MDMA and many other agents that could possibly relieve a great deal of suffering.”

But many clinicians have raised concerns about long-term side effects, such as heart and bladder toxicity. Others have been critical of esketamine, saying there isn’t enough data yet to suggest the drug is safe or effective. Husseini Manji, a neuroscientist who helped develop the drug for Johnson & Johnson at their subsidiary Janssen, has pushed back against these claims.

“When you line up the totality of the studies, it was really an overwhelming amount of data that was all in the same direction,” Manji says in a call. Though just two of the five late-state clinical trials showed significant results, the changes in mood in the three that fell short were “almost identical in magnitude” to the others, Manji says. It was enough for the drug to meet standards for FDA approval.

We can probably expect other ketamine-related drugs to come to market soon. ATAI Life Sciences, a company funding research on the use of magic mushrooms for depression, is developing their own ketamine depression drug. The pharmaceutical company Allergan also developed rapastinel, another ketamine-like drug, though it failed to show any real benefits for patients in later trials. Manji says this is unfortunate for people who could be helped by these kinds of drugs.

“From a patient standpoint, we were hoping it would work,” he says, even though he was not involved in rapastinel’s development. “But sometimes if you really haven’t got the mechanism right and you haven’t really threaded the needle, then sometimes you don’t see these results.”

Drug of Abuse?

Even though ketamine’s medical uses are well-established, most people have only heard of ketamine in the context of a party drug. Because of this bad reputation — and what’s perceived as growing misuse of the drug — several countries, such as China and the UK, have tried to place greater restrictions on ketamine. This would make it harder to study and more expensive in clinical use.

“If it was to ever be rescheduled, places that would be first affected would be you know places that need it most,” O’Carroll says. The WHO has asked at least four times for countries to keep access to ketamine open. “The medical benefits of ketamine far outweigh potential harm from recreational use,” Marie-Paule Kieny, assistant director general for Health Systems and Innovation at WHO, said in 2015.

So far, no countries have put greater restrictions on ketamine, and that’s probably a good thing. Ketamine has a rich history, but its future is still being written.

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Dual studies highlight ketamine’s potential to treat anxiety and addiction

New evidence suggests ketamine can reduce anxiety related to major depression, and substance abuse depression
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Two new studies suggest the psychiatric benefits of ketamine treatment may extend beyond just the targeting of depression. The research demonstrates ketamine may be helpful in targeting both anxiety- and substance abuse-related depression.

Although ketamine is a relatively old drug, originally developed in the 1950s as an anesthetic, over the last decade a growing body of research has affirmed its unique, and rapid, antidepressant effects. The anecdotal effects of the drug on depression have raced ahead of scientific research so quickly that ketamine clinics have popped up all across the United States, where the drug can be administered for up to US$1,000 a dose.

Much is still unknown about how efficacious ketamine actually is for depression. We don’t know ideal dosages, how long the treatments last, or how safe long-term usage is. Two newly published studies are adding to our knowledge about ketamine’s psychiatric uses, adding weight to the drug’s burgeoning new potential.

The first study, led by a team from Massachusetts General Hospital and Harvard Medical School, set out to study how effective ketamine is at treating patients with anxiety-based treatment-resistant depression. This is an important question to resolve, as many traditional antidepressants do not consistently improve anxiety-based symptoms in cases of major depression.

The study took 99 subjects with treatment-resistant depression, half of whom suffered from high anxiety and half of whom displayed no anxious symptoms. The study randomly administered subjects either one of four different intravenous ketamine doses, or midazolam, a general sedative that could serve as a control.

As well as demonstrating ketamine’s novel antidepressant qualities, the study revealed the drug worked equally well in both anxious and non-anxious subjects. This suggests that ketamine’s antidepressant effects are uniquely effective across different types of treatment-resistant depression, something that cannot be said for many major antidepressant drugs.

“In contrast to reports from monoaminergic antidepressants, our data suggest that patients with anxious depression respond equally as well to ketamine compared to those with non-anxious depression,” write the researchers in the published study.

The second new study comes from a team at Yale University School of Medicine. This research investigated whether ketamine could be effective in treating addiction-related depression when administered in tandem with naltrexone.

