The current zeitgeist that has been society’s reawakening to the healing powers of psychedelic medicine has brought to the forefront two very distinct and powerful classes of compounds in the psychedelic medicine toolkit: traditional psychedelic drugs (e.g. mushrooms, LSD, DMT) and dissociative anesthetic drugs (with ketamine being the most notable). Unlike classic psychedelic drugs that primarily act on serotonin (5HT2a) receptors, sub-anesthetic doses of dissociative compounds, like ketamine, have a completely different mechanism of action and, as such, produce a very different type of psychedelic experience, both mechanistically and experientially. Furthermore, recent research into dissociative drugs like ketamine suggests that they have promising implications in the areas of pain management and mental health treatment. This guide will embark on a scientific exploration into this novel class of dissociative compounds, investigating how they uniquely differ from traditional psychedelics and the incredibly promising clinical applications they hold with respect to managing post-operative pain.

 

 

 

What Are Dissociative Drugs?

 

Dissociative drugs, also known as dissociative anesthetics, are a unique class of hallucinogenic compounds that manipulate signaling in the brain to produce a dissociated or “detached” feeling from oneself and the environment. The most common drugs included in this class of compounds are PCP (also known as “angel dust”), ketamine, and DXM (dextromethorphan, the active compound in OTC cough syrup). As the name implies, these drugs are effective at inducing anesthesia when given in the correct doses. These compounds exert their mechanism of action by blocking a class of receptors in the brain known as NMDA (N-methyl D-aspartate) receptors1—a completely different mode of action compared to traditional psychedelic compounds that act on 5HT2a (serotonin) receptors. Recent studies investigating ketamine have revealed to researchers and clinicians radical new possibilities for the clinical application of these compounds in pain management and neuropsychiatry.

 

dissociative drugs ketamine therapy

 

What Is Ketamine?

 

Introduced into clinical practice in the 1960s, ketamine is the most noteworthy of the dissociative anesthetic drugs and “remains invaluable to the fields of anesthesiology and critical care medicine, in large part due to its ability to maintain cardiorespiratory stability while providing effective sedation and analgesia.”2 The ability to provide effective pain relief and sedation without compromising cardiorespiratory stability not only makes ketamine a powerfully efficacious anesthetic, but also contributes to its novel ability in managing acute, even post-operative pain. Further exploration into the neuropharmacological mechanisms of dissociative drugs provides further insight into their unique mode of action and therapeutic potential.

 

 

Ketamine vs. Traditional Psychedelics: The Two Major Ways to Pharmacologically Expand Consciousness Explained

 

The way the human brain and its vastly intricate processes create the reality we experience is one of the most complex and ambitious explorations upon which humankind has ever embarked. To maintain balanced functioning in the brain, an intricate system of excitatory and inhibitory signals from the neurotransmitters glutamate and GABA, respectively, is established by the brain.3 In understanding how to modulate these excitatory and inhibitory signaling pathways in the brain, we have discovered that there are two major ways that the range of human consciousness can be pharmacologically expanded. The first way is by using traditional psychedelics to directly stimulate the wide array of pyramidal cells, largely responsible for what we might call “thinking” in the brain, through serotonin-mediated action. This is the mechanisms behind drugs like LSD, which act as powerful stimulants due to the excitatory effects they exert on these neurons in the brain. “Essentially, if our thoughts and the electrochemical signals responsible for them in our brains can be thought of as water flowing through an aperture, then serotonergic drugs like LSD increase the amount of water (information) going through the same sized hole. The inhibitory component maintaining scope of consciousness, known as the GABAergic Interneuron net, is mostly left intact to fight for control over the increased flow of information,” says Jeffrey Becker, MD, Chief Scientific Officer for Bexson Biomedical. This increase of information can result in an increase in psychic pressure, manifesting as intense anxiety during the “come up” exhibited by traditional psychedelics. In this model, one might imagine the normally “laminar flow” of water through the pipe can become “turbulence” as the pressure increases, sometimes resulting in tremendous anxiety. “Ketamine, on the other hand, works in opposite fashion,” says Becker.  “Instead of forcing more fluid or information through the same sized aperture, ketamine allows greater flow by inhibiting the inhibitory system directly.”  As Ketamine decreases inhibitory tone there is an increase in stimulation of pyramidal cells in the brain. The way this is accomplished mechanistically is certainly unique and worth briefly exploring, as well.

