Coming out of a horse sized K-hole: Ketamine's antagonist action at NMDA receptors and impacts of D1 upregulation in dlPFC

One class of addictive drugs called dissociatives include such drugs as dextromethorphan (DXM), phencyclidine (PCP), and ketamine (K). Ketamine, commonly used in both veterinary and human medicine (high dose) as an anesthetic, is also used recreationally (typically in lower, subanesthetic doses), bringing on feelings of derealization, euphoria, dissociation, depersonalization, hallucinations, spiritual mind trips, etc., and is often used at dance events and parties. More specifically, “[k]etamine is a noncompetitive antagonist at the glutamatergic N-methyl-D-aspartate (NMDA) receptor” usually administered by intramuscular injection (IM) (Narendran, R., Frankle, W., Keefe, R., Gil, R., et al., 2005, p. 2352; action at the NMDA receptor as an indirect antagonist - Carlson, 2010, p. 615). Loose translation of the previous is that ketamine interferes with glutamate transmission at the NMDA receptor (not unlike alcohol, that also acts on GABA(A) receptors – Carlson, 2010, p. 631).

Perhaps not surprisingly, ketamine is linked to memory impairments, as the NMDA receptors are involved in long-term potentiation, implicit in learning (Carlson, 2010, p. 447). However, the long term effects of chronic ketamine use remain largely unknown (Narendran, 2005, p. 2352), while commonly thought to include K-pains – due to deterioration of the bladder, cognitive impairments – including memory, and neural network dysfunctions of various sorts (dearborization, etc. – see also common encyclopedic entries, ketamine was first synthesized in 1962 and is easily researched; see also RxList.com or Wikipedia.com).

Interestingly, the study I reviewed attempted to substantiate effects of chronic NMDA antagonist users (of ketamine) on the dorsolateral prefrontal cortex (dlPFC) because of earlier findings from “animal data indicated that the dorsolateral prefrontal cortex dopamine projections were especially vulnerable to repeated NMDA antagonist administration” (Narendran, et al., 2005, p. 2357). The study found that “D1 (dopaminergic) receptor availability was significantly up-regulated [“a compensatory increase in the sensitivity of receptors” (Carlson, 2010, p. 631); here, in correlation with the number of vials used per week] in chronic ketamine users… relative to comparison subjects … [and that] [n]o significant differences were noted in other cortical, limbic, or striatal regions” (Narendran, et al., 2005, p. 2357). While the authors did not, much to their surprise, find any cognitive deficits in users, it was made explicit that the typical user (who was not admitted to the study due to various psychiatric comorbidities, including polysubstance abuse), “even in the absence of cognitive deficits… repeated ketamine exposure… [is] associated with signs of disruptions of a critical component of cognition, the prefrontal dopamine system” (p. 2357).

In sum, the authors found that more research was needed, despite the evidence of neurotoxicity in animal models, as to the toxicity in humans (2005). They clearly stated, however that “the repeated use of ketamine for recreational purposes affects prefrontal dopaminergic transmission, a system critically involved in working memory and executive function [and might damage brain neurotransmission generally]” (p. 2358).

This study is a good one because of the link between exogenous substances, the dlPFC and receptor sites, with such illnesses as schizophrenia. Schizophrenia is characterized by an imbalance in dopamine transmission, especially at the D1 receptors (DA deficit; cognitive impairment) and the D2 receptors (DA excess; psychosis) (p. 2358). The authors provided the following link: “[t]he fact that chronic ketamine users and patients with schizophrenia exhibit the same endophenotypic trait (up-regulated D1 receptor expression in the dorsolateral prefrontal cortex) supports the hypothesis that in schizophrenia, this alteration might be secondary to NMDA dysfunction” (p. 2358). In fact, many researchers have long since established the link between DA agonists like cocaine and amphetamine, that also cause positive symptoms of schizophrenia (hallucinations, delusions, etc.), as well as PCP (angel dust) and ketamine (Special K or Vitamin K), as capable of causing positive, negative (poverty of speech, anhedonia, etc.), and cognitive symptoms (attentional problems, deficits in learning and memory, poor problem solving, etc.) of schizophrenia and therefore study the effects of these drugs with the hope of curing schizophrenia (Carlson, 2010, pp. 557, 567)