A study in 2018 offered a small but significant finding, revealing that ketamine was ineffective in treating depression when administered alongside naltrexone. These results were important because they suggested that part of ketamine’s antidepressant effects may be related to the activation of opioid receptors, which would mean long-term ketamine use may potentially result in problems with addiction, something that many researchers have long argued against.

Naltrexone, an opioid receptor blocker, is often administered effectively to combat serious substance abuse problems, so if it rendered ketamine ineffective then that would cast doubt on much research into how ketamine actually works to reduce symptoms of depression. The new Yale research was small, with a sample of only five patients, but its results strongly suggest ketamine and naltrexone do not cancel each other out.

All five subjects suffering from alcohol use disorder and depression displayed significant depressive relief from ketamine dosages despite long-term naltrexone consumption. Senior author on the study, John Krystal, says although larger studies still need to be completed the research does suggest ketamine and naltrexone may be a complimentary combination that helps treat substance abuse and its related depression.

“[The results] raise the possibility that for people who have depression complicated by substance abuse disorders, the combination of ketamine and naltrexone may be a strategy to explore in the effort to optimally treat both conditions,” says Krystal.

Although this new study only consisted of five subjects, the prior research linking ketamine to the opioid system was generated from just 12 subjects. So we are still in uncharted territory regarding ketamine’s mechanistic effects of the brain. But the Yale research should assuage some fears that ketamine may be, “merely another opioid in a novel form.”

The ketamine anxiety study was published in the journal Depress Anxiety.

The ketamine naltrexone study was published in the journalJAMA Psychiatry.

Source: Yale News

Efficacy of intravenous ketamine treatment in anxious versus nonanxious unipolar treatment‐resistant depression

Abstract

Objective

To examine the effect of high baseline anxiety on response to ketamine versus midazolam (active placebo) in treatment‐resistant depression (TRD).

Methods

In a multisite, double‐blind, placebo‐controlled trial, 99 subjects with TRD were randomized to one of five arms: a single dose of intravenous ketamine 0.1, 0.2, 0.5, 1.0 mg/kg, or midazolam 0.045 mg/kg. The primary outcome measure was change in the six‐item Hamilton Rating Scale for Depression (HAMD6). A linear mixed effects model was used to examine the effect of anxious depression baseline status (defined by a Hamilton Depression Rating Scale Anxiety‐Somatization score ≥7) on response to ketamine versus midazolam at 1 and 3 days postinfusion.

Results

N = 45 subjects had anxious TRD, compared to N = 54 subjects without high anxiety at baseline. No statistically significant interaction effect was found between treatment group assignment (combined ketamine treatment groups versus midazolam) and anxious/nonanxious status on HAMD6 score at either days 1 or 3 postinfusion (Day 1: F(1, 84) = 0.02, P = 0.88; Day 3: F(1, 82) = 0.12, P = 0.73).

Conclusion

In contrast with what is observed with traditional antidepressants, response to ketamine may be similar in both anxious and nonanxious TRD subjects. These pilot results suggest the potential utility of ketamine in the treatment of anxious TRD.

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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 Consultants Blog

Ketamine is a dissociative anesthetic that acts on the central nervous system by antagonizing the n-methyl-d-aspartate (NMDA) receptors. It is a rapid acting anti-depressant, but there is a lot more attention being paid to it’s efficacy in alcohol and drug abuse treatment.

Ketamine has been shown in some studies to prolong abstinence from alcohol and drug use disorders. It also has been found to reduce cocaine craving and self-administration in untreated patients.

The mechanisms by which this works has been through the disruption of relevant neural networks which blocks reconciliation of drug-related memories, neuroplasticity and neurogenesis, and enhancing psychological therapy.

We know that addiction is a chronic relapsing disorder with cravings, drug seeking, and unpleasant withdrawal symptoms upon cessation of the drug. Relapse rates with current therapies are between 40-80%.