 

ketamine versus traditional psychedelic drugs

 

The Role of “Chandelier Cells” and Ketamine’s Ability to Dissolve “Fear-Based Thinking”

 

The previous paragraph briefly discussed how ketamine can indirectly stimulate pyramidal cells by increasing the “aperture” through which information flows by inhibiting primary inhibitory neurons. The neurological process by which this expansion in consciousness is accomplished is particularly novel and involves interrupting the inhibitory action of axo-axonic cells, also known as “chandelier cells,” which serve to regulate activity in pyramidal neurons through a “stranglehold” mechanism on the initial axon segment.4 Ketamine and other dissociative drugs release the stranglehold that chandelier cells can exert on pyramidal neurons, increasing the flow of information between these cells as the GABA-mediated inhibitory mechanism is released. “We need strong control over pyramidal cell excitatory neurotransmission, but it can become over powered, constricting thought processes into smaller and smaller stereotypies that may be at the heart of depression.   Because chandelier cells act as the final arbiter of whether a pyramidal cell will fire or not, the ability of ketamine to preferentially block NMDA receptors on these specific cells at the sub-anesthetic doses given for depression is quite unique and interesting,” says Becker. This architectural framework which ketamine acts upon is also may be a core component of what makes up our default mode network and defensive structures, basically the foundational units constructing the framework of the ego.5 Preferentially blocking NMDA receptors on chandelier cells may actually lead to a dissolution of this “fear based thinking,” allowing new pathways to form that allow fundamental change over time. As we will soon see, this is crucial in developing successful ketamine-based therapies for pain management.

 

NMDA ketamine dissociative drug mechanism

 

Ketamine Can Prevent the Evolution of Acute Pain to Chronic Pain, Unlike Opioids

 

If a neuron is damaged during surgery, the NDMA receptors in the damaged tissue have the ability to “remember” the events associated with that injury and continue to send pain signals to the brain, sometimes long after the traumatic event has passed. The ability of these neurons to “learn” to keep sending pain signals to the brain, even when there is no longer any insult or injury taking place, is essentially how acute pain evolves into chronic pain. Opioid drugs, such as morphine, Vicodin, and Oxycodone, are often used as first-line treatment for high grade acute pain management. Becker states that, “The issue with these drugs, however, is that while they are effective at diminishing pain in the short term, they can actively promote the evolution of acute pain into chronic pain in some patients.  While this doesn’t always happen, it happens enough to be a major medical management issue and the source of many new addictions and opioid dependencies each year.” This has made opioid use increasingly controversial, especially amidst the current nationwide epidemic.6 The addictive and dangerous nature of opioid drugs is grimly illustrated amidst the throes of the current opioid epidemic, and strongly highlights the need for better management of acute and chronic pain. The current research strongly suggests that the use of ketamine in the treatment of pain in the acute phase can actually prevent that patient’s graduation from acute to chronic pain syndromes in many cases.7 While the exact mechanisms behind this novel pathway is still being understood, the ineffectiveness and risks associated with current pain management strategies highlight the need for bold, new therapeutics. One biotech firm, Bexson Biomedical, is doing just that in developing novel low-dose ketamine-based therapeutics for post-operative pain that patients may be able to use at home.

