Underlying Neural Correlates of PTSD Symptomatology Dispose Individuals Towards Temporary Cannabinoid Therapeutics
November 14th, 2017
Jackson Tyler Boonstra, 11259779
Supervisor: Prof. H.G.J.M. (Eric) Vermetten Ph.D Co-assessor: H.J. (Harm) Krugers Ph.D
MSc in Brain and Cognitive Sciences - Cognitive Neuroscience University of Amsterdam
“There were never so many able, active minds at work on the problems of disease as now, and all their discoveries are tending toward the simple truth that you can’t improve on
Abstract
Objective: PTSD involves fear and anxiety related symptoms, both of which are mediated by
the endocannabinoid system. The objective of this review is to link the neurobiology of PTSD to the pharmacology of cannabinoids in a framework that supports PTSD patient dispositions towards temporary cannabinoid treatment.
Method: Current literature regarding the neurobiology and symptomology of PTSD, the
endocannabinoid system, and the mechanism of action of cannabinoids were reviewed and integrated to develop this framework.
Results: The HPA-axis, hippocampus, and amygdala play pivotal roles in stress, memory
formation, and fear conditioning respectively. The dysregulation and abnormal functioning of these areas underlie PTSD symptomology. Additionally, the endocannabinoid system has shown to modulate these areas, especially during stress and fear paradigms. Cannabinoid therapeutics acting on the endocannabinoid system in these areas do not cure or erase the symptoms but provide temporary alleviation of them. This is due to a biological disposition of the endocannabinoid system in individuals with PTSD coupled with biphasic effects of cannabinoids.
Conclusions: This article provides a framework linking the neurological aspects of PTSD to
the pharmacological profiles of cannabinoids in the temporary treatment of PTSD.
Cannabinoids permit the reduction of PTSD symptoms, but not enduringly, and could even lead to exacerbated them. Predictions of this hypothesis regarding how the use of
cannabinoids for temporary PTSD symptom alleviation could create either a platform for slight resolution or a detrimental crutch are presented. The author describes how the hypothesis is complementary to other ideas of drug use and discusses limitations within cannabis research.
Introduction
Posttraumatic stress disorder (PTSD) is an anxiety disorder comprised of four clusters of symptoms including intrusive and recurrent memories of trauma, avoidance behaviors, negative changes in mood or cognitions, and hyperarousal symptoms (American Psychiatric Association, 2013). According to a 2013 Congressional Research Service report, PTSD has increased by 656% since 2001 and the cost of treatment has doubled for the Department of Defense between 2007 and 2013 (Blakeley & Jansen, 2013). According to the U.S.
Department of Veteran Affairs (2017), an estimated 44.7 million people suffer from PTSD worldwide of which 24.4 million are American. Although this is a prevalent illness research towards the underlying neurobiological dysfunction and pharmaceutical treatment of
pathological stress is within its infancy.
It has been well documented that an endogenous group of cannabinoid receptors in the central nervous system called the endocannabinoid system are responsible for the
medicinal properties of cannabinoids and involved in multiple neurobiological processes that underlie the symptomatology of PTSD (Aisenberg et al., 2017; Malejko et al., 2017; Shoshan & Akirav, 2017). The neural correlates of PTSD symptomology as well as the
pharmacological properties of cannabinoids are both developing fields, but the dynamics of cannabinoids for PTSD therapeutics are less researched. Moreover, cannabis use is prevalent among those with PTSD, with 14% of those seeking treatment reporting using in the last half year (Gentes et al., 2016) and PTSD being associated with increased cannabis use and increased odds off lifetime use (Kevorkian et al., 2015).
Currently, qualifying patients in 28 American states and the District of Columbia now have the right to obtain and use medical cannabis for their PTSD (O'Neil, 2017). While patients claim that cannabis helps alleviate PTSD associated symptoms (Passie et al., 2012; Shoshan & Akirav, 2017) and studies show other cannabinoids may aid PTSD recovery (Hill
et al., 2017; Zer-Aviv et al., 2016), large scale reviews on the health effects of cannabinoids show insufficient empirical evidence to support those claims (O'Neil et al., 2017; Yarnell et al., 2015). Some studies even suggest that cannabis use in PTSD afflicted patients could deter therapeutic effects, worsen certain symptoms, and even cause additional problems (Babson & Bonn-Miller, 2014; Buckner et al., 2017; Ruglass et al., 2017).
Furthermore, research has also shown strong links between PTSD and cannabis use disorder (CUD) with rates of PTSD being higher in those with CUD compared to other substance use disorders (SUD) (Bonn-Miller et al., 2012; Roberts et al., 2015). To date there has been sparse neurological research evaluating the use of medical cannabis in those with PTSD and little consensus on the health effects of cannabinoids, making it devious for practitioners to recommend cannabinoids to their patients. Additionally, the dose-dependent effects and effective temporal window of cannabinoids towards PTSD symptomology are often only briefly mentioned and not taken to be focal or substantial considerations.
With conflicting research showing both positive and negative effects of concurrent PTSD and cannabis use being replicated annually, researchers should work for a consensus on what way cannabinoids alleviate PTSD symptomology. In this paper, we review current literature on the neurology of PTSD and pharmacology of cannabinoids, focusing on regions of interest (ROI) in the brain that have large cannabinoid receptor densities and correspond to underlying PTSD symptomology.
Additionally, we review the dose and temporal effects cannabinoids have towards symptom and sleep modulation in those with PTSD. We aim to reach an overall consolidation of findings into an argument that those with PTSD are disposed neurologically towards temporary cannabinoid therapeutics. In sum, this paper aims to provide a refined
When taken together the collective considerations (Figure 1) discussed within this paper may guide future neurological research on this evolving topic as well as provide an important footnote for those considering cannabis treatments for PTSD.
Figure 1. Considerations, as argued for within this paper, that should be taken into account
during research towards cannabinoids as a treatment for posttraumatic stress disorder.
The PTSD Brain
Posttraumatic stress disorder is defined in the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-V) as anyone who has the following indicators lasting at least one month; re-experiencing symptoms, avoidance symptoms, arousal and reactivity symptoms, and two cognition and mood symptoms (American Psychological Association, 2013). PTSD symptomology reflects the debilitating transformation of neurobiological systems that deal with stress in individuals exposed to trauma (Lanius & Olff, 2017). As a serious and debilitating condition, PTSD can cause individuals to be more susceptible to depression and traumatic brain injury (Thomas et al., 2017), suicide (Raines et al., 2017), drug and alcohol abuse (Dworkin et al., 2017; Neupane et al., 2017) as well as comorbid mental illnesses (Richardson et al., 2017) causing the research and treatment of the disease to be a major health concern.
Neurophysiological connectivity and activation has shown to be disrupted in individuals with PTSD (Kontos et al., 2017; Lopez et al., 2017) in three key areas, the hypothalamic-pituitary-adrenal axis (Dow-Edwards & Silva, 2017), the hippocampus
(Dunkley et al., 2014), and the amygdala (Sripada et al., 2012) making them potential targets for intervention and treatment with psychotherapy and pharmaceutical agents (Lanius et al., 2015).
The Hypothalamic–pituitary–adrenal Axis
The hypothalamic–pituitary–adrenal axis (HPA) is a major neuroendocrine system composed of direct influences and feedback interactions between endocrine glands, the hypothalamus, and pituitary glands as well as the adrenal glands. Some neurobiological models have been proposed that correlate the dysfunctional stress reactions in PTSD such as dysfunctional emotional regulation, stress responses, and behavioral inhibition, to the
changes in the HPA (Bellavance & Rivest, 2014; Marinova & Maercker, 2015).
