Monday, September 14, 2009

Great and Desperate Cures for Addiction


《Chinese Journal of Drug Dependence》1999-04

Does anyone know what aerosol bioelectricity is?? And why it might be used to treat heroin addiction? The entire literature seems to be in Chinese. I came across that particular paper while searching for others, specifically reports on ablative psychosurgery1 for the treatment of opiate addiction in China (Gao et al., 2003 is the first in English). Hence, the title of the present post is a reference to the book by Elliot Valenstein, Great and Desperate Cures: The Rise and Decline of Psychosurgery and Other Radical Treatments for Mental Illness.

Are there other "unusual" Chinese treatments for addiction, beyond what might be expected (e.g., acupuncture and traditional medicine)? Tetrodotoxin (TTX), a neurotoxin found in puffer fish, is a worthy runner up to aerosol bioelectricity. TTX inhibits action potentials by blocking voltage-dependent sodium channels. It has been tested as a treatment for severe cancer pain, which motivated Shi and colleagues (2009) to compare low dose TTX to placebo in abstinent addicts. After watching a heroin-related video, the group receiving TTX reported lower levels of craving and anxiety, without alterations in heart rate or blood pressure. However, these acute results were from a single session with no long-term follow up.

Although Chinese treatments for internet addiction are getting all the headlines these days, drug addiction is actually a much more serious problem. In their review of the literature, Tang et al. (2006) inform us that:
Historically, China has had extraordinarily high rates of opiate dependence. These rates declined drastically following the 1949 revolution; however, opiate abuse has re-emerged in the late 1980's and has spread quickly since then. ... The number of registered addicts in 2004 was 1.14 million (more than 75% of them heroin addicts), but the actual number is probably far higher. Opiate abuse contributes substantially to the spread of HIV/AIDS in China, with intravenous drug use the most prevalent route of transmission (51.2%). Currently, the main treatments for opiate dependence in China include short-term detoxification with opiate agonists or non-opiate agents, such as clonidine or lofexidine [alpha-2 adrenergic drugs that inhibit norepinephrine release]; Chinese herbal medicine and traditional non-medication treatments are also used. Methadone maintenance treatment (MMT) has not been officially approved by the Chinese government for widespread implementation, but some pilot studies are currently underway.
Which brings us back to neurosurgery. But before discussing the results of Gao et al., a quick review. In the last post, we learned about a new and less desperate cure, the application of Deep Brain Stimulation for Severe Alcoholism. The target region in this small clinical trial (n=3) was the nucleus accumbens (NAcc), which has been called a "pleasure center" and "hedonic hot spot" that responds to food and pharmaceutical and financial and sexual rewards. The idea behind NAcc DBS was to reduce alcohol craving and "incentive sensitization" in severely impaired patients who had failed multiple treatments (Heinze et al., 2009). The researchers drew upon the experimental and theoretical work of Berridge and colleagues (2009) distinguishing between the "wanting" (incentive salience) and "liking" (hedonic impact) aspects of reward:
Usually a brain ‘likes’ the rewards that it ‘wants’. But sometimes it may just ‘want’ them. Research has established that ‘liking’ and ‘wanting’ rewards are dissociable both psychologically and neurobiologically. By ‘wanting’, we mean incentive salience, a type of incentive motivation that promotes approach toward and consumption of rewards, and which has distinct psychological and neurobiological features.
"Liking" has been strongly linked to endogenous opioid systems in the NAcc and ventral pallidum [part of the globus pallidus] as shown below.2


From Fig. 1 (Berridge et al., 2009). Forebrain hedonic hotspots in nucleus accumbens shell and in ventral pallidum where mu opioid agonist microinjections cause amplification of ‘liking’ reactions to sweetness. Red/yellow indicates greatest amplification of ‘liking’ for the sensory pleasure.

In contrast, "wanting" has been most strongly associated with dopamine in the NAcc, but in reality...
...brain substrates for ‘wanting’ are more widely distributed and more easily activated than substrates for ‘liking’. Neurochemical ‘wanting’ mechanisms are more numerous and diverse in both neurochemical and neuroanatomical domains... In addition to opioid systems, dopamine and dopamine interactions with corticolimbic glutamate and other neurochemical systems activate incentive salience ‘wanting’. Pharmacological manipulations of some of those systems can readily alter ‘wanting’ without changing ‘liking’. For example, suppression of endogenous dopamine neurotransmission reduces ‘wanting’ but not ‘liking’.
Addiction is conceived as a process by which drugs of abuse produce neural sensitization and compulsive "wanting" even in the absence of "liking". With this literature in mind, Gao et al. (2003) wished to:
...explore a new way of treating drug addiction by ablating the NAcc... using stereotactic surgery, blocking the mesocorticolimbic dopamine circuit, alleviating craving for drugs and lowering the relapse rate after detoxification. On the basis of animal experiments, stereotactic surgery was performed in 28 patients by making a lesion in the NAcc bilaterally to treat opiate drug dependence.
I'm not so sure the surgeons were able to isolate the "wanting" from the "liking" regions of the NAcc, since they seem to be anatomically adjacent as shown below.


