Alcohol addiction is deadly, we know this.  It does not just punish the addict, it punishes their family and society.  For those who find sobriety alone or with help from a detox program, staying sober is a lifelong challenge. Relapse occurs when one resumes drinking and is a detrimental problem that deserves more attention. Understanding some basics of alcohol addiction and how to help prevent relapse can be a bit complicated.  The next section on “choice” will summarize an article on the neurobiology of addiction by Xavier Noel [i].  It simplifies some popular thoughts about how and why addiction works in the brain.  Then, we can see how to target effective treatment with ketamine to help prevent relapse.

Is alcoholism a choice?

The impulse/habit system:

How does the compulsion to drink develop?  A part of our brain, called the amygdala-striatum neural complex, motivates us to achieve rewards. This area is driven by dopamine, a naturally produced neurotransmitter in our bodies that has many effects, including feelings of pleasure, or reward. Alcohol, and other addictive drugs, increase overall dopamine levels in our brain. Therefore, a link forms between automatic, repetitive behaviors, such as pouring a drink, and increased dopamine. These actions are saved in our brain as rewarding. And the brain loves rewards.

Increasing dopamine activity also accelerates the change between the first steps of choosing to have a drink and later craving a drink.  New pathways in the brain form with repetitive behavior. Cues and memories in the environment to drink are noticed more quickly, like hearing glasses clink, or walking in the front door after work. These cues drive the compulsion to drink. The brain’s automatic response is to seek this reward, but can’t we control this behavior?

The control/decision making system:

The decision-making part of our brain is found in the prefrontal cortex. It is also known as the “reflective system”, or executive function system, where we can control impulses. This means we can trade short term rewards, like a drink, for possibly greater long-term goals, such as avoiding a DUI charge.  One explanation is that there is a balance between a “cool” and “hot” system that works out how we respond to triggers or cravings.  The “cool” refers to basic working memory and inhibition of impulses.  The “hot” involves numerous emotional responses that are possible. Damage to either of these systems may impair the ability to say “no” to situations, or drugs like alcohol, that can harm us. Either the impulse side or the emotional side wins when we lose a health balance.

When/How impulse overpowers control:

Poor decision making in alcoholics may also be explained by yet another system called the insular cortex. It responds to imbalance in our bodies from things like sleep deprivation, anxiety and stress. These stressors may hijack our impulse/habit system and increase cravings while promoting decisions to seek out alcohol. Repeated cycles of increased cravings can also essentially rewire brain circuits, reinforcing continued destructive behavior.

Addiction as a “Pathology of Choice”

Other studies support that “faulty brain connections related to decision-making can lead to addictive behaviors and relapse.” [ii]  There is a definite shift from blaming addiction on cravings to finding abnormalities in decision making areas of the brain. Thus, the brain is not able to make the right decisions to ignore the craving.

NMDA receptors are at fault too?

Family history of alcoholism is a risk factor for developing alcohol addiction. A study by Petrakis et al showed one answer may lie in the NMDA (N-Methyl-D-Aspartate) receptor, which is vital to the glutamate system in the brain.  Alcohol alters this receptor’s function, but if the receptor is not normal, that person may be more susceptible to alcohol abuse.[iii]

How can ketamine help?

Ketamine can play a key role in preventing relapse in those who have either completed a detoxification program or managed to stop themselves.

Over-write memories that drive addiction

It is possible a rewarding memory of taking a drink, for example, can be triggered repeatedly by seeing a glass of beer, going to a restaurant, or maybe returning home from work.  These triggers lead to the urge to drink.  Ravi Das from University College London explains why people often quit but return to drinking. “The main problem is the really high relapse rate after treatment,” said Das. “People can successfully quit using over the short term while they’re being monitored in the hospital … but when they return home they’re exposed to those environmental triggers again.”[iv] The good news, is that each time the brain accesses that rewarding memory, the neural connections that code the memory are destabilized.  It is at this moment that ketamine, which blocks the brain receptor required for the formation of memories (NDMA), can help weaken or even erase the memory. In other words, ketamine will help break the power of that trigger.

