Health Editor’s Note: Rob Cichy has a Master’s in Social Work and is an addiction specialist in the St. Louis area. He believes that addiction should be classified as a disease and treated as such with no further labels that would prohibit a successfully treated addict from having permanent restrictions. Why not decriminalize being an addict since addiction may very well be physically/medically based? The proof of this would be that not all of us become addicted to drugs, alcohol, etc. If addiction is viewed as a disease, which will be treated without social stigma attached, we could move towards a society which truly tries to assist those who are addicted and stop putting them in jails, prisons, and marginalizing their care. As you can see from Rob’s research, addiction is much more than just “wanting” to use drugs/alcohol….Carol
I have been involved in the fight against the opioid epidemic since 2011 and have watched as our nation struggled to deal with this emerging plague. Ignorance of the dangers has evolved to the point where most first responders are familiar with Narcan, Vivitrol, and Suboxone as components of medically assisted treatment (MAT) and states are feeling their way through formulating a logical, effective response to this growing tragedy.
As a trained substance abuse counselor and self-taught neuroscientist, I have familiarized myself with this battle from both a micro and macro perspective. Paradoxically, while our nation struggles with growing costs of treating the opioid epidemic, legislators are also being asked to give permission to the de-criminalization of medical marijuana and in some states to approve the legalization of recreational marijuana. Anticipating and understanding the ramifications of both of these drug-related legislative issues can be extremely confusing as the issues involve neuroscience, biological addiction, and toxic behavioral symptoms.
My research focuses primarily on SUD and the “reward pathway” or dopaminergic circuitry in the brain. Hyper-stimulation of the reward pathway will cause the brains normal mix of neurotransmitters to migrate from homeostasis, or balance, to an allostatic state of addiction requiring external substances like alcohol or opiates to maintain this new “balance” dictated by substance abuse. The reward pathway is generally considered to include the ventral tegmental area (VTA), the basal lateral amygdala (BLA), and the nucleus Accumbens (NAc) (Koob, 2008).
The basal lateral amygdala or BLA is also a critical participant in other illnesses such as PTSD and the effects of childhood sexual assault (CSA). The BLA behaves as a “recruiter” during fight/flight/freeze (F3) events such as flashbacks and panic attacks and mediates the participation of the central nervous system (CNS), all sensory input and access to heritable, instinctual responses passed on by our ancestors. The concept of the “addiction” gene is derived from these heritable survival strategies and my research has led me to conclude that the addiction gene is most likely the heritable state of “hypervigilance” that is a common indicator of PTSD, CSA or an unsafe living environment as a child.
One recent development in the struggle to find less toxic and problematic methods to treat veterans with PTSD and/or chronic pain has been the idea of treating those and many other maladies with medical marijuana. Medical marijuana is generally considered to be the cannabidiol variety (CBD) as opposed to strains high in tetrahydrocannabinol (THC). These two types are called cannabinoids and the body’s own variety of these are called endocannabinoids of which there are at least three different types of neural receptors: CB1, CB2, and a lesser understood CB3 (Wilson & Nicoll, 2002). Adding to the complexity of the issue is the fact that these receptors respond differently to both CBD and THC in different parts of the brain. So the question is: What is going on with these different cannabinoid/endocannabinoid receptors in the brain and can they be used to treat PTSD and other illnesses?
Demystifying Marijuana for the Legislator
To understand this complex issue, we should first have an understanding of what illnesses and symptoms are being proposed to be treated by CBD-infused medications/products. State proposals have included such diseases as AIDS/HIV, autism, auto-immune deficiencies, seizures, epidermolysis bullosa, Alzheimer’s disease, peripheral neuropathy, Tourette’s syndrome, PTSD, and intractable pain.
There are even movements where teams of physicians, like Green Health Docs, promote the use of medical marijuana as an aid to recovery from opiate addiction in states where medical cannabis is legal, including Arkansas – which is made possible by obtaining a medical marijuana card. Can this plant that has been used medicinally for thousands of years achieve all of these goals?
To investigate this question, we need to understand what these three cannabinoid receptors are doing and why they are differentiated in the brain. First let’s throw out the CB2 receptor. It is not located in the brain but is abundant in immune tissues and is involved in the body’s auto-immune response. It is likely involved in marijuana’s nociceptive anti-inflammatory, anti-cancer properties.
The receptor we know most about is CB1 which is abundantly expressed in the hippocampus, cortex, cerebellum, and basal ganglia (Kendall & Yudowski, 2016). CB1 is a neurotransmitter receptor that is found mostly concentrated on GABAergic neurotransmitters both pre-synaptically on the axon and on the post-synaptic cell.