While not formally addressed in the article reviewed, is withdrawal from ketamine. I looked up information from a drug treatment center that described both the physiological and psychological processes involved. Since ketamine involves both psychological and physical effects, withdrawal is both a physical and mental process. The person undergoing the process should be kept under close supervision, due to the strength of the psychological addiction. While displacement away from the sources of drugs are a good tactic for the person in withdrawal, along with psychotherapy and behavior modification, another aspect of ketamine withdrawal, which is best addressed in a professional setting, is the physical side of ketamine withdrawal. The user more often than not has neglected their own physical well-being and often needs the help of nutritionists and physicians. (see also http://www.ketamine-effects.com/ketamine-withdrawal.htm)

Prolonged use has been associated with physical and psychological addiction. In the majority of individuals who frequently use ketamine, tolerance does develop to these effects, thus requiring the addicts to consume higher doses.

Although ketamine does not give rise to physical dependence like that seen with morphine, heroin or alcohol, it is associated with a powerful psychological addiction - like that seen with cocaine. Because of its ability to produce intense, vivid psychedelic effects it is frequently abused. The psychedelic effects and out of body experiences have been primary reasons why the drug is abused.

In conclusion, ketamine addiction, like all addiction begins with the acceptance of a problem by the individual. Many drug rehabilitation and treatment facilities are available for ketamine treatment. There are no antidotes to ketamine and the majority of therapy is psychotherapeutic. (see also http://www.addictionsearch.com/treatment_articles/article/ketamine-addiction-abuse-and-withdrawal_23.html)

References

Carlson, N. (2010). Physiology of behavior, (10th ed.). Boston: Allyn & Bacon.

Narendran, R., Frankle, W., Keefe, R., Gil, R., et al. (2005). Altered Prefrontal Dopaminergic Function in Chronic Recreational Ketamine Users. The American Journal of Psychiatry, 162(12), 2352-9. doi: 942933491.

Biopsychologically Informed Treatment of Trauma

Biopsychologically Informed Treatment of Trauma
by
Peter A. Brown, MA


California Institute of Integral Studies
Clinical Psychology
School of Professional Psychology


Biopsychologically Informed Treatment of Trauma

In much of the literature there are ongoing debates surrounding etiology of subcortical abnormalities in Post Traumatic Stress Disorder (PTSD)/trauma, with two prominent hypotheses: the predisposition hypothesis, and the so-called neurotoxicity hypothesis. In my recent paper, I reviewed these two hypotheses and some of the literature in this subfield of biopsychotraumatology and found that both are likely operative (reminiscent of the nature-nurture debate) (Brown, 2009). That said, and with a long-term goal of specialization in neuropsychotraumatology in mind, this paper covers the biopsychologically informed treatment of trauma used in the field today.

The person suffering from PTSD is likely to have a dysfunctional hippocampus that does not distinguish a safe context from a dangerous one, thereby triggering amygdalic-emotional response (see also Carlson, 2010, p. 607). This subcortical process follows the ‘low road’ in amygdalic connectivity parlance, bypassing the (ventro-)medial prefrontal cortex ((v-)mPFC – especially the Anterior Cingulate Cortex – ACC) which is unable to inhibit these triggers (or is itself impaired); the amygdala is highly connected, both ascending to cortical structures like the vmPFC or ACC and descending to other (sub-)pontine structures (including the spinal cord) (Zillmer, Spiers, & Culbertson, 2008, p. 150). Treatment, therefore, would need to address the subcortical, bottom-up processing ‘road’ and not only the top-down, cortical, cognitive ‘road’.

Interestingly enough, the sine qua non of the psychotraumatology specialty is cognitive-behavioral therapy, a high road therapy. Certainly, other treatments, such as pharmacotherapies are viable options, alongside integrative high and low road therapies. In this paper, I review a brief sampling from literatures related to pharmacotherapies and integrative methods, leaving those that focus on cognitive methods to future articles. I think that both pharmacotherapies and integrative therapies are vital to effective treatment, and maintain that biopsychologically informed treatments can help (even if simply to help researchers ask the right questions) to ameliorate efforts in the biopsychotherapeutically oriented treatment programs and research streams currently active today.