The psychedelic experience

The benefits from the psychedelic experience while receiving a ketamine treatment may hold benefits.  Dr. Tobias Stevens, in his presentation on ketamine as a treatment for alcohol use disorder, postulates the hallucinations and altered mental state from ketamine may help change lifestyle choices.  He suggests the experience may alter perceptions and break routine behaviors.[v]  Therefore, a combination of psychotherapy with ketamine, (ketamine psychotherapy or KPT) may prove helpful for some folks. KPT allows the psychedelic effects from ketamine to enhance a psychotherapy session and is shown to be effective helping those with addiction, including heroin and alcohol by Dr. Evgeny Krupitsky.[vi]

Ketamine allows learning

Psychotherapy is a vital mainstay of alcoholism recovery treatment, but why are relapse rates so high?  Maybe, postulates McAndrew et al, the alcoholic brain simply can’t learn the new skills.[vii]  There is a proven decrease in neural growth factors in the brain, BDNF, with alcohol addiction.  With fewer connections between nerves, and less ability to make new connections, the brain cannot learn new skills.  With ketamine and synaptogenesis, which happens to peak 24 hrs after a treatment, well timed psychotherapy can have a greater impact.

What does ketamine for relapse prevention look like?

Ketamine is not a solitary treatment for alcohol relapse prevention.  To say so would oversimplify the disease.  Current studies include interesting combinations with ketamine.

KARE – Ketamine for reduction of Alcoholic Relapse

KARE is a multi-site project running in England that is a clinical trial seeking to explore psychotherapy combined with low dose ketamine as a possible treatment for alcoholism.[viii]  Participants who completed alcohol detoxification receive IV ketamine 3 times interspersed with 7 therapy sessions.  The psychotherapy model, developed by Dr.s Rob Hill and Jen Harris included 3 key areas:

• Risk reduction strategies: Identify high risk situations, cope with cravings, or restructure unhelpful thinking
• Wellness promotion: planning weeks, problem solving, relaxation, and mindfulness
• Education: what is addiction, biological effects of alcohol both acute and chronic, alcohol and sleep, and how alcohol interacts with the brain

Combining ketamine with other medications?

Combining ketamine with other prescription drugs is debatable as there is conflicting evidence.  For example, naltrexone is frequently used with alcohol dependence. It binds opioid receptors and is supposed to take away cravings for opioids and alcohol which can take away reward effects.[ix] In reality, it does reduce overall total alcohol consumption, but not necessarily abstinence. Nimodipine is a calcium channel blocker that is also studied for its’ ability to decrease alcohol-type effects from ketamine treatment.[x]  Additionally, some providers prescribe Baclofen to help suppress cravings.

But, isn’t ketamine addicting?

Are we just trading alcohol addiction for ketamine addiction? This is not true according to several studies.  A study by Krystal, et al in 1998 clearly showed ketamine did not increase cravings on recovering alcohol dependent patients.[xi]  Recently detoxified alcoholics given ketamine did not go on to abuse the drug. Keep in mind, ketamine for alcohol abuse is given by trained providers in a medical setting at doses far less than what one may find on the street. The body does not become physically dependent on ketamine, meaning there are no physical withdrawal symptoms when one stops. However, there is always a possibility of mental dependence on a treatment that is helping.  But, lets put this in perspective.  Many people are dependent, or “addicted”, to a variety of activities, like exercise, weight loss, meditation, because these things reward them, (ie their brain).

Conclusion

Reducing alcohol dependence and relapse has far reaching benefits from decreased personal injury from liver disease, to depression and anxiety, to family relationships, to work stability, or to alcohol related death from accidents.  Once detoxification is complete, ketamine can help people maintain sobriety when used in part with a comprehensive program.  Alcoholics Anonymous (AA), psychotherapy, adjuvant medications and physician oversight can all help cut cravings and save lives.

About The Author

Dr. Van Praag is the medical director of Spring Center of Hope, a ketamine center located in Houston, TX. She is a practicing anesthesiologist with 13+ years of experience caring for patients of all ages.

Visit: https://springcenterofhope.com/about-dr-van-praag/ for additional information.

[i] Noël X,Brevers D, et al. A neurocognitive approach to understanding the neurobiology of addiction Curr Opin Neurobiol . 2013 August ; 23(4): 632–638. doi:10.1016/j.conb.2013.01.018. link

[ii] Bergland C, The Neuroscience of Making a Decision: Various brain regions work together during the decision-making process. Psychology Today online, 05/06/2015. link

[iii] Petrakis I, Limoncelli D, et al Altered NMDA glutamate receptor antagonist response in individuals with a family vulnerability to alcoholism. The American Journal of Psychiatry Oct-2004 161 1776–1782 0002-953X link

[iv] Devlin H, Radical ketamine therapy could treat alcohol addiction. Theguardian.com, 01/24/2017. link

[v] Stevens T. Ketamine as a Treatment For Alcohol Use Disorder. Breaking Convention 2017, YouTube 09/13/2017. link