What does this mean to the layperson? The positioning of CB1 receptors within the GABAergic neurotransmitter circuitry is significant. GABA act on the brain in an inhibitory fashion which makes it crucial to mood regulation. The pre-synaptic and post-cellular positioning allows for “retrograde messaging” where the post-synaptic CB1 receptor signals the glutamate receptor to initiate rapid biosynthesis to start making either anandamide (AEA), from the Sanskrit word for “bliss”, or arachidonic acid (2-AG) to break down the cannabinoid/endocannabinoid floating in the synaptic gap (Ahn, 2008).
This process for “retrograde signaling” or sending instructions back to the pre-synaptic CB1 receptor is a design which allows for the modulation of GABA neurotransmitter expression in both the hippocampus and the cerebellum, two sections of the brain directly involved in symptoms of PTSD. The hippocampus is the home of “narrative memory” or “linear memory” and stores memories, both pleasurable and traumatic. The cerebellum is responsible for regulating motor movement and receives sensory input from the spinal cord and other parts of the brain. The cerebellum coordinates voluntary movements such as posture, balance, coordination, and speech, resulting in smooth and balanced muscular activity and as such is a vital component of the fight/flight/freeze (F3) inherited response system.
Marijuana or the ∆9 THC molecule affects the hippocampus and the cerebellum differently. In the hippocampus, THC acts in an inhibitory fashion on GABA, which is itself inhibitory in purpose and at high doses, THC can affect memory and cognition, and cause catalepsy, tremors and decreased body temperature (Wilson & Nicoll, 2002). In small doses, however, THC acts upon hippocampal pyramidal cells in a “Degaussing” fashion, creating what I dubbed as the “novelty mechanism” or a reset of “expectation of reward” values. These expectation of reward values are stored in the NAc and are used to establish homeostatic neurotransmitter levels and allostatic responses to substance use.
My research has led me to theorize that these “expectation of reward” values are plastic in nature and are constantly updated with event-related occurrences or encounters with the substance of use. The NAc has the ability to initiate slow-wave-sleep (SWS) and subsequently perform “memory consolidation” indicates that the NAc is routinely informing other circuits of the brain of “reward value updates” and likely other F3 related events all pegged to the diurnal circadian rhythm (Cichy, 2018).
It is likely this “Degaussing” of the hippocampus’s “expectation of reward” requirements that creates the phenomenon of improving food taste and making bad movies tolerable.
Alger, in 1992, identified this phenomenon and described its mechanism. He showed that through brief depolarization (degaussing) of a neuron, THC can transiently suppress inhibitory GABAergic synaptic events in that cell. He named this phenomenon “depolarization induced suppression of inhibition (DSI) and it is pictured below (C) as the brief period of inactivity following the substances action upon the GABA neurotransmitter. A and B show CB1 receptors on GABA neuron.
Hippocampal DSI seems to be very specific. It does not affect hippocampal glutamatergic synapses which are excitatory in nature and I believe exist to provide a venue for rapid response to threats. In the cerebellum, however, the feedback messenger in DSI affects glutamatergic synapses in a similar phenomenon to DSI called DSE (depolarization-induced suppression of excitation) which translates into a reduction of symptoms of HPA (hypothalamus-pituitary-adrenal) stimulation, or stress-related agitation.
The positioning of glutamate receptors (mGLURs) post-synaptically suggests that these receptors act as a “brake” on excitatory signals to the cerebellum by biosynthesizing AEA or 2-AG to break down the synaptic cannabinoids. Depolarization and mGluRs appear to be two independent pathways to endocannabinoid synthesis which, together, can additively increase the magnitude of DSI. The phenomena of DSI/DSE accounts for the mild, dopaminergic, feeling of euphoria that accompanies initial marijuana inhalation.
CB1, in addition to suppressing GABA release also suppresses release of the olfactory peptide cholecystokinin (CCK). CCK typically antagonizes the behavioral and neural effects of opiates and suppression of CCK by THC uptake accounts for the synergistic effect that combining marijuana and opiates has on the brain, making marijuana a poor choice for medically-assisted treatment for opiate SUD. CB1 interneurons do, however, form GABAergic synapses with particularly fast kinetics supporting my theory that this network exists to respond to F3 events.
This specialization has different meaning for veteran’s suffering from PTSD. On one hand, suppression of HPA hyper-sensitivity through the use of marijuana to reduce the BLA and cerebellum’s response to PTSD triggers could be possible but powerful strains of THC can also result in agitation and paranoia through overstimulation of excitatory glutamate receptors. Endocannabinoids have long been associated with fear, anxiety and stress and AEA plays a primary role. Following rapid on-demand biosynthesis and degradation upon neuronal activation, AEA is actively degraded by the serine hydrolase enzyme, fatty acid amide hydrolase (FAAH). Exposure to stress rapidly mobilizes FAAH to deplete the signaling pool of AEA and increase neuronal excitability in a key anxiety-mediating region – the basolateral amygdala (BLA) (Gunduz-Cinar & Hill, 2013). In layman’s terms “stress will harsh your buzz” and deplete the mild bliss experienced from stimulating the CB1 receptor in the GABAergic circuitry.