Pre-clinical research on Ketamine has shown effectiveness in alcohol intake in a rat model:

Alcohol-preferring rats could self-administer
0.08% weight/volume saccharin, 10% weight/volume ethanol or
water. After intraperitoneal administration of either ketamine or
memantine, operant responding and motor activity were assessed.
A dose of 20 mg/kg of ketamine reduced ethanol administration
significantly (33.3% less than vehicle-treated rats) without affecting
motor activity and water consumption. Importantly, coadministration
of rapamycin blocked ketamine-mediated reduction
of alcohol intake, but not that of memantine (Sabino et al.,
2013). Similarly, ketamine’s antidepressant effects are suppressed
by rapamycin. mTOR activation is required for the anti-alcohol effect of ketamine, but not memantine, in alcohol-preferring rats

Also:

Both ketamine and NBQX attenuate alcohol drinking in male Wistar rats.

The devastating consequences of alcohol-use disorder (AUD) on the individual and the society are well established. Current treatments of AUD encompass various strategies, all of which have only modest effectiveness. Hence, there is a critical need to develop more efficacious therapies. Recently, specific glutamatergic receptors have been identified as potential novel targets for intervention in AUD. Thus, the current study was designed to evaluate the effects of acute administration of sub-anesthetic doses of ketamine, an NMDA receptor antagonist, as well as NBQX, an AMPA/kainate receptor antagonist on alcohol intake and its possible behavioural consequences. Adult male Wistar rats were trained in drinking in dark paradigm (3 weeks), and following stable alcohol intake, ketamine, NBQX as well as their combination were injected prior to a 90 min drinking session. In addition to alcohol intake, sucrose preference (overnight), and locomotor activity and forced swim test (FST) were also evaluated before and following alcohol intake. Both doses of ketamine (5 and 10 mg/kg) and NBQX (5 and 10 mg/kg) significantly attenuated percent alcohol intake. The combination of the higher dose of ketamine and NBQX, however, did not significantly affect percent alcohol intake. Moreover, animals exposed to alcohol showed decreased sucrose intake (reflective of anhedonia), decreased locomotor activity and swimming in the FST (reflective of helplessness), that were not affected by ketamine and/or NBQX. These results suggest that selective antagonism of the NMDA or AMPA/kainate receptors may be of therapeutic potential in AUD.

Addiction is characterised by disruptions in learning and memory. Addicts develop cue-specific responses to drug-related
cues. One preclinical study examined the effects of ketamine administration on reconsolidation
where memories are rendered more labile following reactivation. After morphine CPP ( conditioned place preference) was induced, rats were intraperitoneally administered 60 mg/kg of ketamine after being reexposed to the conditioned context or while they were in their home cages. After ketamine administration, preference for morphine decreased significantly in the first retest.  This has been interpreted as evidence that ketamine successfully disrupted reconsolidation of the environment-drug memory.

Effects of scopolamine and ketamine on reconsolidation of morphine conditioned place preference in rats

Persistent memory associated with addictive drugs contributes to the relapse of drug abuse. The current study was conducted to examine the effects of scopolamine and ketamine on reconsolidation of morphine-induced conditioned place preference (CPP). In experiment 1, after morphine CPP was acquired, rats were injected with ketamine (60 mg/kg, intraperitoneally) and scopolamine (2 mg/kg, intraperitoneally), respectively, after reexposure to an earlier morphine-paired context or in their home cages. The CPP was reassessed 24 and 48 h after reexposure. An additional group of rats received saline following reexposure to the earlier morphine-paired context. In experiment 2, two groups of rats were only given saline during the CPP training and subsequent administration of ketamine or scopolamine during the reexposure. In experiment 1, rats failed to exhibit morphine CPP when ketamine and scopolamine were administered only after reexposure to a morphine-paired context. CPP was not abolished by ketamine or scopolamine administration in the animals’ home cages. Also, the animals receiving only saline injections showed strong morphine CPP 24 h after a short exposure to the morphine-paired context. In experiment 2, ketamine or scopolamine treatment alone did not induce CPP or aversion. Administration of scopolamine and ketamine, after reexposure to a drug-paired context, resulted in the disruption of morphine CPP, suggesting the potential effects of scopolamine and ketamine in disrupting memory associated with environmental cues and addictive drugs.