Changes to the HPA include an abnormal regulation (low levels) of cortisol
(Stoppelbein et al., 2012) which produces greater levels of corticotropin-releasing hormones (CRH), causing higher levels of adrenocorticotropic hormones (ACTH) to be produced that in turn stimulate more release of glucocorticoids (GCCs) (Fragkaki et al., 2016). Cortisol acts as a breaking mechanism to the HPA by signaling the hypothalamus to cease production of the aforementioned stressor chemicals through a feedback loop; thus, lower levels of cortisol are accompanied by higher levels of arousing stress chemicals reflecting dysfunctional
breaking mechanisms that lead to the physiological hyperarousal symptoms of PTSD (Ford et al., 2014; Pacella et al., 2014). For this reason, targeting the HPA with pharmacological agents that act on this breaking mechanism or effect CRH and ACTH modulation appears to be valuable in PTSD treatment.
Hippocampus
It is well known that the hippocampus plays a pivotal part in memory formation and retrieval (Voss et al., 2017). Constant GCC exposure has been shown to cause hippocampal atrophy (Madalena & Lerch, 2017) which is indicative of the PTSD neural correlate of
reduced hippocampal volume and impaired long-term potentiation (LTP) (Brown et al., 2015; Rooij et al., 2015) and well as other PTSD symptoms related to memory including disrupted emotional processing, avoidance behaviors, and dysfunctional working memory (WM) (Hayes et al., 2012; Schweizer et al., 2011). High concentrations of GCCs have also shown to effect traumatic memory formation by modulating the process of consolidation (Kluen et al., 2016), or the maintaining, strengthening, and modifying of memories already stored in long-term memory.
In rodent models, infusion of GCCs in the hippocampus induced PTSD-like memory impairments and effected neural activations in hippocampal-amygdalar circuitry (Garfinkel et al, 2014; Kaouane et al., 2012). Within human studies, increased GCC levels and the
noradrenergic system have shown to alter the consolidation process of emotional material leading to memory deficits (Lalumiere et al., 2017; Osborne et al., 2016), an effect dependent of β-adrenergic signaling in the basolateral complex of the amygdala (BLA) (Mcintyre et al., 2012). Additionally, loss of anterior to posterior hippocampal connectivity differentiation has been shown within PTSD patients (Lazarov et al., 2017) With all this in mind, the hippocampus is considered a relevant target for pharmacological treatment in individuals with PTSD to help deal with memory and emotional processes that perpetuate
Amygdala and Prefrontal Cortex
The amygdala and hippocampus are part of the limbic system, a subset of brain structures largely involved in the emotional aspects of life and the formation of memories; it has been shown that memory symptomology in PTSD is partly a result of defective
interactions between these regions (Mcdonald & Mott, 2016; Malejko et al., 2017).
Functional imaging studies in PTSD patients have also shown decreased responses in the prefrontal cortex (PFC) and increased activations in the amygdala during stress inducing tasks (Fragkaki et al., 2016). It is well established that the amygdala is associated with fear conditioning (Febbraro et al., 2017; Wabnegger et al., 2017; Zheng et al., 2017) receiving information from multiple brain areas involving memory and emotion including the
hippocampus and neocortex, and projecting to various subregions that mediate stress and fear responses (Campanella & Bremner, 2016; Grewe et al., 2017). The hypoactivation and hyperactivation in the PFC and amygdala respectively link neurobiological alterations to the PTSD symptoms such as distorted mechanisms of extinction learning, hyperarousal,
avoidance behaviors, and re-experiences or flashbacks.
The BLA is mostly comprised of glutamatergic projection neurons which have been shown to coordinate with medial prefrontal cortex (mPFC) activity when involved in fear responses (Duvarci & Pare, 2014; Sangha, 2015). In human studies, trauma-related imagery, emotional faces, and other fear-related stimuli have shown to coincide with increased
amygdala activations (Bruce et al., 2013; Klimova et al., 2013). Even during resting-states the amygdala is shown to be hyperfunctional in those with PTSD (Badura-Brack et al., 2017; Zhu et al., 2016).
Interestingly, the hyperactivity of the amygdala that leads to abnormal fear responses may be due to the lack of inhibition from other brain structures such as the hippocampus and
the mPFC (Akiki et al., 2017; Liberzon & Ressler 2016; Maren et al., 2013). Increased pre-to-post activation of the PFC has been related to increased top-down control in emotional regulation and fear processing (Patel et al., 2012; Oboshi et al., 2014). Rats exposed to acute stress were shown to have increased glutamate transmissions across multiple brain regions including the mPFC, amygdala, and hippocampus (Pitman et al., 2012). The pathophysiology of PTSD then suggests that insufficient top-down control from the mPFC to the amygdala, be it direct or indirect, involves abnormal glutamate levels and transmissions. With attention towards this control, pharmacological therapies should aim to correct and increase adequate functioning of this system.
Besides functional connectivity, stress has also shown to modify amygdala
morphology (Padival et al., 2015; Wilson et al., 2015). PTSD patients have shown to have reduced volumes in prefrontal brain regions compared to healthy controls (Odoherty et al., 2017). Additionally, increased connectivity between the dorsal lateral PFC (dlPFC) and central executive networks has been shown after PTSD treatment (King et al., 2016)
suggesting improved emotional regulation through working memory routes, where traumatic emotional information is not forgotten but ‘relearnt’ (Haubrich et al., 2017). Reduction in amygdala signaling and increased hippocampal and PFC activity has also been shown to correlate with PTSD symptom improvement following treatments (Malejko et al., 2017) outlining neurobiological correlates of symptom reduction as well as possible
pharmacological targets.
System activity within one neural system underlying PTSD symptomology can interfere and effect the output of another system which is seen in the hippocampal-amygdalar and PFC circuitry underlying PTSD (Lazarov et al., 2017; Mcdonald & Mott, 2016).
Pharmacological interventions of a system can alter the relationship, balance, and
be difficult to postulate (Lazarov et al., 2017; Lanius et al., 2015) which needs to be taken into consideration when developing drugs to treat symptoms that could have synergetic effects.
Sleep
Individuals with PTSD along with other trauma-exposed populations report both short and long-term sleep impairments more than general populations (Wellman et al., 2016; Pigeon & Gallegos, 2015). An estimated 70-90% of people with PTSD report sleep disturbances or related issues (Koffel et al., 2016; Giosan et al., 2015) including trouble falling sleeping/insomnia, (Richardson et al., 2017; Mysliwiec et al., 2015; Sinha, 2016; Straus et al., 2015) frequent awakenings (Baglioni et al., 2016; Wyk et al., 2016), and nightmares (Nappi et al., 2012; Miller et al., 2017). Sleep disturbances are a considers a ‘hallmark' of PTSD (Germain, 2013) with the DSM-V including two within its diagnostic criteria (recurrent nightmares & insomnia) (American Psychiatric Association, 2013).
Those with PTSD and comorbid sleep issues have shown to have a higher risk of other mental health issues including substance use disorders (Vandrey et al., 2014). Additionally, sleep disturbances have shown to contribute in the development and
maintenance of PTSD (Koffel et al., 2013; Brownlow et al., 2016) due to its negative effects towards therapies (Vanderheyden et al., 2015; Reist et al., 2017) as well as its adverse effect on the formation of new memories, proper processing, and assimilation of traumatic events into a ‘sustained experience’ (Feld & Born , 2017; Menz et al., 2013; Totty et al., 2017; Vanderheyden et al., 2015; Kobayashi et al., 2016).
The underlying pathophysiology and neural correlates of sleep disruptions in PTSD are not well understood, but research has hypothesized the hyperarousal of limbic structures like the BLA and hypothalamic regions lead to a neurobiological overdrive and subsequent
arousal causing insomnia, awakenings, and variant regulation of REM sleep (REMs) and non-REMs (Eban-Rothschild et al., 2017; Sinha, 2016; Kelmendi et al., 2016; Pace-Schott et al., 2015).
Electroencephalographic (EEG) activity is also a proposed biomarker of PTSD sleep-distribution severity and susceptibility with theta band activity (4–10Hz) shown to be higher in PTSD resilient populations during REM sleep (Cowdin et al., 2014) and sigma band
activity (10–15 Hz) shown to be important for emotional memory consolidation during REMs (Vanderheyden et al., 2015). Reduced slow wave sleep as well as REM sleep disturbances have shown to engender nightmares (Mellman et al., 2014; Detweiler et al., 2016) as well as heighten sympathetic activity during REMs in PTSD patients (Tanev et al., 2017; Ross, 2014).
