Acupuncture therapy for drug addiction

Acupuncture therapy has been used to treat substance abuse. This study aims to review experimental studies examining the effects of acupuncture on addiction. Research and review articles on acupuncture treatment of substance abuse published between January 2000 and September 2014 were searched using the databases ISI Web of Science Core Collection and EBSCO’s MEDLINE Complete. Clinical trial studies on the efficacy of acupuncture therapy for substance abuse were classified according to substance (cocaine, opioid, nicotine, and alcohol), and their treatment protocols, assessments, and findings were examined. A total of 119 studies were identified, of which 85 research articles addressed the efficacy of acupuncture for treating addiction. There were substantial variations in study protocols, particularly regarding treatment duration, frequency of electroacupuncture, duration of stimulation, and choice of acupoints. Contradictory results, intergroup differences, variation in sample sizes, and acupuncture placebo effects made it difficult to evaluate acupuncture effectiveness in drug addiction treatment. This review also identified a lack of rigorous study design, such as control of confounding variables by incorporating sham controls, sufficient sample sizes, reliable assessments, and adequately replicated experiments.


Background
In 1997, the National Institutes of Health accepted acupuncture therapy as an acceptable procedure complementary to Western medicine [1]. Evidence for its therapeutic effects comes mainly from clinical practice and research into pain control, fibromyalgia, headaches, Parkinson's disease, schizophrenia, and depression [2]. Acupuncture therapy can be administered using either manual insertion of needles or electroacupuncture (EA), a mild electrical stimulation of acupoints. Extended acupuncture methods may involve finger pressure (acupressure) and laser therapy [3].
In 1985, Dr. M. Smith finalized the National Acupuncture Detoxification Association (NADA) protocol that is currently practiced in over 250 hospitals in the United Kingdom and United States [4]. In 1996, the World Health Organization accepted acupuncture as a treatment for drug abuse [5]. The latest modification to this treatment protocol was developed in 2005 by Dr. Ji Sheng from Peking University, Beijing, China [6]. Currently, more than 700 addiction treatment centers use acupuncture as an adjunctive procedure [7].
Prominent effects of acupuncture are increases in the levels of enkephalin, epinephrine, endorphin, serotonin, norepinephrine, and dopamine in the central nervous system and plasma [8] that might mediate substance abuse. Acupuncture has been used to treat addiction for three decades . For example, auricular acupuncture (AA) is effective in treating alcohol and drug abuse in both Europe and the United States [4].
However, several clinical trials have indicated that acupuncture was not effective in treating addiction [2,3,31,67,69,[78][79][80]. Thus, the efficacy of the NADA protocol has been reassessed over the last decade [7]. Several factors have been studied to evaluate the efficacy of acupuncture therapy; for example, treatment protocol, choice of acupoints, duration of acupuncture, study design diversity, sample size, addiction history, and assessment techniques.
This study aims to review the published research on acupuncture therapy for substance abuse in relation to study type, authors, funding agencies, countries, agonist substances, and acupoints used for stimulation.
Experimental studies published between January 2000 and September 2014 were systematically reviewed and analyzed to try to resolve the lack of agreement about acupuncture's efficacy for substance abuse.