The capacity of ketamine to treat addiction was not investigated scientifically until decades later when Krupitsky and
Grinenko (1997), published work that reported the use of ketamineto reduce relapse in recently detoxified alcoholics. These
published results were a review of 10 years of previous research.The procedure that was investigated was referred to as Ketamine Psychedelic Therapy (KPT) and had been applied since the mid-80sin the former Soviet Union, until ketamine was banned in Russia 1998.  Ten Year Study of Ketamine Psychedelic Therapy (KPT) of Alcohol Dependence [

KPT consisted of three stages. The first step was the preparation,during which patients underwent a preliminary psychotherapy session where a psychotherapist discussed with them the content of the psychedelic experience. They were told that under the influence of ketamine, they would view the world symbolically, realise about the negative aspects of alcohol dependence and see the positive sides of sobriety. They were also told that they would become aware of unconscious mental concepts about the negative aspects of their addiction, such as their personal problems and their self-identity. These insights would help them to accept new life values, purposes and meaning of life and in turn e to overcome
their alcoholism. The second stage was the ketamine session in which ketamine was intramuscularly injected and the psychotherapist interacted with the patient. The psychotherapist verbally guided the patient, with the aim of creating new meaning and purpose in life. At moments of highly intense psychedelic experience, the smell of alcohol was introduced to the individuals. The idea was to enhance the negative emotional valence of the thoughts related to alcohol during the session. Finally, group psychotherapy was performed after the session. The aim of this session was to help patients integrate
insights of psychedelic experience into their lives. It is reported that this procedure was used in
over 1000 alcoholics with no reported complications.In Krupitsky and Grinenko, 1997 report, relapse rates in a group
of recently detoxified alcohol dependent patients undergoing KPT (n ¼ 111) were compared with another group of alcohol dependent patients who were treated with treatment as usual (n ¼ 100). Both groups underwent alcohol detoxification before treatment. After these sessions, the KPT group received an intramuscular injection of ketamine (2.5 mg/kg) along with the corresponding preparation. The control group received ‘conventional, standard methods of treatment’ in the same hospital. Only 24% of the control group remained abstinent after a year, whereas 66% of the KPT group did not relapse during the same period (p < .01).

In a further study, 70 detoxified heroin-dependent patients were randomised into two KPT groups, who were injected different doses of ketamine, in a double-blind manner (Krupitsky et al., 2002). One group (n ¼ 35) received 0.2 mg/kg i.m. of ketamine, which was considered an active placebo, whereas the experimental group (n ¼ 35) received 2.0 mg/kg i.m. After two years, the higher dose of ketamine resulted in a greater rate of abstinence (17% vs 2% abstinent subjects, p < .05). Additionally, the experimental group had a larger positive change in nonverbal unconscious emotional attitudes and a greater and longer-lasting reduction in craving for heroin. The authors therefore concluded that effectiveness of ketamine
was dose dependent. Ketamine psychotherapy for heroin addiction: immediate effects and two-year follow-up

In 2007, Krupitsky’s lab compared the impact of a single vs three KPT sessions (dose: 2.0 mg/kg, i.m.) (Krupitsky et al., 2007). Fifty nine detoxified heroin dependent patients first received a KPT session. After this, 6 participants relapsed and abandoned the treatment. The remaining participants were randomised into two groups: one received a further two KPT sessions (n ¼ 26) in monthly intervals, whereas the other underwent two counseling sessions (n ¼ 27) also in monthly intervals. After a year, 50% in the 3-session KPT group remained abstinent compared to 22% in the single KPT (p < .05) (Krupitsky et al., 2007). This clearly demonstrates the superior efficacy of three KPT sessions in comparison to
one KPT session, which indicates that the KPT sessions are beneficial.  Single Versus Repeated Sessions of Ketamine-Assisted Psychotherapy for People with Heroin Dependence 

In a private psychiatric practice in the US, another psychiatrist has successfully conducted KPT since 1994. He has not only treated patients with drug addiction, but also individuals with other types of addictions (e.g. food addiction) and other psychological disorders. His reported anecdotal, clinical findings are positive, having adhered strictly to the original protocol.  Ketamine Enhanced Psychotherapy: Preliminary Clinical Observations on Its Effectiveness in Treating Alcoholism. Kolp, Eli,Friedman, Harris L.,Young, M. Scott,Krupitsky, Evgeny The Humanistic Psychologist, Vol 34(4), 2006, 399-422