Altogether, pharmacological treatment of sleep dysfunction in those with PTSD could aid in the recovery from trauma by engendering proper sleeping functionality which effects psychotherapeutic intervention efficiency and other neurological symptoms (American Psychological Association, 2017; Gupta et al., 2013; USDVA 2017).
The Endocannabinoid System
The endocannabinoid system (ECS) is a collection of endogenous cannabinoid receptors located in the central and peripheral nervous systems; they are a group of
neuromodulatroy lipids and corresponding receptors. The ECS has shown to be involved in many neurophysiological processes such as pain-sensation, memory, stress, mood states like anxiety and fear, as well as reward and addiction behaviors (Parsons et al., 2015; Li et al., 2017; Albayram et al., 2012; Han et al., 2012; Vlachou et al., 2014).
Two major cannabinoid receptors within this system have been identified and successfully cloned: the cannabinoid type 1 receptor and the cannabinoid type 2 receptor
(CB1r & CB2r) (Shao et al., 2016). The CB1r is the most prevent guanine-nucleotide-binding protein-coupled receptor (GPCR) in the adult brain (National Institute of Health, 2017) and are enriched at presynaptic and axonal terminals limiting their functionality to synaptic activity modulation (Kendall & Yudowski, 2017; Laprairie et al., 2014). The hippocampus, cortex, basal ganglia, cerebellum, substantia nigra, and globus pallidus have the most abundant CB1r densities in the rodent brain (Marzo et al., 2015). Large concentrations of CB1r in sensory and motor regions of the brain establish its involvement with motivation and cognition (Mechoulam & Parker, 2013).
CB2r are expressed mostly in immune cells but also exist within neurons, glia cells, and endothelial cells and although considerably less present in the brain compared to CB1r (Savonenko et al., 2015) they have recently been found to mediate neural activity like plasticity in the hippocampus via stimulation of mitogen-activated protein (MAP) kinase activity (Stempel et al., 2016; Pacher & Mechoulam, 2011). The concept of the CB2r being the ‘second central cannabinoid receptor’ is being debated due to its unique modulatory and immunochemical profiles (Turcotte et al., 2016).
Callen et al. (2012) found CB1r-CB2r heteromers in several brain regions noting the possibility of bidirectional cross-antagonism where CB1r can negatively modulate CB2r. Both receptors are expressed in both excitatory (glutamatergic) and inhibitory (GABAergic) presynaptic terminals (Katona & Freund, 2012; Ibsen et al., 2017) although postsynaptic localization has recently been observed (Rivera et al., 2014).
Endocannabinoids
The endocannabinoid (eCB) ligands N-arachidonoyl-ethanolamine (AEA) and 2-arachidonoyl-glycerol (2-AG) are the most studied endogenous cannabinoids and are
Both AEA and 2-AG are non-charged lipids that readily cross lipid membranes (Kaczocha et al., 2012), have short half-lives, and can either metabolized or undergo cellular uptake following their release (Blankman & Cravatt, 2013).
Anandamide is a partial agonist of CB1r and CB2r (Malek et al., 2015) and comes from the Sanskrit word ananda meaning 'bliss'; which is fitting for it has been shown to enhance pleasure responses in rats to rewarding stimuli when injected directly into reward-related brain structures like the nucleus accumbens (Trezza et al., 2012). AEA has been shown to affect both the central and peripheral nervous systems (Thomas, 2017).
2-AG is a full agonist of the CB1r and is the most prominent monoglyeride species in the brain (Savinainen et al., 2012; Luchicchi & Pistis, 2012). Unlike AEA, 2-AG is present at high levels within the CNS and its synthesis is calcium-dependent (Grabner et al., 2017).
Endocannabinoids act as fast retrograde messengers that inhibit the release of
neurotransmitters (NT) such as dopamine, opioids, and norepinephrine from the presynaptic cells that they bind to (Castillo et al., 2012; Mechoulam & Parker, 2013). It has also recently been suggested that eCBs also interact with non-cannabinoid receptors (Baranowska-Kuczko et al., 2014).
Endocannabinoids are inactivated by enzymatic hydrolysis involving fatty acid amide hydrolase (FAAH) for AEA and monoacylglycerol lipase (MAGL) for 2-AG (Ueda et al., 2013; Blankman & Cravatt, 2013). FAAH is an integral membrane hydrolase that breaks down AEA and other N-acylethanolamines (Thomas, 2017) and shows preferential targeting to somatodendritic compartments of neurons in the CNS that are postsynaptic to axon terminals that express CB1rs (Blankman & Cravatt, 2013).
MAGL is a key enzyme that hydrolyzes around 85% of the brains 2-AG and converts it to free fatty acids and glycerol (Barricklow & Blatnik, 2013). Continuous inactivation of
MAGL has resulted in significant elevations of 2-AG levels in mice causing compensatory downregulation of CB1r in selective brain areas (Savinainen et al., 2012).
Cannabis Sativa
There are over 113 phytocannabinoids within the Cannabia sativa plant, the major two being delta-9-tetrahydrocannabinol (THC), and cannabidiol (CBD) (Mechoulam et al., 2014). THC is a partial agonist to the CB1r & CB2r (Bossong, 2012; Mechoulam & Parker, 2013) and has greater receptor efficiency then eCBs for it targets CBr in a less selective manner (Puighermanal et al., 2013). Unlike endocannabinoids, THC is metabolized slower (over several hours) but is stored and excreted similar to other metabolites (Morales et al., 2017).
Unlike its counterpart THC, CBD is nonpsychoactive, has a low affinity for CB1r and CB2r, and acts as an indirect antagonist to both receptors (Morales et al., 2017). CBD and THC have synergy (Russo, 2011) with CBD showing to modulate the pharmacological properties of THC including hypothermic and anxiogenic reductions (Todd & Arnold, 2015; King et al., 2017). Additionally, anxiolytic effects of CBD have been associated with it being a partial agonist of 5-HT1A receptors that causes β-Endorphin, an endogenous opioid
neuropeptide to be secreted (Fogaça et al., 2014). CBD has also shown to inhibit FAAH production (Campos et al., 2012).
Cannabinoids along with their targeted CB1r and CB2r have also shown to interact with additional proteins in complexes that modulate functions both at the cell surface and in intracellular organelles in the brain (Pacher & Kunos, 2013; Roitman et al., 2014) but more research is needed to understand all the mechanisms behind brain functions cannabinoids takes part in.
The Endocannabinoid System in the Stressed Brain
The ECS has been extensively shown to be involved in the regulation of mood, anxiety, fear, stress, and emotional memories (Lutz et al., 2015; Campolongo & Fattore, 2016) underpinning its involvement with PTSD symptomology (Hillard, 2014). The presence of CB1r and CB2r in sensory and motor regions of the brain coincide with the notions that CBr play important roles in motivation and cognition (Mechoulam & Parker, 2013). Additionally, the ECS has also been shown to be involved in plasticity, notably in cortical neurons (Njoo et al., 2015). It is important then to understand the neurophysiological and molecular function of the ECS in a brain after stress so that therapeutic and pharmacological targets can be properly aimed at specific PTSD correlates.
CB1r density & availability
There is emerging evidence of abnormal CB1 receptor density in individuals with PTSD. Elevated brain-wide [11C]OMAR VT values (a CB1-selective radioligand) were found in PTSD groups relative to healthy and trauma controls (Pietrzak et al., 2014; Neumeister et al., 2013). CB1r availability in the amygdala of human trauma survivors have been found to mediate threat processing (Pietrzak et al., 2014) and genetic variability towards CB1r
availability in humans have been associated with resistance to extinguish fear (Heitland et al., 2012). Levels of CB1r have additionally been positively correlated with freezing behavior in mice (Korem & Akirav, 2014; Choi, 2012). Similarly, in individuals with major depressive disorder (MD), levels of CB1r mRNA levels in the PFC were higher than control groups matched on age (Choi. 2012).