Literature search
A search of the ISI Web of Science Core Collection and EBSCOHost (MEDLINE Complete) databases for the period January 2000 to September 2014 was conducted to identify acupuncture clinical trials. Keywords, topics available in the databases, and titles were searched for the following terms: "acupuncture, " "electroacupuncture, " "acupoint stimulation, " "transcutaneous, " and "electrostimulation" as single words or combinations (total number of articles: 25 358). The results were refined to exclude non-English language materials. The preliminary findings of the first phase were refined by several parallel filters to identify documents relevant to acupuncture treatment of substance abuse. The operator between the filters was the "OR" command. Single, relevant words were selected for each filter and included any combination of the following: "alcohol, " "addict, " "opioid, " "heroin, " "cigarette, " "nicotine, " "tobacco, " "cocaine, " and "substance" as title, topic, keywords, or abstract text (total number of articles: 230) from both searched databases. The search results were collated and filtered to exclude proceedings papers and letters, yielding 161 studies. The abstracts of these documents were reviewed to exclude papers related to other addiction fields such as the Internet, food, or games; 119 documents comprised the refined, selected results. Three authors (FEM, RR, and TS) independently assessed studies for eligibility and crosschecked the material for study relevance. The publication selection process was shown in Fig. 1.
The articles were classified according to their specifications, including publication date, number of citations, source, authors, organization, and funding agencies. All original research papers were examined for their efficacy and method of treating different categories of addiction to agonist substances (e.g., cocaine, opioid and opiate, nicotine, alcohol, morphine). Original clinical trials that investigated the efficacy of acupuncture therapy were divided into six categories based on substance dependence (cocaine, opioid and opiate, nicotine, alcohol, morphine, and other substances) with a narrative review of their methods and results. Although morphine is an opioid, it has been assigned its own section because of the high number of publications on this topic. Heroin, methadone, and opiates are discussed in the opioid section.
The findings are discussed and compared according to type of addictive substance. There were 96 articles and 29 review papers; 83 articles were original investigations (76 of which were clinical trials of acupuncture efficacy), with 45 articles involving human beings and 38 involving animals. Figure 2 shows the percentage of all documents in each type of category. Original investigations of humans and animals were classified separately according to type of substance dependence. These articles placed more of an investigative emphasis on morphine and alcohol than on other substances.
The total number of citations for all documents was 1495 (mean = 15.83 and standard deviation = 15.27, citation range 2-87 by excluding 29 articles cited zero times or only once). The top ten most cited articles were shown in Table 1 The published articles were associated with various research areas (Fig. 3). About 80 % of the articles focused on neuroscience and neurology, substance abuse, and integrative complementary medicine research areas. Published articles for each year were shown in Fig. 4.
Original experimental research articles were reviewed according to type of substance dependence (Fig. 2); the treatment method, subjects, objectives, and assessments of clinical trials for each group were shown in Tables 2, 3, 4, 5, 6, 7.

Cocaine
Avants and Margolin have evaluated the efficacy of AA for cocaine addiction treatment in four studies on human subjects. Although promising results were reported in their first study on 82 cocaine-dependent subjects [10], another study on 83 cocaine-dependent subjects found AA to be effective in reducing cocaine in only one of two trials [60]. When the original study was repeated with 620 subjects, no effect was found [61]. These researchers also conducted a study in 2005 on 40 cocaine abusers who had tested positive for the human immunodeficiency virus and were under methadone maintenance; no difference was found between the standard and reduced NADA protocols for cocaine use [59].
Three studies on rats were conducted to explore the effects of bilateral stimulation at the Shenmen (HT7) points. Modulation of the central dopaminergic system by acupuncture might be effective in preventing the behavioral effects of cocaine in rats [44]. By regulating neuronal activation in the nucleus accumbens (NAc) shell, acupuncture reduced stress-induced relapse [84]. The effect of acupuncture on the inhibition of cocaineinduced locomotor activity was mediated by A-fiber activation of the ulnar nerve in rats [42]. See Table 2 for study details.

IdenƟficaƟon
Records after combination of results (n = 230) Records screened for exclusion of letters, meetings and conference papers (n = 161) Letters, meetings and conference papers excluded (n=69) Full-text articles assessed for eligibility (n = 119) Full-text articles excluded: abstracts were reviewed to exclude any paper, which was not related to the topic. was a possible adjunctive treatment to pharmacological treatments for heroin detoxification [62]. Acupuncture at Dazhui (GV14) and Baihui (DU20) prevented brain cell apoptosis in heroin-readdicted rats, normalized neuronal ultrastructure in the ventral tegmental area of heroin relapse rats, and protected nerve cells against injury in heroin relapse rats [32,88]. Recent studies of acupuncture's effectiveness as an adjunct therapy in methadone maintenance programs have been controversial. In 2009, Bearn demonstrated a lack of effect for adjunctive methadone maintenance treatment with AA upon withdrawal severity or craving [11]. In 2013, Pei Lin showed a lack of AA effectiveness on the number of daily consumed cigarettes, relapse rate, and withdrawal symptoms, and examined patients' satisfaction and coping with AA as an adjunct treatment to methadone maintenance treatment among Malaysian subjects [57,58]. However, Chan et al. [22] claimed that 2 weeks of acupuncture therapy reduced the daily dose of methadone and was also associated with greater improvement in sleep latency. See Table 3 for study details.