Abstract:

Ketamine is a dissociative anesthetic widely used by physicians in the United States and also a psychedelic drug that physicians can legally prescribe off-label within the United States for other therapeutic purposes. It has been used in Russia and elsewhere to successfully treat alcoholism and other psychological or psychiatric problems, but has not been researched for this purpose in the United States. Results of a series of clinical trials using ketamine for treating alcoholism in the United States are retrospectively reported, along with 2 case studies of how psychotherapy facilitated by this substance helped two individuals achieve abstinence through ketamine’s transpersonal effects. Considering the massive problems caused by alcoholism, the need to begin formal research studies on ketamine psychotherapy for alcoholism is emphasized.

In 2014, 8 cocaine dependent males disinterested in treatment received 3 infusions in a double-blind, cross-over design: 0.41 mg/ kg ketamine, 0.71 mg/kg ketamine, and 2 mg lorazepam (an active benzodiazepine control, which induces mild subjective and anxiolytic effects) (Dakwar et al., 2014b). Infusions lasted 52 min and were separated by 48 h. Before and after each infusion, motivation to quit cocaine and cue-induced craving were assessed. Relative to the lorazepam, motivation to quit cocaine was enhanced and cueinduced craving for cocaine was reduced by the 0.4 mg/kg ketamine (both ps ¼ 0.012), and this latter effect was augmented by the 0.71 mg/kg ketamine dose. During the psychedelic experience,
dissociation and mystical-type effects were assessed. As predicted, the higher dose of ketamine led to greater mystical experiences. Strikingly, these mystical-type experiences, but not the dissociative effects, were found to mediate motivation to quit. However, the small non-treatment-seeking sample, the absence of an inactive placebo and the cross-over design, limit the results.Having said that, the participants showed a significant reduction in the frequency and amount of cocaine
consumed in normal life in the 4 weeks following the experiment, compared to baseline. Dakwar, E., Levin, F., Foltin, R.W., Nunes, E.V., Hart, C.L., 2014b. The effects of subanesthetic ketamine infusions on motivation to quit and cue-induced craving in cocaine-dependent research volunteers. Biol. Psychiatry 76, 40e46. https://doi. org/10.1016/j.biopsych.2013.08.009.

Also, more cocaine research from the same group is here:

Cocaine self-administration disrupted by the N-methyl-D-aspartate receptor antagonist ketamine: a randomized, crossover trial E DakwarMolecular Psychiatry volume22pages76–81 (2017) |

Abstract:

Repeated drug consumption may progress to problematic use by triggering neuroplastic adaptations that attenuate sensitivity to natural rewards while increasing reactivity to craving and drug cues. Converging evidence suggests a single sub-anesthetic dose of the N-methyl-D-aspartate receptor antagonist ketamine may work to correct these neuroadaptations and restore motivation for non-drug rewards. Using an established laboratory model aimed at evaluating behavioral shifts in the salience of cocaine now vs money later, we found that ketamine, as compared to the control, significantly decreased cocaine self-administration by 67% relative to baseline at greater than 24 h post-infusion, the most robust reduction observed to date in human cocaine users and the first to involve mechanisms other than stimulant or dopamine agonist effects. These findings signal new directions in medication development for substance use disorders.

Neural plasticity is defined as the cellular and structural reorganisation
of the brain. Synaptogenesis is a crucial mechanism for
plasticity, since for change to happen within brain circuitry new
synapses between neurons must be formed. Surface expression of
AMPARs and upregulation of other synaptic proteins are involved in
the process of synaptogenesis. Diminished glutamatergic synaptic
transmission and reduced plasticity are thought to be associated
with addiction. Existing models suggest that ketamine’s blockade of NMDA receptors
increases synaptogenesis by stimulating protein synthesis
and the insertion of AMPA receptors. Hence, ketamine’s
effects help to reverse the glutamatergic changes associated
with depression and addiction. 

