Tag Archives: ketamine for Addiction

KETAMINE For Obsessive-Compulsive Disorder | Depression | 703-844-0184 | FAIRFAX, VA | LOUDON, VA| LORTON, VA | |Ketamine For Obsessive Compulsive Disorder| 22308 |22304

NOVA Health Recovery  <<< Ketamine Treatment Center Fairfax, Virginia

CAll 703-844-0184 for an immediate appointment to evaluate you for a Ketamine infusion:

Ketaminealexandria.com    703-844-0184 Call for an infusion to treat your depression. PTSD, Anxiety, CRPS, or other pain disorder today.

email@novahealthrecovery.com  << Email for questions to the doctor

Ketamine center in Fairfax, Virginia    << Ketamine infusions

Ketamine – NOVA Ketamine facebook page – ketamine treatment for depression

facebook Ketamine page

NOVA Health Recovery  << Ketamine clinic Fairfax, Va  – Call 703-844-0184 for an appointment – Fairfax, Virginia

Ketamine Consultants Blog

 

Randomized Controlled Crossover Trial of Ketamine in
Obsessive-Compulsive Disorder: Proof-of-Concept

Ketamine for Obsessive-compulsive disorder  <ARTICLE

Ketamine has effectiveness on the short run when it comes to treating Obsessive-compulsive disorders:

Serotonin reuptake inhibitors (SRIs), the first-line pharmacological treatment for obsessive-compulsive disorder (OCD), have two
limitations: incomplete symptom relief and 2–3 months lag time before clinically meaningful improvement. New medications with faster
onset are needed. As converging evidence suggests a role for the glutamate system in the pathophysiology of OCD, we tested whether a
single dose of ketamine, a non-competitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, could achieve rapid antiobsessional
effects. In a randomized, double-blind, placebo-controlled, crossover design, drug-free OCD adults (n ¼ 15) with near-constant
obsessions received two 40-min intravenous infusions, one of saline and one of ketamine (0.5 mg/kg), spaced at least 1-week
apart. The OCD visual analog scale (OCD-VAS) and the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) were used to assess OCD
symptoms. Unexpectedly, ketamine’s effects within the crossover design showed significant (po0.005) carryover effects (ie, lasting
longer than 1 week). As a result, only the first-phase data were used in additional analyses. Specifically, those receiving ketamine (n ¼ 8)
reported significant improvement in obsessions (measured by OCD-VAS) during the infusion compared with subjects receiving placebo
(n ¼ 7). One-week post-infusion, 50% of those receiving ketamine (n ¼ 8) met criteria for treatment response (X35% Y-BOCS
reduction) vs 0% of those receiving placebo (n ¼ 7). Rapid anti-OCD effects from a single intravenous dose of ketamine can persist for at
least 1 week in some OCD patients with constant intrusive thoughts. This is the first randomized, controlled trial to demonstrate that a
drug affecting glutamate neurotransmission can reduce OCD symptoms without the presence of an SRI and is consistent with a
glutamatergic hypothesis of OCD.

 

Ketamine is a noncompetitive antagonist of the NMDA
receptor (a type of glutamate receptor). Studies in patients
with unipolar and bipolar depression have found that a
single intravenous infusion of ketamine can have antidepressant
effects within 40 min of starting the infusion.
These effects persist for 3–18 days, long after the drug has
cleared the patient’s system (Berman et al, 2000;
Diazgranados et al, 2010a, b; Murrough et al, 2012; Valentine
et al, 2011; Zarate et al, 2006, 2012a). We treated an
unmedicated individual with OCD with ketamine (0.5 mg/kg
IV over 40 min) and found rapid anti-obsessional effects that
returned to baseline by 1-week post-infusion (Rodriguez
et al, 2011). Bloch et al (2012) conducted an open ketamine
trial in 10 subjects with OCD and found modest but
statistically significant improvement in OCD symptoms
over days 1–3 following ketamine infusion compared with
baseline; however, most subjects in this study were taking
multiple other medications at the time of infusion.