Nicotine
Acupuncture stimulation at Zusanli (ST36) exerted a therapeutic effect on nicotine detoxification [21] and acupuncture at Zusanli (ST36) or Shenmen (HT7) might attenuate anxiety-like behavior following nicotine withdrawal by modulating corticotrophin-releasing factor in the amygdala [20]. Smoking withdrawal symptoms could be ameliorated by acupuncture treatment [18]. In one study, acupuncture at Shenmen (HT7) attenuated  cigarette withdrawal symptoms more than acupuncture at Shousanli (LI10) [19]. Real acupuncture (as opposed to sham acupuncture) at Shenmen (HT7) alleviated cueinduced cravings through the regulation of activity in brain regions (medial prefrontal cortex, premotor cortex, amygdala, hippocampus, and thalamus) related to craving scores in the initial abstinence phase [38].
However, one study failed to find any effect of acupuncture on cotinine serum levels, carbon monoxide exhalation, and smoking quit rate in 59 smokers [83]. It has been suggested that DRD2 gene TaqI A polymorphism was related to AA response in smoking cessation treatment [65]. Auricular transcutaneous electrical neurostimulation relieved withdrawal symptoms and decreased  anxiety and stress levels during the detoxification period in a study of six smokers [15]. Auricular transcutaneous electrostimulation therapy might be an acceptable alternative therapy for smoking cessation [72]. See Table 4 for study details.

Alcohol
Conflicting results from two large randomized singleblind, placebo-controlled trials suggested that acupuncture was not effective in reducing alcohol use [16,39]. However, promising results have been found using acupuncture as an adjunctive treatment to carbamazepine medication to reduce the severity of alcohol withdrawal symptoms [39]. In one study, AA failed to reduce the duration and severity of alcohol withdrawal symptoms [43]; another study found no advantage for laser AA in treating alcohol withdrawal [74]. However, research indicated that laser therapy helps to promote the release of endorphins in the body and decreases discomfort accompanying alcohol withdrawal [87]. It might therefore be a safe and painless beneficial adjunct treatment for alcoholism [87]. Acupuncture at Zusanli (ST36) or Sanyinjiao (SP6) modulated postsynaptic neural activation in the striatum

Table 2 Original investigations of acupuncture therapy effects in cocaine-dependent subjects
Acupoints in NADA protocol are located at (sympathetic: in the deltoid fossa at the junction of the infra-antihelix crus and the medial order of the helix, lung: in the center of the cavum concha, liver: located in the posterior to upper portion of the helix crus, kidney: in the cleft between the upper plateau, and the helix) Zhang [88] To verify the relationship between acupuncture, neurotrophic factor expres-    Acupoints in NADA protocol are located at (sympathetic: in the deltoid fossa at the junction of the infra-antihelix crus and the medial order of the helix, lung: in the center of the cavum concha, liver: located in the posterior to upper portion of the helix crus, kidney: in the cleft between the upper plateau, and the helix) and NAc in rats [89]. Acupuncture at Shenmen (HT7) normalized dopamine release in the mesolimbic system [89], modulated mesolimbic dopamine release, and suppressed the reinforcing effects of ethanol [82]. Activation of the endogenous opiate system might be responsible for Zusanli (ST36) and Sanyinjiao (SP6) stimulation effects on alcohol intake in alcohol-dependent rats [64]. EA applied at Zusanli (ST36) was more effective than EA at Shenshu (BL23) at normalizing alcohol-drinking behavior in rats [86]; the activity of serotonergic neurons in the reward system pathway of the brain might be increased and prolonged by acupuncture [85]. EA at the combination Zusanli (ST36) and Neiguan (PC6) (but not at either point alone) prevented sensitization of the mesocorticolimbic pathway induced by ethanol in mice and modulated both the expression of the protein homer1A and glutamatergic plasticity [28]. EA (2 Hz) at Zusanli (ST36) could reduce voluntary intake of ethanol, but not sucrose, in rats [50] and 100 Hz EA treatment at Zusanli (ST36) effectively reduces preference for ethanol and its consumption in rats [49]. In one study, 2 Hz EA at Zusanli (ST36) and Neiguan (PC6) or 100 Hz EA at Dazhui (DU14) and Baihui (DU20) inhibited CB1R upregulation in ethanol-withdrawn mice [29]. The behavioral effects of 2 Hz EA at Dazhui (DU14) and Baihui (DU20), but not 100 Hz EA at Zusanli (ST36) and Neiguan (PC6), depended on extracellular signal-regulated kinase signaling [30]. See Table 5 for study details.