Animal models of addiction, depression and other psychiatric disorders
have been linked to a reduction in adult neurogenesis . It has been suggested that in addiction
the loss of neurogenesis, especially in cortical and hippocampal
regions, may contribute to levels of self-administration and the
vulnerability of relapsing. The reduction of neurogenesis in addiction is supported in
humans by the reduction in BDNF serum levels. In a study, 37
subjects with diagnosis of alcohol dependence showed significantly
reduced BDNF serum levels compared to healthy individuals
. Similarly, cocaine- and heroin-dependentpatients have significantly lower serum BDNF levels and these
seem to recover during withdrawal. Rapid and transient up-regulation of the neuroplasticity marker
BDNF is implicated as a critical component of the antidepressant
mechanism of ketamine . BDNF knock-out mice do not show anti-depressant response to
ketamine in animal models of depression.

Recent research has
demonstrated that ketamine increases peripheral plasma BDNF in
depressed people who respond to treatment but not in treatment
non-responders or patients receiving an active placebo. These BDNF increases in depressed people given ketamine
are robustly correlated with the drug’s antidepressant effects.

It has been found there is a dispersion in normal brain connectivity and the disruption of the usual pattern of communication  in depression and addictions. . The integrity of functional networks decreased, being the
change maximal in functional hubs such as the thalamus, putamen
and high-level association cortices. In particular, connectivity
within the Default Mode Network was reduced between the posterior
cingulate cortex and the mPFC .
The connectivity between the parahippocampal and the retrosplenial
cortex also decreased as well as the segregation between
other major functional networks such as the salience, attention and
different visual networks Infusions of ketamine have shown to decrease connectivity
between and within resting-state consciousness networks.
Connectivity between the mPFC and the rest of the Default
Mode Network (via the posterior cingulate cortex) has been found
to be reduced, along with the integrity and activity of the salience
and visual networks are also affected. Since it is known
that connectivity with the mPFC is elevated in depression , the reduction of connectivity in the Default Mode
Network observed during the psychedelic experience might be a
mechanism that helps treat depressive states, which are very
common in addicts and predictive of relapse.

Given addiction is highly co-morbid with depression   and ketamine’s role within psychiatry changed
dramatically when it was discovered to be an anti-depressant, we
now briefly describe the research concerning ketamine and
depression. In 2000, the first clinical trial hinted at the potential of
ketamine as a treatment for depression. Four subjects diagnosed
with depression were intravenously administered 0.5 mg/kg of
ketamine in a randomised, double-blind design. The results were
compared to the injection of saline solutions in 3 subjects with an
equivalent diagnosis. Comparison on the Hamilton Rating Scale for
Depression (HAM-D) showed moderate evidence for a greater
reduction in scores after ketamine infusion compared to saline
(Berman et al., 2000). The reduction was rapid and outlasted the
subjective effects of ketamine, lasting for 3 days after infusion.
Despite the small sample size and the limited follow-up, this result
and anti-depressant effects observed in animal models of depression
encouraged researchers in the field to perform more studies in humans . Since then, over 30 studies have
examined the antidepressants effects of ketamine in patients with
treatment-resistant major depressive and bipolar disorders.

Ketamine has shown a 65-70% response rate in treating
depression within 24 h, which contrasts with the ~47% response
rate of conventional monoaminergic antidepressants after weeks
or months . Furthermore,
ketamine’s antidepressant actions are almost immediate and last
for approximately a week ,
whereas conventional antidepressive medications take weeks to
have an effect, are given daily and most of them fail to exert long lasting
effects . Furthermore, studies
have consistently shown that after a ketamine infusion there is a
significant reduction in suicidal ideation which also lasts for several
days.Depression and addiction’s co-expression is almost ubiquitous
People with alcohol, opioids, cannabis and
cocaine use disorders show notably higher rates of depression than
the average of the general population. Furthermore, high levels of depression and anxiety
may predispose relapse to: heroin, alcohol, cannabis and cocaine.