CB1r knockout (KO) mice show deficient fear extinction when conditioned with a high intensity footshock (Jacob et al., 2012; Dubreucq et al., 2012) while non-KO mice exposed to similar footshock situations exhibited increased levels of CB1r in the
hippocampus and PFC (Choi, 2012); CB1r levels in the PFC were found to be positively correlated to freezing behavior during this classical fear conditioning paradigm, elucidating the role CB1r have in fear and anxiety (Choi, 2012).
Endocannabinoid concentrations
Neumeister et al. (2013) noted that the ≈20% increase found in CB1r elevation in the amygdala-hippocampal-cortico-striatal circuitry could possibly be due to a combination of upregulated CB1r and decreases in eCB concentrations due to stress. Additional evidence suggests that stress alters endocannabinoid concentrations in limbic areas as well as the PFC (Atsak et al., 2013; Tatomir et al., 2014; Popoli et al., 2011). Chronic stress has also shown to reduce levels of 2-AG in the amygdala (Qin et al., 2015) and effect the on-demand synthesis of 2-AG (Aliczki et al., 2014; Zhang et al., 2014, Tanimura, 2010).
Recent studies found that when healthy controls were exposed to chronic stressors they exhibited diminished 2-AG concentrations that correlated with reductions in positive emotion (Hill et al., 2013, Hill et al., 2014). In addition, deficient 2-AG mediated plasticity was found in the nucleus accumbus of mice that developed a pathological-like form of
anxiety following social stress tests (Bosch-Bouju et al., 2016) while increases in anxiety-like behavior and adverse effects on emotional states were shown in mice that had reduced 2-AG signaling (Shonesy et al., 2014; Jenniches et al., 2016).
Correspondingly, low AEA levels have shown to correlate with both circulating cortisol levels and the degree of intrusive PTSD symptoms (Hill et al., 2017). Moreover, during stress conditions FAAH has been shown to increase while associated AEA levels decrease in brain regions related to the regulating of anxiety, like the amygdala (Bluett et al., 2014; Gray et al., 2015; Hill et al., 2013). Amygdala involvement is consistent with studies
that demonstrate FAAH-mediated fear and anxiety-like behavior regulation in the BLA (Dincheva et al., 2015; Gunduz-Cinar et al., 2013, 2016).
In sum, there is convincing evidence that there is reduced eCB availability (Hill et al., 2013; Jenniches et al., 2016) and increased CB1r densities (Neumeister et al., 2012; 2013) induced by stress in individuals with PTSD. Because sufficient levels of eCBs and CB1r are essential to modulate the behavioral and endocrine stress effects within the brain (Busquets-Garcia et al., 2016), the rectification of them could lead to symptom reduction and better treatment outcomes.
Dopamine
The effects that cannabinoids have towards the regulation of other neurotransmitter (NTs) and their respected receptors are also important factors when considering
pharmacological therapeutics for PTSD. Two main NTs, dopamine (DA) and glutamate (GLU), are modulated by the ECS, signifying cannabinoid modulation of dopaminergic and glutamatergic activity (Zhang et al., 2014; Polissidis et al., 2014; Oleson et al., 2014) both of which underlie multiple brain functions associated with PTSD symptomology. Abnormal activity and regulation of both DA and GLU within corticolimbic structures has been associated with drug addiction and psychoses (Polissidi et al., 2013) which can complicate pharmacological interventions.
Similar to the CB1r, there is evidence that dopamine transporter density is increased in those with PTSD (Hoexter et al., 2012; Van de Giessen et al., 2017). Additionally,
abnormal dopaminergic transmissions (DAT) has correlated with reduced reward function in PTSD (Enman et al., 2015) while the degradation and the pathology of DAT has been implicated in the contribution of PTSD symptomology and co-occurring disorders like substance abuse and depression (Enman et al., 2015). The dopamine D3 receptor gene has
also been implicated in substance use-disorders and certain PTSD symptomologies like emotion reactivity, stress-responding, and executive functioning (Wolf et al., 2014).
Recently, cannabinoids have been shown to play a role in dopamine interactions with research showing that CB1r and CB2r modulate dopaminergic neural activity and dopamine-regulated behaviors (Garcia et al., 2016; Zhang et al., 2014) theorized to be due to eCB modulation of local DAT circuitry (Covey et al., 2017). Cannabinoid receptor agonists and phytocannabinoids have also shown to increase dopamine release in a dose-dependent manner and modify dopamine’s timing behavior (Kuepper et al., 2013; Oleson et al., 2014; Bossong et al., 2015). Due to these noted interactions, eCB effects on other NTs should be greatly considered when prescribing a dopaminergic drug such as cannabis for a psychiatric disorder like PTSD. These studies show the complexities that multifaceted drugs like cannabinoids can have towards altering and modulating neurotransmitters involved in the pathophysiology of PTSD symptoms.
In sum, research to better understand the bidirectional relationship between NTs like DA and eCB synaptic signaling as it relates to the regulation of brain functions and disorders is warranted. There may prove to be some practicality of eCB-based therapies towards the treatment of DAT dysfunction and related disorders if research progresses (Covey et al., 2017). While the neuromolecular pharmacology of cannabinoids is within its research
infancy, this preliminary data suggests that cannabinoids can be used in a therapeutic fashion to manage PTSD symptoms via direct and indirect activations of non-endocannabinoid transmitters like dopamine via eCBs (Awad & Lakshmi, 2015; Loureiro et al., 2015) done in a homeostatic nature that restores excitatory and inhibitory equilibriums necessary for proper emotional reactivity (Silvestri, 2013).
Pharmacological Interventions
Research towards the pharmacological intervention of PTSD through eCB
augmentation and other ECS involved mechanisms is precursory, but results have shown a few ways this may be done. Interventions include administration of full-plant marijuana (cannabis), cannabinoid concentrations like THC and CBD (phytocannabinoids), synthetic cannabinoids like the Dronabinol, Nabilone and Bedrobinol (exocannabinoids), and drugs that act as inhibitors and promoters of eCB enzymatic hydrolysis which typically effect FAAH and MAGL. Regardless of origin (endogenous, exogenous, synthetic, or
phytocannabinoids), the neuropharmacological properties of all cannabinoids have been shown to be distinctly different from one another (Marzo & De Petrocellis, 2012) and as a result should be independently evaluated and researched.
Full-Plant Marijuana (cannabis) for PTSD
Recently there has been a surge of use of Cannabis for Therapeutic Purposes (CTP). Research towards the efficacy and safety of the treatment of PTSD using full-plant marijuana is scarce, but many people interpret preclinical results as promising. Greer et al., (2014) found in an observational study that combat veterans self-reported 75% reduction in
reexperiencing, avoidance, and arousal symptoms of PTSD associated to cannabis use, while a contrary study with 2276 veterans showed associated cannabis use with worsened PTSD symptoms as well as more violent behavior and alcohol and drug use following discharge from treatment (Wilkinson et al., 2015). Another study compared veterans with PTSD who use marijuana to those who did not and failed to find fewer PTSD symptoms associated with more marijuana use (Johnson et al., 2016).
There are many negative psychiatric and neurological outcomes that have been associated with cannabis use that could further exacerbate one’s susceptibility to PTSD
symptom resurgence and have negative impacts on ongoing therapies. One study showed that those who use marijuana were more likely to develop depression and ‘heavy users’ were more likely to develop depression appose to ‘light users’ (Lev-Ran et al., 2014). Long-term use of cannabis has additionally been associated with the down regulation of cortical CB1r (Hirvonen, Goodwin, & Li, 2012; Neuimeister et al., 2012) lower orbitofrontal cortex grey matter volumes (Filbey et al., 2014), smaller amygdala and hippocampal volumes (Lorenzetti et al., 2014), smaller cerebellar volumes (Cousijn, 2012), and lower IQ scores (Meier et al., 2012) all of which propose neurological decline and symptom exacerbation (Brown et al., 2015; Rooij et al., 2015). Due to these types of negative effects, Niesink & van Laar (2013) reported outright “Cannabis is not a safe drug.”