[vi] Krupitsky E, Ketamine psychotherapy for heroin addiction: immediate effects and two-year follow-up. Journal of S/ubstance Abuse Treatment 23 (2002) 273–283.link

[vii] McAndrew A, Lawn W, et al. A proof-of-concept investigation into ketamine as a pharmacological treatment for alcohol dependence: study protocol for a randomised controlled trial. Trials (2017) 18:159 DOI 10.1186/s13063-017-1895-6. link

[viii] KARE: Ketamine for reduction of Alcoholic Relapse. University of Exeter, England. link

[ix] Krystal J, Madonick S, et al. Potentiation of Low Dose Ketamine Effects by Naltrexone: Potential Implications for the Pharmacotherapy of Alcoholism. Neuropsychopharmacology (2006) 31, 1793–1800 link

[x] Krupitsky E, Burokov A, et al. Attenuation of Ketamine Effects by Nimodipine Pretreatment in Recovering Ethanol Dependent Men: Psychopharmacologic Implications of the Interaction of NMDA and L-Type Calcium Channel Antagonists. [Neuropsychopharmacology 25:936-947, 2001  link

[xi] Krystal J, Petrakis I et al.  Dose Related Ethanol-like Effects of the NMDA Antagonist, Ketamine, in Recently Detoxified Alcoholics. Arch Gen Psychiatry Vol 55, April 1998, 354-360  link

Disclaimer: This article represents an informed opinion of the author and/or the opinion of others. It does not constitute medical advice and should not be relied upon to make decisions about medical care. Please consult your physician for questions regarding your specific conditions and possible treatments

Photo Credits:
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Spravato is a new antidepressant medication manufactured by Johnson & Johnson’s pharmaceutical company, Janssen, for management of Treatment Resistant Depression. According to the FDA, “Patients with major depressive disorder who, despite trying at least two antidepressant treatments given at adequate doses for an adequate duration in the current episode, have not responded to treatment are considered to have treatment-resistant depression.”

How is Spravato administered?

Spravato comes as an intranasal spray.  The FDA set strict guidelines for the administration of Spravato which has a Boxed Warning.  The Boxed Warning states that “the patients are at risk for sedation and difficulty with attention, judgement and thinking (dissociation), abuse and misuse, and suicidal thoughts and behaviors after administration of the drug.”  Therefore, the patient must self-administer Spravato at a doctor’s office and the patient cannot take the medication home.  After self-administration, the patient must be watched and monitored for 2 hours after administration.  In addition, the patient must arrange for a driver since they will not be allowed to operate any heavy machinery after the treatment.  The frequency of the administration is as follows: the first month- the medication must be taken twice a week; the second month- the medication must be taken once a week; and thereafter- once every other week.  Click here for Janssen’s prescribing package insert

Does Spravato work?

The FDA reported 3 short-term (four week) clinical trials and one longer-term maintenance-of-effect trial.  “In the three short-term studies, patients were randomized to receive Spravato or a placebo nasal spray. In light of the serious nature of treatment-resistant depression and the need for patients to receive some form of treatment, all patients in these studies started a new oral antidepressant at the time of randomization and the new antidepressant was continued throughout the trials. The primary efficacy measure was the change from baseline on a scale used to assess the severity of depressive symptoms. In one of the short-term studies, Spravato nasal spray demonstrated statistically significant effect compared to placebo on the severity of depression, and some effect was seen within two days. The two other short-term trails did not meet the pre-specified statistical tests for demonstrating effectiveness.  In the longer-term maintenance-of-effect trial, patient in stable remission or with stable response who continued treatment with Spravato plus an oral antidepressant experienced a statistically significantly longer time to relapse of depressive symptoms than patients on placebo nasal spray plus an oral antidepressant.” [1]

What is the cost of Spravato?

The wholesale acquisition cost, or list price, will be between $590 and $885 per session.  This means the first month of treatment will range from $4720 to $6785.  This does not include the costs of a physician visit and monitoring.  The medication will most likely be added to most major health insurance plan’s formulary.  There is no information yet regarding in what specialty tier Spravato will be placed and what the out of pocket expenses will be for the patients.  In addition, we are uncertain what the pre-authorization approval process from the insurance companies will entail.

Where can I get Spravato? 

The FDA says, “due to safety concerns, the drug will only be available through a restricted distribution system and must be administered by a certified medical office where the health care provider can monitor the patient.”  Only clinics that are certified in REMS (Risk Evaluation and Mitigation Strategy) can treat and monitor patients enrolled in REMS.  In addition, only specialty pharmacies that are certified in REMS will be allowed to dispense Spravato directly to the medical offices.  REMS is a program required by the FDA to manage known or potential serious risks associated with a drug product.