Memories and their creation and alteration is felt to be at the heart of cues and triggers and relapse in addiction. Once consolidated, memories are thought to be stored in a
stabilised state after initial acquisition. Shortly after reactivation
(i.e. remembered) of consolidated memories, these are rendered
transiently unstable and labile, before they then re-stabilise. This
process has been named reconsolidation . After reconsolidation,
the memories are stored again, but they may have been slightly
altered or updated. Each time memories are reactivated the latest
version is retrieved and they are again susceptible to change. During reconsolidation memories may be vulnerable to
manipulation and disruption. This was first demonstrated in animals
using fear conditioning. Rodents were trained to associate a
neutral stimulus with a shock such that the neutral stimulus elicited
a fear response. Researchers eliminated this fear response by
pharmacologically disrupting the reconsolidation process . Reward memories can also be disrupted such that a
neutral stimulus that once elicited appetitive behaviour no longer
does so. Therefore, non-pharmacological and drug therapies that
aim at weakening drug-cue memories via manipulation of reconsolidation
are of interest. Preclinical studies have shown that ketamine affects reconsolidation
of drug memories. . A recent review has suggested that ketamine (along with other psychedelics)
may be able to disrupt maladaptive appetitive memories
(Fattore et al., 2017).  Psychedelics and reconsolidation of traumatic and appetitive maladaptive memories: focus on cannabinoids and ketamine

Article ABSTRACT:

Rationale

Clinical data with 3,4-methylenedioxymethamphetamine (MDMA) in post-traumatic stress disorder (PTSD) patients recently stimulated interest on the potential therapeutic use of psychedelics in disorders characterized by maladaptive memories, including substance use disorders (SUD). The rationale for the use of MDMA in PTSD and SUD is being extended to a broader beneficial “psychedelic effect,” which is supporting further clinical investigations, in spite of the lack of mechanistic hypothesis. Considering that the retrieval of emotional memories reactivates specific brain mechanisms vulnerable to inhibition, interference, or strengthening (i.e., the reconsolidation process), it was proposed that the ability to retrieve and change these maladaptive memories might be a novel intervention for PTSD and SUD. The mechanisms underlying MDMA effects indicate memory reconsolidation modulation as a hypothetical process underlying its efficacy.

Objective

Mechanistic and clinical studies with other two classes of psychedelic substances, namely cannabinoids and ketamine, are providing data in support of a potential use in PTSD and SUD based on the modulation of traumatic and appetitive memory reconsolidation, respectively. Here, we review preclinical and clinical data on cannabinoids and ketamine effects on biobehavioral processes related to the reconsolidation of maladaptive memories.

Results

We report the findings supporting (or not) the working hypothesis linking the potential therapeutic effect of these substances to the underlying reconsolidation process. We also proposed possible approaches for testing the use of these two classes of drugs within the current paradigm of reconsolidation memory inhibition.

Furthermore, a meta-analysis of pre-clinical
studies found evidence suggesting that NMDAR antagonists can
be used to target reward memory reconsolidation, and more successfully
than adrenergic antagonists such as propranolol (Das
et al., 2013)  Das, R.K., Freeman, T.P., Kamboj, S.K., 2013. The effects of N-methyl d-aspartate and B-adrenergic receptor antagonists on the reconsolidation of reward memory: a meta-analysis. Neurosci. Biobehav. Rev. 37, 240-255.:

Abstract

Pharmacological memory reconsolidation blockade provides a potential mechanism for ameliorating the maladaptive reward memories underlying relapse in addiction. Two of the most promising classes of drug that interfere with reconsolidation and have translational potential for human use are N-methyl-d-aspartate receptor (NMDAR) and B-Adrenergic receptor (B-AR) antagonists. We used meta-analysis and meta-regression to assess the effects of these drugs on the reconsolidation of reward memory in preclinical models of addiction. Pharmacokinetic, mnemonic and methodological factors were assessed for their moderating impact on effect sizes. An analysis of 52 independent effect sizes (NMDAR = 30, B-AR = 22) found robust effects of both classes of drug on memory reconsolidation, but a far greater overall effect of NMDAR antagonism than B-AR antagonism. Significant moderating effects of drug dose, relapse process and primary reinforcer were found. The findings suggest that reward memory reconsolidation can be robustly targeted by NMDAR antagonists and to a lesser extent, by B-AR antagonists. Implications for future clinical work are discussed.