Ketamine Therapy | Ketamine Doctors | 703-844-0184 | Fairfax, Virginia | Depression causes RAPID AGING due to Oxidative stress | NOVA Health Recovery, Alexandria, Va 22306

NOVA Health Recovery  <<< Ketamine Treatment Center Fairfax, Virginia

CAll 703-844-0184 for an immediate appointment to evaluate you for a Ketamine infusion:

Ketaminealexandria.com    703-844-0184 Call for an infusion to treat your depression. PTSD, Anxiety, CRPS, or other pain disorder today.

email@novahealthrecovery.com  << Email for questions to the doctor

Ketamine center in Fairfax, Virginia    << Ketamine infusions

Ketamine – NOVA Ketamine facebook page – ketamine treatment for depression

facebook Ketamine page

NOVA Health Recovery  << Ketamine clinic Fairfax, Va  – Call 703-844-0184 for an appointment – Fairfax, Virginia

Ketamine Consultants Blog
________________________________

Reasons to treat depression rapidly – Depression causes rapid aging> Consider using a rapid – acting antidepressant!

Depression ‘makes us biologically older’  BBC Article

Major depressive disorder and accelerated cellular aging

Patients with major depressive disorder (MDD) have an increased onset risk of aging-related somatic diseases such as heart disease,
diabetes, obesity and cancer. This suggests mechanisms of accelerated biological aging among the depressed, which can be
indicated by a shorter length of telomeres. We examine whether MDD is associated with accelerated biological aging, and whether
depression characteristics such as severity, duration, and psychoactive medication do further impact on biological aging. Data are
from the Netherlands Study of Depression and Anxiety, including 1095 current MDD patients, 802 remitted MDD patients and 510
control subjects. Telomere length (TL) was assessed as the telomere sequence copy number (T) compared to a single-copy gene
copy number (S) using quantitative polymerase chain reaction. This resulted in a T/S ratio and was converted to base pairs (bp).
MDD diagnosis and MDD characteristics were determined by self-report questionnaires and structured psychiatric interviews.
Compared with control subjects (mean bp = 5541), sociodemographic-adjusted TL was shorter among remitted MDD patients
(mean bp = 5459; P = 0.014) and current MDD patients (mean bp = 5461; P = 0.012). Adjustment for health and lifestyle variables did
not reduce the associations. Within the current MDD patients, separate analyses showed that both higher depression severity
(P<0.01) and longer symptom duration in the past 4 years (P = 0.01) were associated with shorter TL. Our results demonstrate that
depressed patients show accelerated cellular aging according to a ‘dose–response’ gradient: those with the most severe and
chronic MDD showed the shortest TL. We also confirmed the imprint of past exposure to depression, as those with remitted MDD
had shorter TL than controls

In this large cohort study we demonstrated that currently
depressed persons had shorter TL than never-depressed controls.
Based on an estimated mean telomere shortening rate of 14–20
bp per year as found in this and other studies,20,23,26 the
differences observed indicate 4–6 years of accelerated aging for
the current MDD sample as compared to controls. We also showed
evidence for the imprint of past exposure to depression since
those with remitted MDD also had shorter TL than control
subjects. These observed associations remained significant after
controlling for lifestyle and somatic health variables, suggesting that the shortened telomeres were not simply due to unhealthylifestyle or poorer somatic health among depressed persons.
Finally, the association between MDD and TL showed a ‘dose–
response’ gradient, since the most severely and chronically
depressed patients had the shortest telomeres.

MDD is thus associated with shortened TL, which resembles
accelerated biological aging. The disorder has previously also been
associated with dysregulations of the hypothalamus–pituitary–
adrenal (HPA) axis,43,45 the immune system,46,47 the autonomic
nervous system (ANS)48,49 and increased oxidative stress.50
Shortened telomeres, in turn, are suggested to be a consequence
or a concomitant of these dysregulated biological stress systems.
In line with this, several in vitro and in vivo studies found increased
cortisol,51 oxidative stress52 and pro-inflammatory cytokines53
to be associated with shorter TL. Dysregulations of these stress systems could contribute to telomere shortening in MDD patients.9,12
However, the exact biological mechanisms that mediate the relation
between depression and telomere shortening, as well as the
direction of the link, remain to be further explored.

Oxidative stress shortens telomeres

Elevated DNA Oxidation and DNA Repair Enzyme Expression in Brain White Matter in Major Depressive Disorder.