Literal wounds to the brain

One current article I reviewed argued for the re-medicalization of the PTSD construct in order to help fight against pathologization and stigmatization of PTSD and victims of trauma Nash, Silva, & Litz, 2009). In fact, the authors pointed out the deliberate decision to stigmatize ‘shell shock’ so as to prevent desertion during the world wars: “stigma was attached to mental health labels intentionally as a deterrent to stress-casualty epidemics” (p. 794). This re-neurologization of the modern research paradigm is revitalizing the work of Pierre Janet, a contemporary of Freud, who dealt with dissociation’s (theoretical) effects on brain function at the beginning of the 20th century (p. 792). In fact, the most recent studies indicate that severe stress can literally injure the brain and calls for this paradigm shift in thinking about traumatic stress (p. 792). While much of the rhetoric of the writing in the field, and of the article reviewed, (discussing etiological mechanisms) dovetails with the CBT literature, interesting conclusions merit attention, especially in the
extinction of fear-based conditioning… mediated by the medial prefrontal cortex, and social cue recognition… mediated by the orbitofrontal cortex, in addition to the hippocampus and amygdala…[and the ACC, a] brain center essential for the inhibition of situationally inappropriate or irrelevant thoughts and emotions, as well as for the situation specific regulation of autonomic arousal, including pulse and blood pressure. (p. 792)

What the authors fail to mention are the treatment modalities toward which they allude: behavioral modification (‘extinction’ etc., along the lines of classical conditioning), socially based therapies (milieu, systems, etc.), and biofeedback oriented psychoeducation (relaxation, mindfulness, guided imagery, hypnosis, etc.). They call for treatments that include remedying “deficits in memory…extinction of fear-based learning, [gaining] authority over one’s own emotions and thoughts, and the regulation of autonomic arousal” (p. 792).

The most valuable contribution of the article was articulation of the position that the suffering and impairment of those who suffer from PTSD, (especially soldiers, sailors, airmen, and marines),
are not due to their own failure or weakness, any more than any other physical wound would be. …this conception can provide a framework for more effective primary and secondary prevention programs in the military and other community settings, as have been adopted recently by the Navy and Marine Corps. By lessening the barriers to early recognition, the stress injury model may also promote more effective and targeted early interventions, such as those based on cognitive-behavioral therapy. (pp. 793-4)


Pharmacotherapeutic Treatment of Trauma

In light of what researchers know of the excitotoxicity of glutamatergic cascades, (as seen in Traumatic Brain Injury, depression, etc.) and along the lines of the excitotoxic hypothesis of PTSD (see also Brown, 2009), combined with the typical high-road focus of CBT oriented research and therapies, the field needs and fortunately uses medications as a growing, primary treatment modality. For example, phenytoin/Dilantin is an anticonvulsant used in epilepsy treatment that seems to modulate glutamatergic transmission, and was recently studied as to the cognitive and neurophysiologic impacts in PTSD patients (Bremner, et al., 2005, p. 159). The authors found that “[p]henytoin treatment resulted in a significant 6% increase in right brain volume … [and] [i]ncreased hippocampal volume was correlated with reductions in symptom severity” (p. 159). The mechanistic postulate is phenytoin antagonizes glutamate excitation and blocks the effect at the NMDA receptor (p. 163). Noting that the right side was ameliorated over the left, the authors called attention to the well-known contribution of the right brain to emotion and non-verbal cognitive processes, over and above that of the left side (p. 163).

The most important aspect of this study was the demonstration that medications used in neuropsychiatric treatments actually had effects on the very physiology of the brain itself (p. 163). This line of research, and that of other pharmacotherapies, such as propranolol (see also Pitman, et al., 2004, pp. 241-2) and paroxetine (one year SSRI treatment yielding a 5% increase in hippocampal volume and a 35% improvement in verbal declarative memory function in PTSD patients; Vermetten as cited in Bremner, et al., 2005, p. 160) are some of the most promising research that I reviewed, considering the biopsychological focus in the treatment of trauma.


Biopsychologically Focused Psychopharmacological Treatment

Another area of vital importance to the traumatology specialty is memory. It is commonly known that the amygdala influences the aroused encoding and consolidation of memory and that the extreme arousal of trauma leads to persistent memory traces (McCleery & Harvey, 2004, p. 487). While traumatically consolidated memories are stubbornly resistant to treatment, “the strength of memory for a learned task can be modified (either weakened or enhanced) by treatments, including drugs and hormones (adrenaline, glucocorticoids, …[though] the longer the gap… [before] treatment, the less effective the modification (McGaugh as cited in McCleery & Harvey, 2004, p. 488). This line of research suggests the modification by hormonal means can act on the activation of adrenergic and muscarinic cholinergic receptors in the basolateral nucleus of the amygdala (BLA), thereby leading to alternative interventions on those areas of the brain involved in traumatic memory (McCleery & Harvey, 2004, p. 488).