Unlike lithium or other prescription medications used to treat psychiatric disorders, different strains of the cannabis plant (chemovars) contain and produce a large array of active substances making the prescribing of it as a medicine unprecise; the plant one consumes one week may be vastly different in chemical makeup from the plant one consumes the next week due to growing, curing, and shipping methods that are not standardized or heavily monitored (Peschel, 2016). The relaxed attitude of cannabis as a safe drug of low possible dependence comes from its inability to cause an overdose, the temporal compulsions for an addict to use being more spaced out (every few hours appose to every hour like a nicotine addict) and the low percentage of people who become addicted in comparison to other illicit drugs
(MacDonald & Pappas, 2016). While the percentage of those who get addicted is much lower compared to other drugs, the percentage is still quite high and thus should not be ignored.
Substance dependence, similar to PTSD, is a debilitating brain-based disorder. Although generally thought to be nonaddictive, cannabis dependence has been clearly documented; between 2001 and 2013 the use of cannabis has almost doubled in the United Sates from nearly 6% to 10% with a corresponding increase in the percentage of those
diagnosed with CUD (Hasin et al., 2015). Evidence points to cannabis elevating the risks of developing psychotic illnesses and worsening the course of mental health conditions in individuals with PTSD and other SUDs. Additionally, people with PTSD who use cannabis reported experiencing more problems associated with cannabis use compared to individuals without PTSD (Boden et al, 2013). Important to note is the risk factors involved with CTP; some patients with PTSD who went on to develop CUD had lessened benefits from
traditional PTSD treatments (Bonn-Miller et al., 2013), greater withdrawal symptom severity during cannabis cessation (Boden et al., 2013), and ‘poor short-term cessation outcomes’ (Bonn-Miller, 2015).
Both cognitive behavioral therapy (CBT) and prolonged exposure therapy (PE) have proven to be effective behavioral treatments for PTSD, but past research has shown an inverse correlation between cannabis use and PTSD symptom reduction following inpatient treatment (Bonn-Miller & Vujanovic, 2011). Cannabis has shown to be used as an avoidant coping mechanism for those with PTSD to help with sleep and anxiety (Metrik et al., 2016) but patients who engage in less avoidance behaviors during PTSD treatment have shown to have greater outcomes from therapy (Betthauser et al., 2015). There has been additional evidence linking avoidance behaviors to both PTSD and cannabis use (Betthauser et al., 2015; Bordieri et al., 2014; Boden et al., 2012, Boden et al., 2013). Furthermore, Bonn-Miller et al. (2015) found a correlation between PTSD symptoms severity and self-reported
motivation to use cannabis to manage emotional distress. In a separate case study review, U.S. veterans were reported saying “[Cannabis is] a great distraction.”, “[Cannabis] cures the PTSD.”, and “I self- medicate…[Cannabis] is my mental and social support system.” (Hill et al., 2013).
Impairments in the dopamine release systems caused by long-term cannabis use correlate with deficits in neurocognitive performances like attention, lower verbal memory,
processing speeds, and worsened verbal memory (van de Giessen et al., 2016) along with corresponding lower levels of brain activity in corresponding areas like the dorsal anterior cingulate cortex and the hippocampus (Carey et al., 2015; Zalesky et al., 2012). Marijuana abusers have also shown to have blunted reductions in the dopamine system (Bloomfeild et al., 2016) including in the striatum which is consistent with decreased brain reactivity and DAT underlying negative emotionality and addictive behaviors (Volkow et al., 2014). Conversely, a meta-analysis conducted by Marconi et al. (2016) of 10 studies found a large increased risk for schizophrenia among heavy cannabis users compared to controls, even though schizophrenia is believed to be caused by dopaminergic expansion (Brisch, 2014), showing the damaging neurological effects cannabis can have that are still not well understood.
Coming from a perspective of harm reduction, with benefits of CTP having not yet been empirically demonstrated and additional psychotherapies being needed for those who develop CUD with comorbid PTSD, along with patients’ self-reported cannabis-coping reasons, CTP does not appear to be an advantageous avenue of PTSD treatment. CTP for PTSD may represent too great a risk for some patients who exhibit psychotic symptoms and for those who are vulnerable to the development of SUDs. With these risks in mind, those undergoing CTP for PTSD should either be closely monitored for CUD development or should find an alternative pharmacological avenue. If cannabis truly has an avoidance function, symptom improvement would theoretically be temporary at best and could subsequently deadlock emotional processing necessary for proper recovery (Aston et al., 2016; Metrik et al., 2012).
Tetrahydrocannabinol (THC)
Full-plant cannabis can have an entourage of effects due its composition and ratio of multiple cannabinoids (Schier et al., 2012) and thus has different pharmacological properties than an isolated cannabinoid such as pure THC. Rabinak et al (2014) and Gorka et al (2016) found that THC administration in humans modulates prefrontal-limbic circuits during fear extinction, thought to be due to vmPFC CB1r activation causing neuronal plasticity which increase top-down inhibition of fear output neurons within the amygdala (An et al., 2017). While the vmPFC has shown to underlie both emotional responses and fear (Sierra-Mercado, 2011), little is known about how these fear memory retrieval circuits change over time (Sacco & Sacchetti, 2010), and even less is known about how THC effects these circuits and
synaptic function overall (Hoffman & Lupica, 2013) causing treatment with THC to be risky.
In one study, oral admiration of THC given in 5mg doses twice a day was shown to improve global PTSD symptom severity, sleep quality, frequency of nightmares, and hyperarousal symptoms in patients (Roitman et al., 2014). This was the only study that has completed an open-label pilot study of THC, but 80% of the participants were taking benzodiazepines, and due to the legal status of the drug where the research took place the beneficial effects of the drug were likely to have been exaggerated so the participants could pass psychiatric clearance and receive the drug ‘legally’ (Roitman et al., 2014).
Another sleep study found that THC decreased total REMs and REM density
(Schierenbeck et al., 2008) which can deter proper PTSD recovery involving sleep-emotional processes like consolidation of extinction memory (Pace-Schott et al., 2015). Cannabis intoxication and chronic use have additionally shown to negatively impact sleep and decrease REMs (Gates et al., 2014; Garcia & Salloum, 2015) thought to mostly be due to THC.
While THC has shown to significantly reduce amygdala activity and display mediating effects on negative mood processing (Rabinak et al., 2013), preclinical animal models and human experimentation have shown that THC at higher does is anxiogenic and propsychotic (Blessing et al., 2015; Niesink & van Laar, 2013). Another study found that administration of THC in low doses caused anxiolytic effects in rats during an elevated maze test, but high doses increased anxiety-like behaviors (Moreira et al., 2008) making the continued use of it for symptom alleviation inadvisable.
Furthermore, THC has shown to impair functional connectivity of reward circuitry (Fischer et al., 2014), decrease functional corticostriatal connectivity (Ramaekers et al., 2016), and cause defects in inhibitory circuits (Vargish et al., 2016). Additionally, THC has shown to stimulate mesolimbic dopamine release, a brain area and phenomenon associated with addictive substances (Koob & Volkow, 2010), negative emotional and addiction severity (Volkow et al., 2014), memory formation and social interaction (Loureiro et al., 2015), and functional connectivity related to reward networks (Filbey & Dunlop, 2014) further
complicating its true function and safety.
Interestingly, while there are currently no FDA approved medications for the
treatment of CUD, THC was shown to reduce withdrawal symptoms of cannabis when orally administered in low doses (Copeland & Pokorski, 2016; Weinstein & Gorelick, 2011). While more research is necessary to fully discover the long and short-term effects THC has towards multiple neural circuits and synaptic activity over time, evidence thus far mostly points to foreseeable defects, disruptions, and decreases.