Which brings us to the previously discovered mysterious CB3 group of receptors. What is their purpose and how are they modulated. Known early on as GPR55, scientists in 2007 declared this cell membrane receptor “a novel cannabinoid receptor” (Ryberg & Larrson, 2007). Since the CB3 receptor does not respond to ∆9 THC stimulation, marijuana’s effects on cognition and learning must be derived solely from the CB1 network. Earlier I introduced you to 2-AG, an endocannabinoid produced by the body known as 2-arachidonyl glycerol. 2-AG’s targets and functions are very similar to CBD in the CBD oil extracted from cannabis. Similar to 2-AG, LPA (lysophosphatidylinositol, more specifically 2-arachidonoyl lysophosphatidylinositol) is the primary cannabinoid produced inside the human body that targets the GPR55 receptor (CB3).
LPA is an “agonist” or activator of the CB3 receptor known as GPR55, which means LPA signals to the GPR55 receptor to express itself and initiate certain physiological functions. 2-AG and its functional relative, CBD, are “antagonists” to GPR55, which essentially means that 2-AG and CBD block GPR55 from expressing itself. Adding to the potential modulation of CB3 receptors is the fact that an enzyme called monoacylglycerol kinase, can convert 2-AG into LPA and vice versa in a process known as “interconversion” (Onaivi & Sugiura, 2005).
Stimulating the CB3 receptors with antagonists has huge potential in fighting a variety of cancers since the receptor seems to be involved with stimulating cancerous growth. Many cancers show an elevated level of LPA which some scientists interpret as potentially pointing to an overactive GPR55 receptor as a potential cause of cancer. CB3 receptors have also been implemented to be involved in several other important physiological processes including blood vessel vasodilation (important in controlling blood pressure), platelet function, fat cell storage and growth, immune system regulation, modulating insulin release, and vitamin D3 metabolism (Tudori & Imbernon, 2017).
One of the most successful therapies for treating PTSD is a process known as “Prolonged Exposure Therapy”, in which a narrative is used to bring the individual to a state in which a “window of opportunity” exists to initiate memory consolidation/extinction and assimilate any disassociative memories. Pharmacological studies have shown that potentiation of AEA endocannabinoid (eCB) signaling, through inhibition of eCB uptake enhance extinction of contextual fear conditioning for both recent and remote memories. Local manipulation of eCB signaling in the BLA modulates fear extinction. eCB signaling appears to have the ability to promote habituation to fearful stimuli and reduce fear expression over time and seems to utilize CB1 receptors on glutamatergic terminals as well as the possible release of CCK from a discrete population of interneurons within the amygdala (Hill & Campolongo, 2018). The fact that eCB signaling can both impair retrieval and promote extinction of traumatic memories indicates that once PTSD has been diagnosed, there may be a use for cannabinoids in assimilating any emotionally aversive memories
So what have we learned about marijuana’s potential as a treatment protocol for PTSD and opioid SUD? Here are the facts:
- The human body has receptors in the brain known as CB1, CB2, and CB3. CB1 responds primarily to THC and has both pre- and post-synaptic receptors that allow for endogenous stimulation as well as external substance ingestion to stimulate the cannabinoid circuitry. CB2 receptors work solely with the auto-immune system. CB3 receptors appear to interact best with cannabidiol CBD and CBD oils and extracts and modulate cancerous growths and many other physiological processes.
- THC is a poor choice for medically-assisted treatment for opioid SUD. THC ingestion stimulates the reward pathway with “Degaussing” of reward expectations and peptide expression following DSI. The olfactory peptide CCK antagonizes the behavioral and neural effects of opiates and suppression of CCK by THC uptake accounts for the synergistic effect that combining marijuana and opiates has on the brain. Recovery from opioid SUD requires allowing the reward pathway to return to homeostasis through abstinence and THC ingestion prohibits this.
- The endocannabinoid system plays a role in memory consolidation and fear extinction. CBD may be helpful in treating symptoms of PTSD such as flashbacks, hypervigilance, anxiety and avoidance through modulation of memory consolidation and extinction.
- Caution must be used with application of medical marijuana. Dose specific modulation of the eCB circuitry can produce different results. Small doses of CB1 receptor agonists relieve anxiety whereas higher doses of agonists can promote it.