Highlights

► Meta-analysis of NMDAR and B-adrenergic antagonists in preclinical reward reconsolidation. ► Larger effects of NMDAR (r = .613) than B-adrenergic (r = .24) antagonists were found. ► ‘Relapse process’, trace type, reinforcer and drug dose moderated effect sizes. ► NMDAR antagonists particularly might be of clinical use in treating addiction.

 

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                                 Mystical experiences and psychedelic effects

Mystical experiences and psychedelic effects provoked by
classic psychedelic drugs have been shown to be psychologically
beneficial in long-term studies.They have not only been linked with positive
outcomes in various treatments, but also to ‘life-changing’,
‘spiritually meaningful’ and ‘eye opening’ events.In the ketamine studies described
above, anecdotal and qualitative reports suggest that the subjective
psychedelic experience seemed to help patients. For example, to
help them: undergo a cathartic process, improve relationships with
the world and other people, maintain positive psychological
changes and enhance self-awareness and personal growth.During KPT, patients reported a feeling of ‘resolution’ and
‘catharsis’ of some psychological problems, mainly those related to
alcohol. Furthermore, the degree of mystical experience was also
linked to the insight and impact of KPT reported by patients
. Interestingly, the intensity of the negative experiences (experiences associated
with negative emotions, fear and horror) during the
ketamine session was associated with longer remission. This was
blindly and quantitatively assessed by analysing patient’s selfreports.
Moreover, spirituality, self-concept, emotional attitudes
to other people and positive changes in life values and purposes
were improved after the ketamine experience.

Notably, ketamine’s mystical experiences, but not dissociative
effects, were found to mediate ketamine’s increase motivation to
quit 24 h after the infusion in cocaine addicts .
Moreover, consistent with previous studies, it was also observed
that mystical experiences were positively dose-dependent. This
study therefore provides evidence that the mystical experience
induced by ketamine is important in its therapeutic mechanism
. Speculatively, mystical experiences may help
to rapidly shift patients’ mindsets towards the integration and
acceptance of a sober lifestyle.

The acute disruptions of the functional networks, especially the
alterations to the default mode network, are related to the psychedelic
experience. In fact, the degree of network dissolution in
LSD and psilocybin is correlated with the intensity of the psychedelic
experience . The disruption to the default mode network may engender a reduction
in rumination and maladaptive repetitive thoughts. Psychological
therapies for addiction often aim to help the patient consider
different ways of life, especially those without the drug, and a
pharmacological agent such as ketamine which expedites that
process may be useful in treating addiction.

Speculatively, ketamine can
provide a unique mental state during and after acute drug effects
that facilitates and enriches therapeutic experiences, which in turn
may improve efficacy and lengthen treatment effects. Furthermore, synaptogenesis
and neurogenesis are putatively critical in learning new
information . The uptake of psychological therapy may
therefore be facilitated after ketamine infusions due increases in
synaptogenesis and neurogenesis, and thus improved learning of
relapse-reducing strategies, such as those used in relapseprevention
based cognitive behavioural therapy (CBT). In fact, the
idea that neurogenesis and synaptogenesis work synergistically
with psychological therapies is becoming recognised as a new
approach in the treatment of mental disorders . Theoretically, the administration of ketamine (which can
produce a ‘psychedelic’ experience) may open people’s minds so
they are more able to embrace what is presented during therapy as
well as enhancing the uptake of new therapeutic content.

The promise of ketamine in the treatment of addiction is supported
by research with large treatment effect sizes, especially in
comparison to existing treatments. In recently detoxified alcoholics,
ketamine treatment increased one-year abstinence rates in
alcoholics from 24% in the control to 66% in the ketamine group
(Krupitsky and Grinenko, 1997) and reduced cocaine self administration
by 67% relative to baseline in non-treatment
seeking cocaine users (Dakwar et al., 2016). These results clearly
demonstrate profound effects of ketamine administration (with
and without therapy) on drug and alcohol use, of an order of
magnitude which is 2 or 3 times more effective than existing
pharmacotherapies.

Ketamine for the treatment of addiction Evidence and potential mechanisms

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