 

ketamine therapy dissociative psychedelic drug pain management

 

Bexson Biomedical Boldly Develops At-Home Ketamine Treatment for Post-Operative Pain

Bexson biomedical Logo

 

There are over 50 peer-reviewed studies demonstrating ketamine’s ability to effectively manage pain, and many others establishing its safety and dosing guidelines in clinical practice. Furthermore, ketamine-based therapeutics have a unique advantage at maneuvering through otherwise long, expensive, and rigorous regulatory barriers and getting to market faster than new, untested chemical compounds. The haphazard use and abuse of opioids in the treatment of pain, and its ultimate culmination into the modern-day opioid crisis, highlights the need for more effective, non-opioid therapies for pain management, now more than ever before. One biotech company, Bexson Biomedical, is harnessing the promising research demonstrating ketamine’s effectiveness as a painkiller in the hope that it will serve as an adjunct and/or alternative to opioids in the treatment of postoperative pain. Currently, the post-operative pain market is valued at over $12 billion dollars, and fosters the highest risk of developing opioid addiction. Dr. Becker, Chief Science Officer at Bexson Biomedical, hopes that their “novel treatment platform, which entails a new subcutaneous formulation of ketamine for delivery by a wearable patch pump, can significantly benefit patients by providing a real alternative to opioids in pain management.”  They also hope this large market will eventually monetize many other pain and mental health ketamine-based therapy programs down the road. The subcutaneous method designed by Bexson is similar to the process by which diabetics take insulin, and offers more predictable and controlled dosing than current nasal, oral and sublingual approved and compound formulations of ketamine. Bexson hopes this will make at-home use possible, currently a large value proposition of the therapy they are developing.

 

ketamine therapy chronic pain post operative pain

 

A Look Ahead to the Future of Ketamine Therapeutics

 

Interest in the ability of ketamine to provide effective acute pain relief has expanded all the way to the military, where ketamine is beginning to replace morphine on the battlefield.8 Not explored in this scientific review is ketamine’s rapid anti-depressant effects and positive impacts on severe neuropsychiatric disorders, such as PTSD. This is worth mentioning, since there is distinct overlap between the processes that govern pain and the development of severe psychiatric illnesses, such as major depressive disorder (MDD) and PTSD. For instance, a 2014 study in Military Medicine found that burned U.S. service members who received perioperative ketamine exhibited a significantly lower prevalence of PTSD than those who did not.9 Based on the research presented in this piece, it seems that the key to unlocking a deeper understanding of these chronic pain pathways, and the subsequent development of severe mental illness and their relationship to memory formation, is likely to lie within the functioning of NMDA receptors. As ketamine-based therapeutics and other NMDA receptor antagonists are developed, their promising applications in the treatment of severe pain and mental illness is certainly something to look out for.

 

 

Works Cited

 

  1. Abuse, N. I. on D. What Are the Effects of Common Dissociative Drugs on the Brain and Body? National Institute on Drug Abuse https://www.drugabuse.gov/publications/research-reports/hallucinogens-dissociative-drugs/what-are-effects-common-dissociative-drugs-brain-body (–).
  2. Li, L. & Vlisides, P. E. Ketamine: 50 Years of Modulating the Mind. Front. Hum. Neurosci. 10, (2016).
  3. How excitatory/inhibitory balance is maintained in the brain. ScienceDaily https://www.sciencedaily.com/releases/2015/12/151217130450.htm.
  4. Wang, Y., Zhang, P. & Wyskiel, D. R. Chandelier Cells in Functional and Dysfunctional Neural Circuits. Front. Neural Circuits 10, (2016).
  5. Gerhard, D. M. et al. GABA interneurons are the cellular trigger for ketamine’s rapid antidepressant actions. J. Clin. Invest. 130, 1336–1349.
  6. Rosenblum, A., Marsch, L. A., Joseph, H. & Portenoy, R. K. Opioids and the Treatment of Chronic Pain: Controversies, Current Status, and Future Directions. Exp. Clin. Psychopharmacol. 16, 405–416 (2008).
  7. Bell, R. F. & Kalso, E. A. Ketamine for pain management. Pain Rep. 3, (2018).
  8. Wedmore, I. S. & Butler, F. K. Battlefield Analgesia in Tactical Combat Casualty Care. Wilderness Environ. Med. 28, S109–S116 (2017).
  9. McGhee, L. L. et al. The Intraoperative Administration of Ketamine to Burned U.S. Service Members Does Not Increase the Incidence of Post-Traumatic Stress Disorder. Mil. Med. 179, 41–46 (2014).