Another interesting approach is in the use of centrally acting noradrenergic beta-(receptor antagonists)blockers in order to inhibit the emotional enhancement of memory (p. 488); I think of prazosin/Minipress, a similar drug, though it acts on alpha-1-receptors and is typically used off-label for PTSD related nightmares in both veterans and civilians (Singh, personal communication, 2008; see also Friedman, Davidson, & Stein, 2009, who suggest the aforementioned, as well as alpha-2-receptor agonists like clonidine and guanfacine, p. 564). Contrariwise, yohimbine stimulates noradrenergic enhancement of memory (McCleery & Harvey, 2004, p. 488). Both these are interesting in examining the best course of treatment (considering a conservative approach) matched to the individual and the context – naturally fraught with problems. The undergirding is that when a memory is invoked and made labile, it may be acted upon and before reconsolidation, alteration can occur. In fact, “there is preliminary evidence … that a beta blocker administered soon after a traumatic event may reduce the strength of fear conditioning” (Pitman as cited in McCleery & Harvey, 2004, p. 488). Other methods under investigation include disruption of the conditioned fear response in rats by inhibiting protein synthesis after reactivating the memory (McCleery & Harvey, 2004, p. 489). However, the authors also point out that “[t]here is still little direct evidence for the reconsolidation hypothesis in humans” (p. 489), which naturally limit externalization of these findings.

I find it very interesting that the field seems to contradict itself in many areas, for example, that of the role of arousal in trauma and in trauma treatment:
in a positive psychosocial context … [arousal in response to traumatic events] forms an essential part of the mechanism of adaptation. Initial memories of a traumatic event will inevitably be distressing and, as described above, successful psychological adjustment seems to involve the incorporation of both increased factual detail and more positive interpretations … into declarative memory. This therapeutic processing… will also be promoted by arousal…[and] the success of exposure treatment is greater when there is a higher degree of arousal during treatment …with the possible exception of extremely high levels. The addition to exposure treatment of interventions specifically designed to reduce anxiety/arousal… has not been found to improve outcome. (p. 492)

Many studies note that using a more neurobiological consideration of the role of arousal and how pharmacotherapies might be helpful, for example in drastically reducing arousal states and promoting amnesia after trauma: psychotherapy plus beta blockers to reduce the strength of memories, beta blockers plus exposure therapy, and even administering beta blockers as soon as possible post-trauma (p. 492), similar to the proposed use of propranolol (Pitman, et al., 2004). However, the authors warn that while these drugs may be helpful in preventing overconsolidation of traumatic memory traces, they could also prevent incorporation of safety information, thus preventing timely recovery (McCleery & Harvey, 2004, p. 487). So for people who might even recover well (which it is still very difficult to completely determine propensity for PTSD development, “drug treatments are likely to be of benefit only if targeted very carefully at high risk individuals, whom it may not be possible to identify accurately in the acute phase” (p. 493) might be harmed by hasty use of beta blockers (or propranolol, or benzodiazepines - BZs - that induce anterograde amnesia in the BLA) (p. 488; see also Friedman, Davidson, & Stein, 2009, who maintain that BZs are contraindicated for PTSD monotherapy, p. 566).

In conclusion to the section on pharmacotherapies, due to the fact that trauma survivors need a robust cortisol response in order to contain sympathetic arousal, and that those with highest risk for development of PTSD typically do not show one, it is promising to consider that the use of “stress-level hydrocortisone treatment… was associated with a reduction in PTSD symptoms” (McCleery & Harvey, 2004, p. 493). However, this
preventative strategy…given the continuing uncertainty about the status of the HPA axis in PTSD patients and the fact that acute cortisol administration has been found to enhance emotional memory, this strategy too cannot be regarded as being without risk of harm. (p. 493)

Note that the brain might be damaged due to psychological distress by action of “stress-induced disturbance of the hypothalamic-pituitary-adrenal axis” (Sapolsky as cited in Schmahl, et al., 2009, p. 294), glucocorticoids, and glutamate active in the limbic system (see also Carlson, 2010; Zillmer, et al., 2008), but the exactness of the predispositional versus the neurotoxic etiologies of chronic PTSD is still debated (see also Brown, 2009).