Looking Forward: Addiction and “Mental Illness”
As most veterans know, PTSD and other combat related injuries don’t occur in a bubble and often there is a co-occurring substance use disorder that accompanies these injuries. Professionals in addictions treatment fought for years to have addiction recognized as a physical disease and not characterized as a lack of moral character or will. My research has provided compelling evidence that there exists a “permanent record” of homeostatic preferences to the neurotransmitter soup that bathes our brain. “Expectation of reward” values are stored there and receive nightly updates through slow-wave-sleep memory consolidation and phasic dissemination utilizing the diurnal rhythm.
When the “expectation of reward” is not met because of withdrawal, the NAc responds by activating the HPA axis through craving signals sent to the medial pre-frontal cortex to initiate hunter/gatherer behavior and find the substance of abuse. Discomfort and agitation increase until the expectation of reward requirements are met. This complex process can often result in personal and socially toxic behavior that can be characterized as “mental illness”. The problem with this “label” is that the behavior is perfectly rational under the physical distress of withdrawal. The behavior is no different than a diabetic seeking a sugar cookie to modulate their insulin levels. We don’t call the cookie eater “mentally ill” and we should not categorize a physical addiction and behavior driven by it as “mentally” ill. It is a biological disease that has predictable and repeatable stages. I was once a 3rd stage alcoholic.
Recovery from addiction is physical also. Prolonged abstinence will always allow the brain to return to homeostasis over time (6 mos-1 year) and cause the extinction of craving cues. This creates a recovered addict, who has no personal or socially-toxic behaviors driven by craving cues. However, the records in the NAc regarding the dopaminergic reward circuitry are permanent in that the repeatable “high dopamine levels” that the SUD conditioned, lay dormant and reoccurrence of substance use will reawaken these dopamine requirements and the individual will quickly be back to the same destructive using level as before.
The design of the NAc dictates that addiction is a chronic illness. The NAc and BLA are also involved in processing F3 events and as such, heritable survival strategies are also very difficult to erase by design. This peculiarity makes PTSD as difficult to treat and extinguish as any life-threatening addiction. However, once symptoms have been addressed any mal-adaptive coping strategies are usually abandoned and social productivity resumes.
Why are these distinctions important? In 2018, according to data from the Gun Violence Archive, a total of 67 mass shooting incidents have occurred as of April 22. These “lone gunmen” are compelling individuals to call for stricter gun control legislation and confiscation of guns from individuals who appear to be a threat to themselves or others seems to be high on the list of possible solutions to this civil unrest. If legislation is passed with wording that includes “mentally ill” that could potentially make sufferers of SUD technically eligible for gun confiscation, whether they are a threat to anyone or not and that sweeping label could catch up a lot of veterans. So legislators, please be very careful when you craft any gun control legislation to be accurate with your labeling and specific to your intent. There is nothing worse that poorly crafted legislation with unintended consequences.
Ahn, K. M. (2008). Enzymatic Pathways That Regulate Endocannabinoid Signaling in the Nervous System. Chemical Review, 1687-1707.
Cichy, J. R. (2018, March Wednesday). The Critical Role of the Nucleus Accumbens in Obesity. Retrieved May 11, 2018, from ResearchGate: https://www.researchgate.net/publication/323685483_The_Critical_Role_of_the_Nucleus_Accumbens_in_Obesity
Gunduz-Cinar, O., & Hill, M. (2013). Amygdala FAAH and anandamide. Mediating protection and recovery from stress. Trends Pharmacology Science, 637-644.
Hill, M., & Campolongo, P. (2018). Integrating Endocannabinoid Signaling and Cannabinoids into the Biology and Treatment of Posttraumatic Stress Disorder. Neuropsychopharmacology REVIEWS, 80-102.
Kendall, D., & Yudowski, G. (2016). Cannabinoid Receptors in the Central Nervous System: Their Signaling and Roles in Disease. Frontiers in Cellular Neuroscience, 294-298.
Koob, G. F. (2008). Addiction and the Brain Antireward System. Annual Review of Psychology, 29-53.
Onaivi, E., & Sugiura, T. (2005). Endocannabinoids: The Brain and Body’s Marijuana and Beyond. Boca Raton, FL: CRC Press.
Ryberg, E., & Larrson, N. (2007). The orphan receptor GPR55 is a novel cannabinoid receptor. British Journal of Pharmacology, 1092-101.
Tudori, E., & Imbernon, M. (2017). GPR55: a new promising target for metabolism? Journal of Molecular Endocrinology, 191-202.
Wilson, R., & Nicoll, R. (2002). Endocannabinoid signaling in the brain. Science, 678-682.