Fig. 2 (Berridge et al., 2009). Expansion of mu opioid hotspot in nucleus accumbens with delineation of ‘liking’ versus ‘wanting’ zones. Green: the entire medial shell mediates opioid-stimulated increases in ‘wanting’ for food reward. Orange-red: circumscribed cubic-millimeter sized hedonic hotspot generates increases in ‘liking’ after the same opioid stimulation. Blue: a small hedonic ‘coldspot’ suppresses ‘liking’ reactions to sucrose, whereas a larger purple zone suppresses ‘disliking’ reactions to quinine.

Were the surgeries successful? Not so much:
The mean follow-up period was 15 months. Relapse has not occurred in 11 cases up till now. Drug-free time in these patients has been more than half a year in 4 cases (more than a year in 3 cases), and less than half a year in 7 cases. Relapse occurred in 15 cases after surgery. Drug-free time in these patients was more than half a year in 3 cases, between 1 month and half a year in 10 cases and less than 1 month in 2 cases.
Plus there were side effects in some patients: personality changes were seen in 2 and temporary memory loss in 4. Last but not least was the issue of informed consent, which wasn't discussed at all in the paper. Alarmingly, the psychological state of the patients before surgery seems to suggest they lacked capacity to give informed consent:
Analysis of the results showed that the patients’ psychohygienic situation was poor prior to the operation and their personalities were characterized by unstable emotion, being seriously distressed by tonicity and prone to following their own course, running risks and doing everything without considering the consequences, paranoid state, low intelligence level, mental aberration and weak-willedness.
In comparison, the careful screening procedures of Heinze et al. (2009) and the reversible nature of their intervention are vastly superior. Comments on my previous post have ranged from unbridled enthusiasm for DBS 3 (also see Best Before Yesterday) to skepticism ("We still have no idea whether this will this actually work"), with caution and curiosity in between. I suspect the antipsychiatry trolls [the comment is priceless] might come out of the woodwork for this one. In this case, I would agree that criticism is warranted.

Footnotes

1 Wikipedia warns us that "The medical procedure of psychosurgery should not be confused with psychic surgery — surgery purportedly performed by paranormal means."

2 "Liking" has also been associated with endocannabinoid and GABAA-benzodiazepine systems in the brain.

3 For more information on DBS for intractable depression, see The Neurocritic's archival posts:
The Sad Cingulate

Sad Cingulate on 60 Minutes and in Rats

NAcc Localization for DBS
...and two articles by science writer David Dobbs:
A Wiring Diagram in the Brain for Depression

A Depression Switch?

References

Berridge KC, Robinson TE, Aldridge JW. (2009). Dissecting components of reward: 'liking', 'wanting', and learning. Curr Opin Pharmacol. 9:65-73.

ResearchBlogging.org

Gao, G., Wang, X., He, S., Li, W., Wang, Q., Liang, Q., Zhao, Y., Hou, F., Chen, L., & Li, A. (2003). Clinical Study for Alleviating Opiate Drug Psychological Dependence by a Method of Ablating the Nucleus accumbens with Stereotactic Surgery. Stereotactic and Functional Neurosurgery, 81 (1-4), 96-104 DOI: 10.1159/000075111

Heinze, H. et al. (2009). Counteracting incentive sensitization in severe alcohol dependence using deep brain stimulation of the nucleus accumbens: clinical and basic science aspects. Frontiers in Human Neuroscience, 3.

Shi J, Liu TT, Wang X, Epstein DH, Zhao LY, Zhang XL, Lu L. (2009). Tetrodotoxin reduces cue-induced drug craving and anxiety in abstinent heroin addicts. Pharmacol Biochem Behav. 92:603-7.

Tang YL, Zhao D, Zhao C, Cubells JF. (2006). Opiate addiction in China: current situation and treatments. Addiction 101:657-65.

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8 Comments:

At September 15, 2009 8:24 PM, Blogger The Daily Reviewer said...

Hi!

Congratulations! Your readers have submitted and voted for your blog at The Daily Reviewer. We compiled an exclusive list of the Top 100 neuroscience Blogs, and we are glad to let you know that your blog was included! You can see it at http://thedailyreviewer.com/top/neuroscience

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At September 15, 2009 11:19 PM, Anonymous Noah Gray said...

Sorry. I am not bringing as exciting of news as Angelina...

All I wanted to do was complain. If you were going to include my lame-ass quote here, the *least* you could have done was correct it and remove the second "this." I don't need extra help reminding people of my ineptitude.

 
At September 16, 2009 12:02 AM, Blogger The Neurocritic said...

Yay! Are there even 100 neuroscience blogs in existence? Wait... The Daily Reviewer looks remarkably like Alltop.

Noah - I didn't even notice the 2nd "this" when I pasted it in... repetition blindness?

 
At September 17, 2009 8:32 AM, Anonymous Anonymous said...

Does anyone know anything about the rigor of peer-review in China? My impression, from reviewing papers in the field of neuroscience and cognitive neuroscience from China, is that they tend to be pretty bad. Not only the English, that is a different issue. They tend to be poor conceptually and methodologically. If the papers that are sent to Western journals are that bad, I imagine that a lot of the literature in Chinese, published in Chinese journals is probably low quality. Any comments?