Integrative Treatment Approach: EMDR

So, because of the difficulties in targeting those at risk for development of PTSD in the acute phase (and even the risk of harming them) with pharmacologic intervention, and that “[t]op-down approaches… do not process the episodic memories or resolve physiological hyperarousal” (Solomon & Heide, 2005, p. 56), what is the best treatment approach?

It is clear that people will, even after years of therapy, come into contact with events that ‘trigger’ them physiologically, and that their response is not of a logical, top-down, high-road, cortical nature, especially of the sort that therapies like CBT target (p. 56). In contrast,
[b]iologically informed therapy focuses on processing …[e]pisodic memories [that] are … transferred from the limbic system to the neocortex and filed away along with other narrative memories. Biologically informed therapy includes bottom-up processing, which focuses on what is going on in the body. This approach helps clients connect with their bodies and with their feelings. It facilitates their learning to tolerate intense feelings and to release emotion appropriately. Survivors learn to calm their physiology. (p. 57)

Eye Movement Desensitization and Reprocessing (EMDR) therapy involves visual, tactile, and auditory (even proprioceptive) stimuli that alternately stimulate the left and right hemispheres (p. 58). Some say “repetitive redirecting of attention [especially through eye movement] in EMDR induces a REM sleep-like state… that facilitates the activation of episodic memories…[which] are processed and integrated into neural networks in the neocortex as semantic (narrative) memory” (p. 58). This therapy is proving to increase
bilateral activity in the…[ACC, a] part of the brain that modulates the limbic system and helps us distinguish real from perceived (but not real) threat. The increase …[in ACC] activity suggests a decrease in hypervigilance… [there was also an] increase in prefrontal lobe metabolism, suggesting greater ability to make sense of incoming sensory stimulation. (p. 58)


Conclusions

It is clear that both high road and low road therapies must work together, alongside those underpinning hypotheses (neurotoxic v. predisposition) in order to develop innovative applications in prevention and treatment of PTSD and base them on biopsychological bases. Perhaps in a foreshadowing of what is still yet to come, Sapolsky (2002) suggests that, should the neurotoxicity hypothesis stand, the field needs to develop a kind of post-traumatic golden hour of response along with antidote to the cascade of glucocorticoids and glutamate in the brain (p. 1113; not unlike the propranolol preventative treatments - Pitman, et al., 2004, pp. 241-2).

As I mentioned elsewhere, single case findings from researchers treating PTSD patients with EMDR for 90 minutes per week for 8 weeks, show that this therapy increased total baseline hippocampal volume by some 11% (Letizia, 2007, pp. 475-6). I imagine that through ongoing studies such as these, in combination with various other methods of treatment, will give the field more questions to consider to the age-old human problem of suffering and its alleviation. The integrative application of biopsychology is indeed a powerful force in this change.


References

Bremner, J., Mletzko, T., Welter, S., Quinn, S., Williams, C., Brummer, M., … Nemeroff, C. (2005). Effects of phenytoin on memory, cognition and brain structure in post-traumatic stress disorder: A pilot study. Journal of Psychopharmacology, 19(2), 159-165. doi:10.1177/0269881105048996

Brown, P. (2009, November 14). Traumatic predisposition or neurotoxicity: Examining hippocampal volume and PTSD. [Web log post]. Retrieved from http://peterallenbrown.blogspot.com/2009/11/traumatic-predisposition-or.html

Carlson, N. (2010). Physiology of behavior, (10th ed.). Boston: Allyn & Bacon.

Friedman, M., Davidson, J., & Stein, D. (2009). Psychopharmacotherapy for adults. In E. Foa, T. Keane, M. Friedman & J. Cohen (Eds.), Effective treatments for PTSD: Practice guidelines from the international society for traumatic stress studies (2nd ed.). (pp. 269-278). New York, NY, US: Guilford Press.