The Role of Oxidative Stress in Depressive Disorders

Abstract:

Studies of the World Health Organization suggest that in the year 2020, depressive disorder will be the illness with the highest
burden of disease. Especially unipolar depression is the psychiatric disorder with the highest prevalence and incidence, it is cost-intensive and has a relatively high morbidity. Lately, the biological process involved in the aetiology of depression has been the focus of research.
Since its emergence, the monoamine hypothesis has been adjusted and extended considerably. An increasing body of evidence points to
alterations not only in brain function, but also in neuronal plasticity. The clinical presentations demonstrate these dysfunctions by accompanying cognitive symptoms such as problems with memory and concentration. Modern imaging techniques show volume reduction of the hippocampus and the frontal cortex. These findings are in line with post-mortem studies of patients with depressive disorder and they point to a significant decrease of neuronal and glial cells in cortico-limbic regions which can be seen as a consequence of alterations in
neuronal plasticity in this disorder. This could be triggered by an increase of free radicals which in turn eventually leads to cell death and consequently atrophy of vulnerable neuronal and glial cell population in these regions. Therefore, research on increased oxidative stress in unipolar depressive disorder, mediated by elevated concentrations of free radicals, has been undertaken. This review gives a comprehensive overview over the current literature discussing the involvement of oxidative stress and free radicals in depression.

Membrane damage in blood of patients with depression has
been shown by elevated of omega 3- fatty-acids [45] and by increased
lipid peroxidation products in patients with DD [42, 45,
[46, 47]. Furthermore, DNA-strand brakes have been reported in
the blood of these patients [48]. DD has been linked to increased
serum levels of malondialdehyde (MDA), a breakdown product of
oxidized apolipoprotein B-containing lipoproteins, and thus a
marker of the rate of peroxide breakdown [49, 50].

In patients with DD (Depressive Disorders), elevated levels of MDA adversely affect
the efficiency of visual-spatial and auditory-verbal working memory,
short-term declarative memory and delayed recall declarative
memory [51]. Higher concentration of plasma MDA in patients
with recurrent depression is associated with the severity of depressive
symptoms, both at the beginning of antidepressant pharmacotherapy,
and after 8 weeks of treatment. Statistically significant
differences were found in the intensity of depressive symptoms,
measured on therapy onset versus the examination results after
8 weeks of treatment [51]. Although this is used as a marker of lipid peroxidation, it is considered to be less stable than 8-iso-PGF2a, and more susceptible to confounding factors such as antioxidants from diet [52]. Therefore, the best way to investigate oxidative disruptions to lipids in humans is via assessing levels of F2-
isoprostanes [52-54]. These are stable compounds produced in the
process of lipid peroxidation [52, 54]. 8-iso-PGF2a are specific F2-
isoprostane molecules produced during the peroxidation of arachnidonic acid. However, the mean serum level of 8-iso-PGF2a was shown to be significantly higher in a group of patients with DD,
controlling for lifestyle variables such as body mass index, alcohol
consumption, and physical activity [55, 56]. Cerebral membrane
abnormalities and altered membrane phospholipids have been suggested by an increased choline-containing compound seen in the
putamen of patients with DD [57] which has been interpreted as a
result of increased oxidative stress in patients with DD.

A Meta-Analysis of Oxidative Stress Markers in Depression

Results
115 articles met the inclusion criteria. Lower TAC was noted in acute episodes (AEs) of depressed patients (p<0.05). Antioxidants, including serum paraoxonase, uric acid, albumin,
high-density lipoprotein cholesterol and zinc levels were lower than controls (p<0.05); the serum uric acid, albumin and vitamin C levels were increased after antidepressant therapy
(p<0.05). Oxidative damage products, including red blood cell (RBC) malondialdehyde (MDA), serum MDA and 8-F2-isoprostanes levels were higher than controls (p<0.05). After
antidepressant medication, RBC and serum MDA levels were decreased (p<0.05). Moreover, serum peroxide in free radicals levels were higher than controls (p<0.05). There were
no difference

Conclusion
This meta-analysis supports the facts that the serum TAC, paraoxonase and antioxidant levels are lower, and the serum free radical and oxidative damage product levels are higher
than controls in depressed patients. Meanwhile, the antioxidant levels are increased and the oxidative damage product levels are decreased after antidepressant medication. The
pathophysiological relationships between oxidative stress and depression, and the potential benefits of antioxidant supplementation deserve further research.

Some studies have demonstrated that depressed patients’ oxidative product levels in their peripheral blood [3, 4], red blood cells (RBC) [4], mononuclear cells [5], urine [6], cerebrospinal
fluid [7] and postmortem brains [8] were abnormal. Antioxidant system disturbance in peripheral blood has also been reported [9]. Autoimmune responses against neoepitopes
induced by oxidative damage of fatty acid and protein membranes have been reported [10, 11].
Lower glutathione (GSH) levels [12] and a negative relationship between anhedonia severity
and occipital GSH levels [13] were found through magnetic resonance spectroscopy (MRS).

