A Brief Tour Of The Brain
To understand how ketamine works, its helpful to be familiar with some basics of neurobiology. The brain is made of brain cells called neurons which signal to each other via chemicals called neurotransmitters. The cell sending the signal squirts out a chemical substance, and the chemical lands on the surface of the cell receiving the signal. This receiving cell has specialized receptors on its surface, which the chemicals fit into. When this happens, the signal has been received, and it sets in motion the appropriate event in the receiving cell.
The main neurotransmitters in the brain used to transmit and process information are called glutamate and GABA. Glutamate increases activity in the brain while GABA decreases activity. When activation is transmitted through networks of neurons via glutamate, the receiving cells register the presence of this neurotransmitter via multiple types of receptor. One type is the AMPA receptor, which produces activity in the receiving cell. The other major type is the NMDA receptor. When activated, these receptors cause a strengthening of the connection between the two neurons, allowing learning to occur. It is the NMDA receptor that ketamine targets.
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Drugs And Treatment Regimens
Psilocybin was suspended in 0.9% saline and sonicated until fully dissolved. Drug was administered in a volume of 1 ml/kg, subcutaneous route. Ketamine hydrochloride was suspended in 0.9% saline and administered at a volume of 1 ml/kg, via the intraperitoneal route. M100907 HCl was dissolved in 0.9% saline solution containing 0.3% Tween and injected SC, 30 min pre-psilocybin or vehicle. Dizocilpine maleate , was administered SC in a volume of 1 ml/kg. Doses are expressed as that of base. Pretreatment times for psilocybin, ketamine and dizocilpine was 10 min, except in the observation test when test onset was immediately post injection. A 10 min pretreatment time was adopted for the PR and 5-choice tests to ensure significant drug exposure at test onset.
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Where Can You Receive Ketamine Therapy
Legal ketamine clinics now exist throughout the United States, a list can be found here. A ketamine nasal spray is also available for depression. Access to this treatment is likely to only increase over time as many more people continue to find relief from their depression through the use of ketamine.
Psilocybin Demonstrates Superior Antidepressant
Animals injected with psilocybin displayed decreased immobility in the FST when compared with the control group 5 weeks after administration , symbolizing an antidepressive-like effect. Furthermore, there was no sign of the effects diminishing over time, indicating that the therapeutic effects of a single dose of psilocybin likely last far beyond the five weeks.
Rats administered ketamine displayed significantly decreased immobility compared to the control group when tested at weeks one and two. However, the drugs durability waned, with immobility increasing at week 3 to the point where it was indistinguishable from the saline-treated animals.
The authors state that these results agree with clinical studies in humans described in the literature. The human studies demonstrate a long-lasting therapeutic effect of psilocybin following a single-administration, compared to the relatively transient antidepressant effect of ketamine.
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How Is Ketamine Different From Psilocybin
Psilocybin, or magic mushrooms as theyâre more colloquially known, have been at the center of discussions on psychedelics since the first conversations happened. Psilocybin, the active ingredient in magic mushrooms, was one of the first classical psychedelics to be properly introduced to the West. This came after amateur mycologist R. Gordon Wassonâs visit to the curandera Maria Sabina in Mexico several decades ago.
The LIFE magazine article sparked conversation in many circles, with some individuals going off for their own experiences, and some starting to look into the Westâs own historical and traditional use of psychedelic compounds.
In the clinical context, psilocybin has also made a name for itself through its efficacy in treating a host of conditions and ailments, as has been documented since psychedelic therapy studies first began. Psilocybin was used in the classic âGood Fridayâ experiment, the landmark smoking cessation study, and the mystical experience & psychedelics study. Psilocybin has a strong recreational, mystical, and clinical history behind it âand for good reason.
In this resource, weâre going to explore the subtle yet profound distinctions between ketamine and psilocybin, including the neurobiology of the compound and the phenomenological differences of the experiences.
Pcp Vs Ketamine: The History
Experts initially created PCP to act as a general anesthetic and analgesic for humans. Researchers quickly realized that the adverse effects of the drug would be too severe for human use.