Will Optimum Ketamine Center become a REMS center and offer Spravato?

We are currently obtaining more information regarding this process.  We already know it is a multistep process that will require some time. In addition, we have yet to receive any information from the Center for Medicare and Medicaid Services (CMS), who is responsible for coding and setting the fee schedules for Medicare.  All private insurers follow the guidelines set by CMS.  Therefore, there are still quite a few unanswered questions regarding the logistics of treating with Spravato.   We hope to have more answers for you in the coming months.

What is Esketamine, the main compound in Spravato?

Esketamine is half of the active ingredient of the medication Ketamine.  Ketamine is a medication containing equal parts R-ketamine and S-ketamine (Esketamine).  R-ketamine and S-ketamine are mirror images of each other. The pharmaceutical company Janssen isolated the S-ketamine molecule to create a medication they can patent and sell.  At Optimum Ketamine Center, we use Ketamine (containing both active components) to treat mood disorders. This includes both the R-ketamine and the S-ketamine.

Pixabay/JamesDeMers

What is Ketamine?

Ketamine is a medication that is FDA approved for anesthesia.  It is being used off-label for the management of treatment resistant depression.  It is a NMDA (N-methyl-D-Aspartate) receptor antagonist.  NMDA receptors are found on nerve cells where they transmit and receive signals. They are critical for the development of the central nervous system, generation of rhythms for breathing and movement, and the processes underlying learning, memory, and neuroplasticity[2] (your brain’s ability to adapt to new situations or injury).

Are Esketamine (S-ketamine) and R-ketamine the same?

 No. They have different properties.[3] [4]

The studies we have so far regarding R vs S Ketamine have all been from mice and rat models. Nevertheless, it appears that the R- and not the S-Ketamine is the more potent anti-depressant and has longer lasting antidepressant effects.  Furthermore, the S-Ketamine exerts a greater dissociative effect than R-ketamine.

Is Ketamine and Esketamine absorption the same whether it is given intranasal or intravenously?  

No. Intranasal administration has been shown to be less predictable with greater variability in onset times and peak blood levels[5] than with intravenous administration.  The amount available after intranasal administration varies anywhere from 8% to 45%[6][7] whereas the amount available after intravenous administration is nearly 100%.

Disclaimer:  Dr. June Lee is the Medical Director of Optimum Ketamine Center.  She is a board certified with the American Board of Anesthesiologists and a member of the American Society of Ketamine Physicians.   Optimum Ketamine Center website does not provide medical advice, diagnosis, or treatment.  Dr. Lee’s blog is not intended for medical diagnosis or treatment.  The information provided on this website is intended for general consumer understanding only. The information provided is not intended to be a substitute for professional medical advice.  For medical advice or assistance, readers should consult their healthcare professional.

Optimum Ketamine Center
665 W. North Ave, #101
Lombard, IL 60148
(708) 244-8663
www.optketamine.com

[1] FDA approves new nasal spray medication for treatment-resistant depression; available only at a cerfified doctor’s office or clinic. March 5 2019 https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm632761.htm

[2] Activation Mechanisms of the NMDA Receptor. Blanke and VanDongen, Biology of the NMDA receptor. CRC Press/Taylor & Francis; 2009.  https://www.ncbi.nlm.nih.gov/books/NBK5274/

[3] R-Ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Yang, Shirayamata et al. Transl Psychiatry (2015) 5, e632;doi:10, 1038, published on-line 1 September 2015 https://www.nature.com/articles/tp2015136.pdf

[4] R (-) ketamine shows greater potency and longer lasting antidepressant effects than S (+)-ketamine. Zhang, Li, Hashimoto.  Pharmacol Biochem Behav. 2014 Jan;116:137-41. E published 3 December 2013https://www.sciencedirect.com/science/article/pii/S0091305713003328?via=ihub

[5] S-ketamine and s-norketamine plasma concentrations after nasal and I.V. administration in anesthetized children.  Weber et al.  Pediatric Anesthesia, December 2004 Volume 14, Issue 12 p983-988

[6] Plasma concentration profiles of ketamine and norketaminafter administration of various ketamine preparations to healthy Japanese volunteers.  Yanagihara et al Biohpar Drug Dispos, 2003 Jan: 24(1):37-43

[7] Sub-dissociative-dose intranasal ketamine for moderate to severe pain in adult emergency department patients.  Yeaman et al. Emerg Med Australas. 2014 June;26(3):237-42

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