Cannabidiol (CBD)
Cannabidiol is a nonpsychoactive phytocannabinoid that can account for up to 40% of a cannabis plants extract (Campos et al., 2012) and has been highly suggested to have a
downregulating impact on anxiety in animals (Iseger & Bossong, 2015) and humans (Das et al., 2013, Bergamachi et al., 2011) as well as antipsychotic effects (Leweke et al., 2016). CBD has been shown to reduced anxiety, cognitive impairment, and discomfort in individuals with Generalized Social Anxiety Disorder (SAD) when they performed a simulated public speaking test (Bergamaschi et al., 2011). In other studies, Campos & Ferreira (2012) and Twardowschy et al. (2013) found increased expression of 5HT1A receptor (serotonin) mRNA in brain areas related to PTSD after predator exposure, while administration of CBD
prevented these changes. These effects were theorized to be due to facilitation of 5HT1A-receptor mediated neurotransmissions appose to direct ECS alterations.
Another study where mice were injected with microdoses of CBD into their
infralimbic cortex showed facilitated fear extinction which was mediated by the CB1r (Monte et al., 2013). Additionally, CBD has shown to enhance AEA levels and alleviate some
psychotic symptoms (Leweke et al., 2012) showing its modulatory effects on
endocannabinoid functionality and suggesting pharmacological effectiveness towards PTSD symptom reduction.
People with PTSD often report trouble sleeping; REM sleep suppression was found to be efficiently blocked by CBD but showed to have little effect towards the alteration of non-REMs suggesting that CBD blocks anxiety-induced non-REMs alterations due to its anxiolytic effects appose to effecting sleep regulation directly (Hsiao et al., 2012). Conversely, other studies suggest that CBD may increase alertness and not be beneficial on sleep quality (Zhornitsky & Potvin, 2012; Goonawardena et al., 2011).
Exposure therapy for PTSD involves inhibitory learning, and deepened/reinforced extinction (Craske et al., 2014). It has been suggested that CBD has potential in aiding PTSD therapies by regulating fear learning via dampening of fear expression, disruption of fear
reconsolidation, and facilitation of fear extinction (Jurkus et al., 2016). When administered post-extinction, CBD was shown to enhance consolidation of extinction learning and cause anxiolytic effects (Gomes et al., 2010; Das et al, 2013; Schiavon et al., 2016). A reduction of amygdala response to fearful faces was found due to CBD (Fusar-Poli et al, 2009) possibly due to disruptions of forward connectivity in prefrontal-subcortical regions and limbic and paralimbic cortical areas implicated in the pathophysiology of anxiety (Fusar-Poli et al, 2009b). PFC infusion of CBD in rodents impaired contextual fear memory consolidation by reducing PFC influence on cortico-limbic circuits (Rossignoli et al., 2017), and was
additionally associated with a reduction in dopamine turnover (Rossignoli et al., 2017) further demonstrating compelling PTSD symptom alleviation properties.
Low dose THC and high CBD together in a ratio of 1:10 has shown to be equally as effective as low dose THC at mitigating aberrant aversive memories similar to ones that underlie PTSD (Stern et al., 2015). At higher doses, CBD was shown to increase anxiety within rats (Elbatsh et al., 2011); this anxiolytic-like effect during chronic administration is analogous to THC. Although it has been suggested that higher CBD content protects against negative THC-induced adverse effects (McPartland et al., 2015; Niesink & van Laar, 2013), to date no study has been conducted to specifically address the dynamics between these two main phytocannabinoids and how they correlate to anxiety (Blessing et al., 2015; Haney & Evins, 2015).
In light of all this, CBD is viewed as a more suitable drug then cannabis and THC in the treatment of fear-related symptomology that underlies PTSD, partly due it causing less side-effects and having less toxicity. In a review of animal and human studies, CBD was shown to have ‘an adequate safety profile [and] good tolerability', reduce anxiety, and not affect cognition (Zettl et al., 2016). CBD, like THC, has also shown to have biphasic effects, so adequate therapeutic windows in the pharmacological intervention for different anxiety
disorders still need to be determined (Schier et al., 2012). Other studies done in humans support anxiolytic roles of CBD, but the research is currently limited to acute doses (Blessing et al., 2015). Furthermore, the molecular mechanisms behind CBD’s biphasic and dose-dependent anxiolytic effects, along with its long-term effects, remain largely unknown (Zanettini et al., 2011) and like THC, they need to be further researched so that proper medical guidance can be specified.
Synthetic cannabinoids (exocannabinoids), Inhibitors, and Promotors
Preclinical pharmacological manipulations of the ECS with cannabinoid agonists have been shown to enhance extinction processes and help avoid retaining memories that trigger trauma (Bitencourt et al, 2013) showing their potential to treat PTSD. It has been suggested that FAAH inhibitors could aid in CTP for PTSD without increasing abuse-risk and cognitive deficits that are related to THC; compared to smoked cannabis, exocannabinoids have a low abuse liability and causes much milder withdrawal symptomology during cessation (Haney & Evins, 2015) suggesting they are a safer pharmacological avenue.
Inhibiting FAAH has shown to enhance AEA levels and alleviate psychotic symptoms (Leweke et al., 2012) while the CB1r/CB2r agonist WIN55,212-2 prevented the development of an enhanced startle response, impaired extinction, and stress related neuroendocrine responses (Korem and Akirav, 2014) demonstrating exocannabinoid use as a
pharmacological agent for PTSD. In a recent study, systemic cannabinoid receptor activation with WIN55,212-2 prevented the effects stress had on HPA axis function by enhancing inhibition via corticosterone level reduction (Ganon-Elazar & Akirav, 2012). Comparatively, other studies found that the blockade and genetic deletion of CB1r lead to extended
corticosterone secretion creating a continued stress response, and that the termination of HPA-axis activity via stress-induced glucocorticoid signaling of the mPFC is mediated by
local eCB signaling (Aisenberg et al., 2017; Hill et al., 2012; Hill & Tasker 2012). To summarize this data, the ECS plays a pivotal role in modulating HPA axis activity, particularly in its responses to stress, and studies suggest effective synthetic cannabinoid treatment possibilities.
Furthermore, enhanced AEA and 2-AG signaling in the hippocampus of Wister rats using pharmacological blockades of FAAH and MAGL has shown to decrease acute fear responses, while enhanced AEA signaling in the BLA showed to prevent traumatic memory formation (Lee et al., 2016). This data suggests that eCBs have a synergetic relationship, and work differentially and interactively to regulate behavioral responses to trauma in multiple areas of the brain which sustain PTSD. These synergetic activities warrant targeted research towards each interaction effect, for they can complicate pharmacological understandings and confound treatment outcomes if not identified.
In a human placebo-controlled double-blind study, healthy participants administered the synthetic cannabinoid Dronabinol 2-hours prior to an extinction session had less
reinstatement of a fear response the next day (Rabinek et al, 2013). Dronabinol has additionally been shown to decrease amygdala reactivity to fearful stimuli during social-threat tasks (Phan et al, 2008). In another study, a 4mg dose of the synthetic cannabinoid Nabilone showed to significantly improve PTSD-associated insomnia, nightmares, and other PTSD symptoms such as hyperarousal (Shalev et al., 2013; Camerson et al., 2014).
Significant improvements in insomnia and nightmare were also reported in patients who were given nabilone (Cameron et al., 2014; Jetly et al, 2015) though the sample sizes were small.
Side effects of CB1r antagonists are typically mood-related and include elevated anxiety (Christensen et al, 2007; Moreira et al, 2009) or sedative and dizzying effects. High doses of dronabinol have shown to cause anxiety where as low doses prove to aid in fear
extinction and counteract anxiety disorder symptoms (Vandrey et al., 2013; Bedi et al., 2010) suggesting that, like phytocannabinoids, synthetic cannabinoids have a biphasic
dose-dependent therapeutic effect. Likewise, future research needs to establish optimal doses and monitor tolerance development of oral cannabinoids (Bedi et al., 2010). It should also be noted that contradictory effects have been reported about sleep latency and REMs as it relates to both natural and synthetic cannabinoids, demonstrating that sleep effects in short and long-term use of different cannabinoids have not been well defined (Belendiuk et al., 2015).