The unfortunate side effects associated with PCP ultimately led to the synthesis of ketamine. Researchers continued experimenting with compounds similar to that of PCP and, in the 1960s, synthesized ketamine.
Today, ketamine is a common medication used to induce and maintain anesthesia in medical settings worldwide. Continuous investigations suggest that ketamine is an effective treatment for depression, especially TRD .
Both ketamine and PCP are known as dissociative anesthetics, and they do have some additional similarities. Both are capable of causing the following.
- Unconsciousness
- Analgesia
- An altered state of consciousness
Unfortunately, both drugs have addictive potential, and PCP is especially notorious for illicit use on the streets of the U.S. Both substances are also combined with other drugs when used illicitly.
Street names for ketamine:
Common street names for PCP:
- Angeldust
- Rocket fuel
- Elephant tranquilizer
But with all the similarities between the two, you may be curious about what distinguishes ketamine from PCP.
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Quantification Of Ketamine Psilocybin And Psilocin By Lc
Plasma samples were analyzed by an AB Sciex API4000 QTRAP liquid chromatography/mass spectrometric system equipped with an ESI source in positive ion mode and coupled to an Agilent 1,200 liquid chromatographic system. Ketamine hydrochloride, ketamine-d4 hydrochloride, psilocin, psilocybin, psilocin-d10 and procainamide were purchased from Sigma-Aldrich.
For ketamine quantification, 50/50 methanol/acetonitrile containing internal standard , ketamine-d4 was added to plasma sample to precipitate proteins. The supernatant was diluted with mobile phase for injection prior to analysis. Chromatographic separation was performed on a Zorbax XDB-C18 column at 25°C using gradient elution and 95% methanol/5% 10 mM ammonium formate, pH 3.0 ). The multiple reaction monitoring parameters for ketamine and IS were m/z 238.1 to 125.1 /220.2 and m/z 242.1 to 129.1, respectively. The calibration dynamic range was 0.55,000 ng/ml.
For psilocybin and psilocin quantification, 50/50 methanol/acetonitrile containing IS was added to plasma . The supernatant was diluted with 0.1% formic acid in water prior to analysis. Two serially connected Javelin Aquasil C18 columns at 25°C were used with gradient elution and 0.1% formic acid in methanol ). The MRM parameters for psilocybin, psilocin, psilocin-d10 and procainamide were m/z 285.09 to 58.2, m/z 205.2 to 58.2, m/z 215.2 to 66.2 and m/z 236.1 to 163.0, respectively. The calibration range was 0.5200 ng/ml for psilocybin and 0.1200 ng/ml for psilocin.
Ptsd Expert Changes Her Mind
Rachel Yehuda, PhD, a PTSD expert and a professor of psychiatry and neuroscience, is director of the Center for Psychedelic Psychotherapy and Trauma Research and director of the Traumatic Stress Studies Division at the Icahn School of Medicine at Mount Sinai in New York.
Yehuda told CBS News last week that she was previously skeptical about psychedelics being of any benefit to patients.
When I first heard about this, I thought to myself, How could this possibly be a good idea? she said. Psychedelics were illegal and designated by our government as being of potential harm and no medical benefit.
However, in 2016, the FDA phase 3 trials of MDMA, and Yehuda has since changed her view.
Yehuda told CBS that the results from MAPS first phase 3 trial were just astounding.
Two-thirds of the people that were treated with a course of MDMA no longer have PTSD, she noted.
The FDA now recognizes MDMA-assisted psychotherapy as a breakthrough approach, which could help lead it to full approval.
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Psychedelic Drugs: Lessons From Ketamine And Psilocybin
Psychedelics are making their way out of the counterculture and back into the mainstream, with research and media interest in the mind-altering substances growing substantially. Some have even called psychedelics psychiatrys brave new world.1
The revitalization of psychedelics has occurred alongside a shift away from the research and development of traditional psychiatric medications by leading pharmaceutical companies.1 Research on psychedelics, however, remains difficult given serious legal and regulatory barriers to studying these substances in laboratory settings. The history of psychedelics in the counterculture of the 1960s and in traditional indigenous medicine, as well as controversies surrounding their study and recreational use, have continued to make psychedelics somewhat taboo.1,2
Innovative research centers at top institutions, such as Johns Hopkins and Imperial College, as well as the Multidisciplinary Association for Psychedelic Studies , have rigorously pursued the study of potential psychedelic treatments for psychiatric disorders in recent years.3 In addition, private enterprises like Compass Pathways, which became the first psychedelics company to go public in September 2020, and nonprofit organizations like Usona Institute are investing heavily in the future of psychedelics.4
Ketamine: A Model for Other Psychedelics?