Oxidative stress is defined as a persistent imbalance between oxidation and anti-oxidation, which leads to the damage of cellular macromolecules [14, 15]. The free radicals consist of reactive
oxygen species (ROS) and reactive nitrogen species (RNS). The main ROS includes superoxide anion, hydroxy radical and hydrogen peroxide, and the RNS consists of nitric oxide
(NO), nitrogen dioxide and peroxynitrite. Nitrite is often used as a marker of NO activity. Interestingly, the brain appears to be more susceptible to the ROS/RNS because of the high
content of unsaturated fatty acids, high oxygen consumption per unit weight, high content of key ingredients of lipid peroxidation (LP) and scarcity of antioxidant defence systems [16].
The oxidative products include products of oxidative damage of LP, protein and DNA in depression. As a product of LP, abnormal malondialdehyde (MDA) levels in depression have
been reported [17]. 8-F2-isoprostane (8-iso-PGF2α) is another product of LP [18] that is considered
to be a marker of LP because of its chemical stability [19]. The protein carbonyl (PC), 8-hydroxy-2-deoxyguanosine (8-OHdG) and 8-oxo-7, 8-dihydroguanosine (8-oxoGuo) are
the markers of protein, DNA and RNA oxidative damage, respectively [3, 20, 21]. The oxidative damage to cellular macromolecules changes the structure of original epitopes, which leads to the generation of new epitopes modified (neoepitopes). The antibodies against oxidative neoepitopes
in depression have been found [10, 11, 22–24]. On the other hand, the antioxidant defence systems can be divided into enzymatic and non-enzymatic antioxidants. The nonenzymatic
antioxidants include vitamins C and E, albumin, uric acid, high-density lipoprotein cholesterol (HDL-C), GSH, coenzyme Q10 (CoQ10), ceruloplasmin, zinc, selenium, and so on.
The enzymatic antioxidants include superoxide dismutase (SOD), glutathione peroxidase (GPX), catalase (CAT), glutathione reductase (GR), paraoxonase 1 (PON1), and so on.

Discussion
The present findings support oxidative stress may be disordered in depressed patients, which is demonstrated by abnormal oxidative stress marker levels. In this meta-analysis, at first we
found in depressed patients: 1) the serum TAC, PON, uric acid, albumin, HDL-C and zinc levels were lower than controls; 2) the serum peroxide, MDA, 8-iso-PGF2α and RBC MDA levels
were higher than controls. To explore the effect of the antidepressant therapy to oxidative stress
markers, we reviewed the studies which had changes. And it came to the conclusions: 1) the serum uric acid, albumin, and vitamin C levels were increased; 2) the serum nitrite, RBC and
serum MDA levels were decreased.

The serum antioxidant levels are significantly lower in depression in our study and previous
reports, including PON, albumin, zinc, uric acid HDL-C, CoQ10 [146] and GSH [4, 38].
Meanwhile, the oxidative damage product levels are significantly higher. The body couldn’t
scavenge the excess free radicals (peroxide), leading to damages of main parts of cellular macromolecules
such as fatty acids, protein, DNA, RNA and mitochondria. The longitudinal antidepressant
therapy can reverse these abnormal oxidative stress parameters. It has proved
these phenomena occur in depression, such as increased levels of MDA, 8-iso-PGF2α, 8-oxoGuo
and 8-OHdG [3, 21]. Oxidative stress plays a crucial role in the pathophysiology of
depression. Some genes may be a potential factor. Lawlor et al (2007) reported the R allele of
PON1Q192R was associated with depression [147]. In addition, poor appetite, psychological
stressors, obesity, metabolic syndrome, sleep disorders, cigarette smoking and unhealthy lifestyle
may also contribute to it [148]. Furthermore, oxidative stress activates the immuneinflammatory
pathways [148]. But some studies supported decrease in albumin, zinc and
HDL-C levels was probably related to increased levels of pro-inflammatory cytokines (such as
interleukin-1 (IL-1) and IL-6) [59, 70–72, 117] during an acute phase response, which illustrated the activated immune-inflammatory pathways also activates the oxidative stress. These two mechanisms influence each other. On the other hand, the oxidative damage to cellular macromolecules changes the structure of original epitopes, which leads to generation of newepitopes modified (neoepitopes). Oxidative neoepitopes reported up to now include the conjugated oleic and azelaic acid, MDA, phosphatidyl inositol (Pi), NO-modified adducts and oxidized low density lipoprotein (oxLDL) [11, 22–24]. Maes et al reported the levels of serum IgG antibody against the oxLDL and IgM antibodies against the conjugated oleic and azelaic acid, MDA, Pi and NO-modified adducts were increased in depression [11, 22–24]. Depleted antioxidant defence in depression suggests that antioxidant supplements may be useful in clinical management. Preliminary evidence has indicated that patients treated with CoQ10 showed improvement in depressive symptoms and decrease in hippocampal oxidative DNA damage [149]. In our analyses, vitamin C and E levels did not differ between depressed patients and controls, but many studies have reported that vitamin C and E supplements could improve depressive moods [150, 151].