 
At September 28, 2009 8:21 PM, Blogger Maia Szalavitz said...

When I first read about the neurosurgery being done to "treat" addiction in China, I immediately emailed the editors of the *Western* journal that published this completely unethical research with nary a comment as to the fact that what the surgery is basically trying to do (or is quite likely to achieve at any rate) is make people *permanently and irreversibly* pleasureless and amotivated.

This is obviously not going to cure addiction-- treatments that block pleasure are already known not to work, for obvious reasons. Addicts are seeking to feel better-- making them feel bad isn't likely to stop them trying.

Given that there are many, many noninvasive treatments that do not carry the risk of death and brain damage and permanent anhedonia, the idea of even trying this on humans is, well, horrifying and inhumane.

Apparently the Chinese stopped, at least according to the Wall Street Journal. But the journal editors never replied-- and to my mind, they should all be ostracized from the scientific community for publishing and legitimizing this human rights violation.

Has anyone else tried to go after the journal?

 
At October 01, 2009 11:35 PM, Blogger The Neurocritic said...

Maia - I found the Guidelines for Authors at the Stereotactic and Functional Neurosurgery journal website and was surprised to see there was NO mandate for describing human subjects protection. By contrast, here are the requirements at NeuroImage:

Ethics:

When human subjects are used, manuscripts must be accompanied by a statement that the experiments were undertaken with the understanding and written consent of each subject, with the approval of the appropriate local ethics committee, and in compliance with national legislation and the Code of Ethical Principles for Medical Research Involving Human Subjects of the World Medical Association (Declaration of Helsinki) [ External link http://www.wma.net/e/policy/b3.htm]...

This is standard for even the most innocuous and non-invasive cognitive psychology experiments. For example Psychological Science sends you to the Wiley-Blackwell site:

4.2 Protecting the rights of research participants/subjects.

It seems mighty strange to me that a neurosurgery journal would not have an explicit policy to protect the rights of patients.

 
At October 02, 2009 5:53 AM, Blogger Maia Szalavitz said...

When I first read the paper, I raised the issue on an addictions discussion list that is frequented by some major people in the field and I also contacted some high level experts whom I know for help-- I can't remember what actions they took, but I'm pretty sure I'm not the only one who tried to contact the editor with concerns.

Fortunately, we soon heard that the research had been discontinued.

But what horrifies me is that anyone could have thought this was in any way a good idea. Why on earth would stopping people from feeling *natural* pleasure or desire cure addiction? How can you justify going into someone's brain when there are effective and non invasive treatments available without that risk?

Sure, methadone isn't perfect-- but it unsurprisingly has a far higher success rate than this nonsense and it carries none of the risk.

Perhaps you can contact the editors or editorial board with more success than I did?

 
At June 28, 2011 3:57 AM, Blogger Jessica Forester said...

After 6 months of offering stem cell therapy in combination with the venous angioplasty liberation procedure, patients of CCSVI Clinic have reported excellent health outcomes. Ms. Kasma Gianopoulos of Athens Greece, who was diagnosed with the Relapsing/Remitting form of MS in 1997 called the combination of treatments a “cure”. “I feel I am completely cured” says Ms. Gianopoulos, “my symptoms have disappeared and I have a recovery of many functions, notably my balance and my muscle strength is all coming (back). Even after six months, I feel like there are good changes happening almost every day. Before, my biggest fear was that the changes wouldn’t (hold). I don’t even worry about having a relapse anymore. I’m looking forward to a normal life with my family. I think I would call that a miracle.”
Other recent MS patients who have had Autologous Stem Cell Transplantation (ASCT), or stem cell therapy have posted videos and comments on YouTube. www.youtube.com/watch?v=jFQr2eqm3Cg.
Dr. Avneesh Gupte, the Neurosurgeon at Noble Hospital performing the procedure has been encouraged by results in Cerebral Palsy patients as well. “We are fortunate to be able to offer the treatment because not every hospital is able to perform these types of transplants. You must have the specialized medical equipment and specially trained doctors and nurses”. With regard to MS patients, “We are cautious, but nevertheless excited by what patients are telling us. Suffice to say that the few patients who have had the therapy through us are noticing recovery of neuro deficits beyond what the venous angioplasty only should account for”.
Dr. Unmesh of Noble continues: “These are early days and certainly all evidence that the combination of liberation and stem cell therapies working together at this point is anecdotal. However I am not aware of other medical facilities in the world that offer the synthesis of both to MS patients on an approved basis and it is indeed a rare opportunity for MS patients to take advantage of a treatment that is quite possibly unique in the world”.
Autologous stem cell transplantation is a procedure by which blood-forming stem cells are removed, and later injected back into the patient. All stem cells are taken from the patient themselves and cultured for later injection. In the case of a bone marrow transplant, the HSC are typically removed from the Pelvis through a large needle that can reach into the bone. The technique is referred to as a bone marrow harvest and is performed under a general anesthesia. The incidence of patients experiencing rejection is rare due to the donor and recipient being the same individual.This remains the only approved method of the SCT therapy.

 

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