Psilocybin and Psychedelic-Assisted Psychotherapy
Psychedelics: Are We Ready for Psychiatrys Brave New World?
References
The Need For Further Clinical Trials
For botulinum toxin, the main need is for a trial replicating its antidepressant effect. Preferably this should have a better placebo control, as outlined previously, and should include some measure of the expectations of patients. In the original study, presumably patients consented to participate only if they desired botulinum toxin treatment anyway or had definite expectations about its success. Given the existence of 1 positive study, it should be possible to recruit a more representative group of depressed patients.
For psilocybin, most studies so far have been on healthy participants, and there is a need for more studies on patients. The problem here is to select patients with symptoms that might plausibly be helped by psilocybin. Currently www.clinicaltrials.gov lists 3 trials with psilocybin that are recruiting patients: 2 controlled trials in cancer patients with diagnoses of anxiety or depression, and 1 open study on patients with alcohol dependence. A recent meta-analysis of 6 studies published between 1966 and 1970 using a single dose of lysergic acid diethylamide to treat alcoholism found a significant therapeutic effect for up to 6 months after treatment, although the effect was no longer significant at 12 months. This provides a good rationale for testing psilocybin in individuals with alcoholism.
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Move Over Psilocybin And Ketamine: A New Compound Derived From A Naturally
Structural similarities between ibogaine and tabernanthalog .
David E. Olson
The compound is tabernanthalog , synthesized from the hallucinogen ibogaine by UC Davis chemical neuroscientist David E. Olson. Ibogaine is an extract of the naturally-growing African plant, iboga. A drug for medicinal use in humans is in development clinical trials are anticipated.
An article in the May 25, 2021, issue of Molecular Psychiatry depicts the work by Olson, UC Santa Cruz molecular biologist Yi Zuo, and other collaborators, and also spells out the rationale behind modeling TBG on ibogaines key structural elements. While ibogaine has demonstrated anti-anxiety and anti-depression effects and is used in some drug and alcohol rehab clinics around the world, it will probably never be licensed for use in the United States. This is because, at therapeutic doses, it can cause dangerous heart arrhythmias and fatal heart attacks. At high doses, it is neurotoxic. Enter Olsons TBG. His hope for the new synthetic compound is that, in humans, it will prove to have all of ibogaines benefits and none of its toxicity or hallucinogenic potential. While the compound is still untested in humans, Zuo and Olsons Molecular Psychiatry paper about it shows that sort of promise.
UC Davis chemical neuroscientist David E. Olson.
Johanna van de Woestijne Coriolis Films LLC. Used ourteesy of david E. Olson.
Anxiety, Depression, Addiction, and the Psychedelic Connection
How The Va Sees It
Despite what some see as growing evidence that psychedelics can positively treat people with PTSD and other psychological conditions, VA officials havent given them much attention.
Gary J. Kunich, a spokesman for the VA, told Healthline that the use of psychedelic treatments such as MDMA-assisted psychotherapy and psilocybin-assisted psychotherapy are not part of the standard of care for treatment of mental health conditions at the Veterans Health Administration and is not an approved clinical treatment.
The use of psychedelics as part of a research protocol might be permissible, he added, but this would require Institutional Review Board and Research and Development Committee approval at the local facility.
He continued, The Veterans Health Administrations Office of Mental Health and Suicide Prevention is closely monitoring the developing scientific literature in this area.
When considering evolving scientific literature around innovative mental health treatments, Kunich said, the VA looks for outcomes from rigorous and well-designed clinical trials as well as things such as Food and Drug Administration approval or recommendations in clinical practice guidelines.
When implementing a new, evidence-based mental health treatment, VHA puts safety of veterans first and foremost, he said.