The Disposition Towards Temporary Cannabinoid Therapeutics
The therapeutic goal within the treatment of PTSD is a reduction of the threat
response, re-learnt emotional memories, and a global reduction in symptom intensity (Haney & Evins, 2016). To achieve this, novel pharmacological agents are being sought out. Many traditional pharmacological therapies for PTSD such as selective serotonin reuptake
inhibitors (SSRIs) have downfalls such as their temporal effectiveness (it can take several weeks for the therapeutic effects to ‘kick in’ and some patients do not respond to them) and their side effects (appetite and weight fluctuations, loss of libido, and gastrointestinal
troubles) (Cartwright et al., 2016). Complications and risks with SSRIs and other drugs make cannabinoids an alluring alternative option for PTSD treatment, but this alternative does not come without its own complications.
Intervention strategies using a variety of cannabinoids have shown an ability to prevent and even reverse effects stress can have on the ECS and subsequently alleviate PTSD symptoms. While these findings continue to suggest biological plausibility for effective cannabinoid interventions, much of this research is preliminary and preclinical. Cannabis has vastly different effects on individuals due to ‘a complex interplay of genetic, physical,
psychological, and contextual factors’ (Tambaro & Bortolato, 2012) as well as a wide variety of chemovars and modes of administration (MOA) making the prescribing of it inexact.
It is even possible that cannabinoid interventions and adjunct treatments could nullify the benefits of specialized PTSD treatments, exacerbate anxiety and depression, and cause additional psychiatric and memory problems that would deteriorate the mental health of an afflicted individual. Because of the diversity in the drug’s effect and lack of sufficient research into the mechanisms and neural correlates of the ECS, cannabinoid use for PTSD has yet to be translated into a meaningful research agenda. Precise pharmacological
intervention techniques also remain piecemeal. Therefore, before conclusions can be drawn about the effectiveness of cannabinoids for PTSD, heavy considerations toward the
underlying neural correlates, dose-dependent effects, and temporal windows of effectiveness need to be greatly considered in future research.
The Disposition
Previous research has indicated reduced levels of eCBs in both humans and animals (Hill et al., 2013; Neumeister et al., 2012, 2013; Dlugos et al., 2012) as well as elevated brain CB1r availability is associated with PTSD (Pietrzak et al., 2014; Neumeister et al., 2013). It is possible that eCB levels and receptor alterations (along with other subsequent NT changes like DAT) represent an adaptive and protective response of neuroanatomy to stress (Hill et al., 2013, 2014), but this natural allostatic activity could prove to sustain PTSD symptoms which is why pharmacological agents are thought to be needed.
When collectively examined, these biomarkers suggest that abnormal
endocannabinoid signaling and receptor densities are implicated within the pathophysiology of PTSD. This has lead researchers to believe that cannabinoids hold great potential towards the pharmacological treatment of individuals with PTSD and related anxiety disorders.
Correction of proper ECS signaling is thought to be crucial for symptom reduction to protect an individual from over-reactions to fear and stress by ensuring such events are reacted to aptly.
In theory, leveling out these irregularities with pharmacological aid can prove
successful towards symptom reduction, but again, this rise and fall of eCBs and CB1r density may be a natural compensatory effect that brains have toward stress, so clinicians should be mindful towards medicating away this response.
Temporarily
Although evidence points to cannabinoids helping to alleviate patients from PTSD symptoms these effects are noted only for a short amount of time suggesting the therapeutic properties of cannabinoids for PTSD are temporary at best. While many studies provide preliminary evidence suggesting the safety of cannabinoids during short-term use, conclusions cannot be draw about the long-term impacts. Continued use of full-plant cannabis has shown to exacerbate PTSD symptomology and cause additional issues which lead to worse outcomes during therapy (Babson & Bonn-Miller, 2014; Buckner & Zvolensky, 2014; Ruglass et al., 2017). This is thought to be due to THC’s psychotogenic effects (Di Forti et al., 2009) coupled with its summated neurotoxicity (Dinish-Oliveira, 2016). There then seems to be a transient nature of PTSD symptomology extinction due to dose-dependent reversal effects of full-plant cannabis, THC, and other cannabinoids for comparable reasons.
Furthermore, the biphasic effects that cannabinoids have on sleep are troubling and sometimes contradictory. It has been reported that acute THC administration reduces sleep latency, but higher doses and chronic administration creates a tolerance to such sleep-effects (Schierenbeck et al., 2008) which is in line with previous research showing that the
down-regulation of CB1r could lead to rebound effects in continued use and thus worsen PTSD therapy outcomes (Wilkinson et al., 2016).
CBD has also shown biphasic effects on sleep, were low doses increase wakefulness when administered with THC (Zhornitsky & Potvin, 2012; Goonawardena et al., 2011) but higher doses can cause sedative effects (Chagas et al., 2013). CBD being a wake-promoting compound could be in part due to it stimulating wake-related areas like the hypothalamus and dorsal raphe nucleus (Murillo-Rodríguez et al., 2014) and due to it enhancing DAT in sleep-cycle areas like the nucleus accumbens (AcbC) (Murillo-Rodríguez et al., 2011). While acute administration of cannabis and cannabinoids has shown to facilitate falling sleep and increase Stage 4 sleep (Babson et al., 2017), cannabis withdrawal has been associated with difficulty sleeping, anger, nervousness, and strange dreams (Katz et al., 2014), conversely suggesting that cessation of the drug may cause such temporary therapeutic effects to disappear.
Evidently indeterminate within most research toward eCBs and the ECS is the specifications on temporal-windows of effectiveness. Because memory of a traumatic event has been proposed as a risk factor for the development of PTSD, it is speculated that there is a golden window of opportunity after exposure to a traumatic event where interventions have the greatest potential to dramatically alter the course of PTSD symptom development (Zohar et al., 2011). Such optimal temporal specifications of effective interventions and cessation of cannabis and cannabinoids for PTSD (when to start and when to stop) have yet to be clarified and should be critically considered during future investigations. It is also important to study if the intervention strategy when initiated and terminated disrupts any inherent recovery
processes produced by aforementioned neurological dispositions. Moving forward, it is imperative for both researchers and clinicians not to underestimate the detrimental effects continued manipulation of the ECS could possibly cause.
Cannabis for Therapeutic Purposes (CTP)
In 2013 the American Psychiatric Association (APA) stated “There is no current scientific evidence that marijuana is in any way beneficial for the treatment of any psychiatric disorder. In contrast, current evidence supports, at minimum, a strong association of cannabis use with the onset of psychiatric disorders. Adolescents are
particularly vulnerable to harm, given the effects of cannabis on neurological development.” They further specify that “Further research on the use of cannabis-derived substances as medicine should be encouraged and facilitated by the federal government… [and] …The adverse effects of marijuana, including, but not limited to, the likelihood of addiction, must be simultaneously studied”
As a result of the APA’s recommendations, studies have been performed to investigate CTP, yet many studies had notable limitations including small sample sizes, retrospective reporting of ‘significant relief of several major PTSD symptoms when using cannabis’, and a lack of placebo and dose-controlled groups (Roitman, 2014) making the evidence fragmentary and considerably insignificant. Evidence regarding the transition from therapeutic use of cannabis to problematic use is also piecemeal, making it difficult to compare the risks and benefits of CTP (Walsh et al., 2017). Additionally, many studies relying on self-report did not check the potency (chemovar) or MOA of cannabis used by participants which undermine the utility of conclusions.
Despite all this, a growing number of countries have begun to expand their CTP programs. Developments include exploration of physical health effects to addressing mental health concerns due to CTP patients’ propensity for psychiatric comorbidity (Bonn-Miller et al., 2014; Walsh et al., 2013). Because of the mixed evidence, all case reports and reviews
call for more extensive research towards the therapeutic effectiveness of CTP as well as cannabinoids for PTSD to be performed (Passie et al., 2012).