Malondialdehyde plasma concentration correlates with declarative and working memory in patients with recurrent depressive disorder

Abstract

Oxidative stress has been implicated in the cognitive decline, especially in memory impairment. The purpose of this study was to determine the concentration of malondialdehyde (MDA) in patients with recurrent depressive disorders (rDD) and to define relationship between plasma levels of MDA and the cognitive performance. The study comprised 46 patients meeting criteria for rDD. Cognitive function assessment was based on: The Trail Making Test , The Stroop Test, Verbal Fluency Test and Auditory-Verbal Learning Test. The severity of depression symptoms was assessed using the Hamilton Depression Rating Scale (HDRS). Statistically significant differences were found in the intensity of depression symptoms, measured by the HDRS on therapy onset versus the examination results after 8 weeks of treatment (P < 0.001). Considering the 8-week pharmacotherapy period, rDD patients presented better outcomes in cognitive function tests. There was no statistically significant correlation between plasma MDA levels, and the age, disease duration, number of previous depressive episodes and the results in HDRS applied on admission and on discharge. Elevated levels of MDA adversely affected the efficiency of visual-spatial and auditory-verbal working memory, short-term declarative memory and the delayed recall declarative memory. 1. Higher concentration of plasma MDA in rDD patients is associated with the severity of depressive symptoms, both at the beginning of antidepressants pharmacotherapy, and after 8 weeks of its duration. 2. Elevated levels of plasma MDA are related to the impairment of visual-spatial and auditory-verbal working memory and short-term and delayed declarative memory.

Antioxidant /Antidepressant-like Effect of Ascorbic acid (Vitamine
C) and Fluoxetine
Another study investigated the influence of ascorbic acid
(which is an antioxidant with antidepressant-like effects in animals)
on both depressive-like behaviour induced by a chronic unpredictable
stress (CUS) paradigm and on serum markers of oxidative
stress and in cerebral cortex and hippocampus of mice [120]. The
CUS-model is an animal model for induced depression-like behaviour
in animals. Depressive-like behaviour induced by CUS was
accompanied by significantly increased lipid peroxidation (cerebral
cortex and hippocampus), decreased catalase (CAT) (cerebral cortex
and hippocampus) and glutathione reductase (GR) (hippocampus)
activities and reduced levels of glutathione (cerebral cortex).
Repeated ascorbic acid as well as fluoxetine administration significantly
reversed CUS-induced depressive-like behaviour as well as
oxidative damage. No alterations were observed in locomotor activity
and glutathione peroxidase (GPx) activity in the same sample.
These findings pointed to a rapid and robust effect of ascorbic acid
in reversing behavioural and biochemical alterations induced in an
animal model [120].  Ascorbic acid treatment, similarly to fluoxetine, reverses depressive-like behavior and brain oxidative damage induced by chronic unpredictable stress.

 

Ketamine Therapy | Ketamine Doctors | 703-844-0184 | Fairfax, Virginia | Ketamine and Psychedelic drugs – for depression and neuroplasticity | NOVA Health Recovery, Alexandria, Va 22306

NOVA Health Recovery  <<< Ketamine Treatment Center Fairfax, Virginia

CAll 703-844-0184 for an immediate appointment to evaluate you for a Ketamine infusion:

Ketaminealexandria.com    703-844-0184 Call for an infusion to treat your depression. PTSD, Anxiety, CRPS, or other pain disorder today.

email@novahealthrecovery.com  << Email for questions to the doctor

Ketamine center in Fairfax, Virginia    << Ketamine infusions

Ketamine – NOVA Ketamine facebook page – ketamine treatment for depression

facebook Ketamine page

NOVA Health Recovery  << Ketamine clinic Fairfax, Va  – Call 703-844-0184 for an appointment – Fairfax, Virginia

Ketamine Consultants Blog
_______________________________________________________________________________________________


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