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Rapid And Transient Psychoactive Effects
Arguably the most salient feature of these pharmacotherapies is their rapid and transient induction of psychoactive symptoms. With regard to ketamine, a major goal of current research is to produce a widely distributable antidepressant agent that lacks psychoactive side effects. Thus, ketamine research has largely sought to understand the mechanisms underlying its antidepressant efficacy rather than study its psychoactive profile. Furthermore, ketamines antidepressant effects occur at subanesthetic doses that appear to be relatively well-tolerated and create mild, transient psychoactive effects. For instance, a recent study assessing side effects associated with a 0.5-mg/kg ketamine infusion in 163 participants with TRD across 4 clinical trials reported that only 50% experienced SP-like psychoactive effects , and 80% reported feeling strange, weird, or bizarre . This is not to say that ketamines psychoactive effects are not well-documented . In fact, the earliest descriptions of subanesthetic-dose ketamine administration in HVs reported effects such as altered perception of time and space, loss of a sense of self, and visual hallucinations . Since then, multiple studies have confirmed that psychoactive effects occur at or below this standard antidepressant dose .
Final Thoughts On Ketamine And Psilocybin For Ocd
Current treatments for OCD have left many patients dissatisfied and seeking alternatives. Psychedelics could potentially offer some hope.
Although more research is necessary, initial studies on psilocybin and ketamine have produced promising results. However, most psychedelic drugs remain illegal. There are a few exceptions, and ketamine clinics, in particular, are becoming more widespread.
Before trying psilocybin or ketamine for OCD, check the laws in your area to find out what options are available. And always seek guidance from a qualified professional before using psychedelics to treat any medical condition.
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Ketamine Therapy Vs Antidepressants
Traditional antidepressant medications act on the serotonin system and slowly build up their effects over weeks. Researchers still do not know why they can help to soothe the symptoms of depression in some patients. Ketamine is more effective for patients who receive no benefit from these serotonergic antidepressants. Arguably the most important difference is the time course of the effects. The rapid onset of ketamines antidepressant effect makes it a potentially life-saving option for those who are suicidal. However, in both cases, long-term treatment is typically required, as the symptoms often return without repeated doses.
Which Substance Is Right For You: Ketamine Vs Esketamine
The success rate of ketamine treatments is nearly double those of traditional refractory depression treatments. This means patients are reporting greater and more rapid relief from depressive symptoms. So, ketamine vs. esketamine, which one is right for you? Both treatments are now FDA-approved but have some crucial differences that people seeking treatment have to consider. A few things to keep in mind include:
- There is currently only one prescription form of esketamine on the market: medicated nasal spray.
- Medical professionals primarily prescribe esketamine as a supplement to traditional SSRI treatments for patients seeking greater relief from refractory depression.
- Ketamine infusions are not recommended for patients already using neurotropic medications like SSRIs.
At this time, ketamine treatments cannot be accessed as the first resource for those suffering from mental illness. Its important to remember that to be able to receive ketamine or esketamine treatments, patients need to be categorized as treatment-resistant. This is an individual discussion that should happen between patients and their doctors.
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A Psychedelics Renaissance Could Be Coming
The origins of the governments apprehensive approach to psychedelic-based mental health treatment stretch back decades. In the 1950s and 60s, the federal government invested heavily into researching drugs like LSD and psilocybin. But after the Controlled Substances Act of 1972, federal funding into the possible benefits of psychedelics quickly evaporated.
That stance may be changing. In September, researchers at Johns Hopkins University received funding from the National Institute on Drug Abuse to investigate whether psilocybin could help people quit cigarettes. it appears to be the first federally funded direct study in decades of the mental health benefits ofa traditional psychedelic drug. At the same time, the DEA, which keeps tight caps on how much psychedelics are available to US researchers, recently proposed increasing the nationwide availability of psilocybin from 30 grams to 1,500 grams.
Theres a lot of enthusiasm. And that makes sense because there are many people who have suffered for many years for whom this has brought relief, Sharmin Ghaznavi, an associate director of Massachusetts General Hospitals Center for the Neuroscience of Psychedelics, told Recode. But we have a lot that we need to learn, and we owe that to our patients.