Uniquely, the discovery of the CB1r and eCBs was made when investigating the psychoactive properties of cannabis which has led to the subsequent development of synthetic cannabinoids that have been used for a variety of reasons completely unrelated to marijuana. Researchers have taken heed of this discovery origin by moving away from full-plant
intervention/treatment strategies to create safer and better tested novel approaches toward ECS interventions. Considering all complexities, the use of constituents of cannabis such as CBD and synthetic cannabinoids (appose to full-plant) as adjuncts to therapies would seems to be a better (but not the best) path of treatment due to their less harmful pharmacokinetic profiles and distinctly different (less detrimental) metabolic pathways (Trezza &
Campolongo, 2013). The 5HT1A receptors have also been suggested to be a better target then direct CB1r or CB2r manipulation for similar reasons. These endogenous and synthetic cannabinoids have not (yet) shown to have such strong biphasic effects as their
phytocannabinoid siblings signifying conceivably favorable treatment directions.
Coping
Cannabis is widely thought to be a coping mechanism in patients with PTSD (Boden et al., 2014) serving as an avoidance function (Bujarski et al., 2016). People with PTSD report coping-orientated reasons for cannabis use (Buckner & Zvolensky, 2014; Boden et al., 2013’ Bujarski et al., 2012) usually for sleep (Bonn-Miller et al., 2013, 2014; Metrik et al., 2016) possibly due to cannabinoids sedative and mildly relaxing effects (Conray & Arnedt, 2014). This fact is largely problematic for negative (avoidance) coping has shown to make symptoms of PTSD ‘worse in the long run’ (U.S. Department of Veterans Affairs, 2017).
This coping technique falls under a self-medication theory (SMT) where people use substances to compensate for underlying problems that have not been properly treated (Awad & Voruganti, 2015). This would support the neurological disposition of high CB1r densities and low eCB levels, whereas patients use cannabis to remedy these abnormalities. Self-medicating with marijuana has been described as paradoxical due to its biphasic and individualistic effects on people (Babson et al., 2013). Some think using marijuana to self-medicate and supporting self-medication efforts legitimizes and normalizes illicit drug use to cope with serious emotional problems, but other say users do not necessarily ‘seek euphoria, but rather a relief of dysphoria’ (Khantzian, 2017). Personal coping strategies to manage anxiety measured with the Marijuana to Cope with Social Anxiety Scale (MCSAS) have been related to cannabis-related problems (Buckner et al., 2012) suggesting that treatment
programs should decrease cannabis use within their therapeutic avenues instead of encouraging it.
The SMT reinforces the disease model of addiction (DMA) (Hartney & Gans, 2017) where a change in the brains mesolimbic pathways and associated areas (i.e. the ECS) is part of the etiology of addition. This further complicates comorbidity issues within PTSD. One study showed that greater PTSD symptom severity is associated with greater drug cravings, and that distress from nightmares and hypervigilance predicted greater next-day cravings (Simpson et al., 2012). Additionally, sex differences in cannabis coping reasoning have also documented (Bujarski et al., 2016). Although cannabis being used to cope has been
documented, especially within the PTSD community, the mediating factors and underlying mechanisms are not well understood. It is not known whether the benefits of ‘cannabis coping’ outweigh the risks (Haney & Evins, 2016). Understanding the functional interplay between comorbid substance use, PTSD symptoms, and both the SMT and the DMA would
help to refine treatment decisions and aid future theory building. Generally speaking, CTP does not appear to be an adequate method for PTSD symptom reduction.
Alternatives
Although habitual self-medication could diminish a drugs usefulness and
subsequently turn it into a pharmacological crutch, constructive self-medication with formal or informal introspection could highlight an important ‘well-rounded coping repertoire’ such that temporary use of cannabis and cannabinoids could be classified as a ‘healthy and
balanced coping regimen’ (Elliott et al., 2015). Self-reported cannabis-related coping strategies may additionally be used to prospectively track treatment outcomes; those who report using cannabis to relive stress and improve socialization may show to have better outcomes then those who report using to ‘detach’ (Elliott et al., 2015). Furthermore, self-reported coping strategies, if tracked, can be utilized while creating models of patient intervention.
But in many treatment programs participants are supported to become more aware of their internal resources and acquire skills (over drugs) that can be used to cope more
effectively with stress and PTSD symptoms. These techniques include guided meditation, yoga, stretching, breathing exercises, and various other therapeutic activities (Bremner et al., 2017; Kolk et al., 2014; Shannon & Opila-Lehman, 2016). One study reported “The ultimate goal is to gradually taper [our patient] off the use of CBD oil and transition [her] into lifelong coping strategies” (Shannon & Opila-Lehman, 2016).
Following that studies goal coupled with the proposed temporary effects cannabinoids have at relieving PTSD symptoms, another respectable approach could be to treat
cannabinoid therapeutics similar to other pharmacological-aids where patients are helped and encouraged to eventually discontinue use by reducing their doses in increments. A tapering
schedule would depend on the severity of one’s condition, their reaction to and history with cannabinoids, along with other factors; specific dose reductions over specified intervals should be individualized. Still, due to the addictive properties and potential harms of
cannabis, total cessation and prevention of use instead of quantified temporary treatment may be a more important aim of PTSD therapy. To avoid circumstances that might have harmful effects on patients, and to promote the greatest recover path, more research is drastically needed to compare the effects of tapering cannabinoids and natural phytocannabinoids to that of other administrative routines and full abstinent programs.
Future Considerations
There has been an insufficient amount of evidence supporting the use of cannabinoids for PTSD and little research towards the direct and indirect correlations of trauma-related psychopathology to the ECS. Although the preclinical data suggesting the effectiveness of CTP for anxiety and stress related disorders is ‘intriguing’ (Haney & Evins, 2016) there have not been well-controlled trials towards the effectiveness of cannabinoids for those with PTSD. Additionally, very little is known about the effects cannabis has being used along-side traditional medicines.
Moving forward, along with biphasic dose effects and temporal windows, an additional clarification is needed towards PTSD populations who may differ in operative reactions to ECS treatments. University of Amsterdam cannabis researcher Janna Cousijn speculates that there may be two simplified groups, those who benefit from cannabis and those who do not, and aimed investigations towards these groups would be a constructive step within cannabis research as a whole (Cousijn et al., 2012). There are also specified subgroups within PTSD populations including but not limited to the varying severity of symptomology, the type or condition of the traumatic event, and the length of time one has
been suffering or has gone untreated. Defining these subpopulations of PTSD inflicted individuals and cannabis users should be an aim in the research so future studies can work towards coherence while evaluating clinical outcomes.
Factors such as sex and genetic differences, both of which have shown to effect PTSD and cannabinoid responses (Neumeister et al., 2013; Craft et al., 2013; Lu et al., 2008;
Onaivi, 2009) should also be taken into consideration. Active hormonal systems play a role in the modulation of the ECS in adults, although knowledge about sex differences in
cannabinoid pharmacology remains limited (Craft et al., 2014). Further investigation towards neurobiological and biomedical sex differences in the development and regulation of the ECS will help to guide future treatments of CUD and ECS-based therapies for the sexes and for a multitude of disorders including PTSD (Beery & Zucker, 2011).
Discouragingly, studies with the methodological rigor needed to assess both the safety and efficacy of cannabinoid therapies could prove to be difficult and near impossible to perform. Marihuana/hemp, cannabis resin, marihuana extracts, hemp extracts, and
cannabinoids continue to be classified as Schedule I drugs under the federal U.S. drug policy. Under this law they are legally acknowledged to have a high potential for abuse, no currently accepted medical use, and a lack of accepted safety for use under medical supervision. Without appropriate FDA-approved studies many fear that the massive gap in knowledge surrounding the medical outcomes and side effects of cannabinoids cannot be known. In July of 2017, a nonprofit group called the Cannabis Cultural Association filed a U.S. District Court lawsuit against the DEA and Justice Department stating that having cannabis as a Schedule I drug is "so irrational that it violates the U.S. Constitution” (Pasquariello, 2017) exemplifying the seriousness many have toward research initiatives. Cannabis and its constitutes also remain similarly illegal in almost every other country in the world (Willoughby, 2011), although that legal landscape has recently been changing.