Letizia, B., Andrea, F., & Paolo, C. (2007). Neuroanatomical changes after eye movement desensitization and reprocessing (EMDR) treatment in posttraumatic stress disorder. The Journal of Neuropsychiatry and Clinical Neurosciences, 19(4), 475-476. doi:10.1176/appi.neuropsych.19.4.475

McCleery, J., & Harvey, A. (2004). Integration of psychological and biological approaches to trauma memory: Implications for pharmacological prevention of PTSD. Journal of Traumatic Stress, 17(6), 485-496. doi:10.1007/s10960-004-5797-5

Nash, W., Silva, C., & Litz, B. (2009). The historic origins of military and veteran mental health stigma and the stress injury model as a means to reduce it. Psychiatric Annals, 39(8), 789-794. doi:10.3928/00485713-20090728-05

Pitman, R., Sanders, K., Zusman, R., Healy, A., Cheema, F., Lasko, N. … Orr, S. (2004). Pilot study of secondary prevention of posttraumatic stress disorder with propranolol. Curr Psychiatry Rep., 6(4), 241-2.

Sapolsky, R. (2002). Chicken, eggs and hippocampal atrophy. Nature Neuroscience, 5(11), 1111-1113. doi:10.1038/nn1102-1111

Schmahl, C., Berne, K., Krause, A., Kleindienst, N., Valerius, G., Vermetten, E., & Bohus, M. (2009). Hippocampus and amygdala volumes in patients with borderline personality disorder with or without posttraumatic stress disorder. Journal of Psychiatry & Neuroscience, 34(4), 289-295.

Solomon, E., & Heide, K. (2005). The biology of trauma: Implications for treatment. Journal of Interpersonal Violence. Special 20th Anniversary Issue, 20(1), 51-60. doi:10.1177/0886260504268119

Zillmer, E., Spiers, M., & Culbertson, W. (2008). Principles of neuropsychology, (2nd ed.). Belmont, CA: Thomson Wadsworth.

The Synaptic Button and Drug Action

The synapse of the terminal button, both pre- and post-synaptically (that is, from transmitting to receiving button) are also effected by a mechanism called hyperpolarization of the dendritic autoreceptors where they are activated by neurotransmitter or antagonist drug action (that binds to and blocks the receptors) thereby reducing the rate of firing of the neuron, effectively acting as an antagonist (Carlson, 2010, p. 113). Certainly, drugs that block the autoreceptors antagonistically, reduce the effect of hyperpolarization (which is regulatory by nature) and thereby work as agonists (reducing this regulatory effect) (p. 113).

Drugs can affect synaptic transmission in a variety of ways. Carlson (2010) mentions at least 11 ways, ranging from drugs serving as precursor agonists (like L-Dopa on dopamine), inhibits synthesis of neurotransmitter antagonist (like PCPA on serotonin), prevents storage of neurotransmitter in vesicles as antagonist (reserpine on monoamines), stimulates release of neurotransmitter as agonist (spider venom on acetylcholine-ACh), inhibits release of neurotransmitter as antagonist (toxin on ACh), stimulates postsynaptic receptors as agonists (nicotine and muscarine on ACh), and naturally several others like blocks as antagonists, blocks or stimulates autoreceptors, blocks reuptake as agonists, or inactivates as agonists that which is transmitted synaptically. Certainly, the two basic forms of these are agonists and antagonists (drugs that are facilitating versus inhibiting postsynaptic effects) (p. 111).

Drug reactivity in tolerance and sensitization are both similar and different (compensatory mechanisms v. direction of effect). Drug reactions are similar in these two phenomena because drugs follow a dose-response curve that reciprocates larger drug effects with increase doses, up to a maximum effect, where dose increases no longer produce drug reactivity, and increase prevalence of side effects and risk (p. 107). Drug effects that diminish with repeated dosage are called tolerance; and effects that increase are called sensitization (p. 108). Drug tolerance effects are the bane of illicit drug users (think heroine), in that the brain works to maintain optimal levels of functioning at all times and with repeated (and increasing) doses of exogenous substances, the brain produces opposite reactions to compensate (hence the opposite withdrawal symptoms upon substance stop) (p. 109). Further, the sites where the substances bind become less sensitive to the drug as it is used more frequently and the receptors actually decrease in number, also knows as a compensatory mechanism (similar to the decrease in effectiveness of coupling, another compensatory mechanism) (p. 109). In contrast to tolerance mechanisms, sensitization is more rare (p. 109). Because sensitization causes ever-larger drug effects, compensatory mechanisms direct regulatory efforts away from physiologic processes, as in respiratory depressive effects of barbiturates or opiates that show sensitization (especially in combination) versus their euphoric and/or analgesic properties that show tolerance effects (p. 109).


References
Carlson, N. (2010). Physiology of behavior, (10th ed.). Boston: Allyn & Bacon.