Morphine
Compared with 100 Hz, 2 Hz peripheral electric stimulation (PES) at Zusanli (ST36) and Sanyinjiao (SP6) inhibited the expression of morphine-induced conditioned place preference (CPP) (see [52] for information on CPP) via activation of opioid receptors [75]. One study found that the release and synthesis of enkephalin in the NAc was accelerated by 2 Hz stimulation of Zusanli (ST36) and Sanyinjiao (SP6) [53]. In addition, EA suppression of opiate addiction might involve the release of endogenous μ-, δ-, and κ-opioid agonists in the NAc shell [52] and might activate the cannabinoid, endogenous opioid, and dopamine systems to induce CPP in rats [81]. PES (100 Hz) at Zusanli (ST36) and Sanyinjiao (SP6) activated the suprasegmental δ-and κ-opioid receptors in the central nervous system, which cause the anticraving effects of PES in rats [70]. It was also found that the expression of preproenkephalin and preprodynorphin mRNAs in the NAc was mediated by 2 Hz or 100 Hz PES, with the release of endogenous μ-, δ-, and κ-opioid agonists to suppress morphine-induced CPP [71]. Stimulation at Zusanli (ST36) and Sanyinjiao (SP6) (100 Hz) for 30 min normalized the activity of ventral tegmental area dopamine neurons [34], downregulated p-cAMP response element binding, and accelerated dynorphin synthesis in the spinal cord [76].
Some research suggests that 2 Hz EA is a potential complementary therapy for improving immune dysfunction in opiate addicts [51] and that 2 Hz or 100 Hz EA facilitates the recovery of male sexual behavior in rats during morphine withdrawal [27]. Thirty minutes of EA of 2 Hz or 100 Hz at Zusanli (ST36) and Sanyinjiao (SP6) reversed the morphological alterations induced by chronic morphine administration [25]. In addition, by increasing NREM sleep, REM sleep, and total sleep time, EA could be a potential treatment for sleep disturbance during morphine withdrawal [48].
EA at Shenshu (BL23) attenuated the expression of the proto-oncogene c-Fos in the central nucleus of the amygdala [54]. Acupuncture at Shenmen (HT7) inhibited neurochemical and behavioral sensitization to morphine by decreasing dopamine release in the NAc [41]. Acupuncture at Shenmen (HT7) significantly suppressed morphine-induced increase in locomotor activity and Fos expression in the NAc and striatum [45]. Acupuncture at Yanggu (SI5) can reduce the reinstatement of morphineseeking behaviors by mediating the gamma-aminobutyric acid receptor system [46,47]. See Table 6 for study details.

Other substances
Studies of methamphetamine, cannabis, illicit/psychoactive drugs, and polydrug users are shown in Table 7. Twelve studies used the NADA 5-point protocol and AA as their treatment method. The findings indicated that people dependent on drugs preferred acupuncture treatment [9], which was associated with a decrease in psychological distress [12] and an increase in confidence [14], but showed no efficacy for drug consumption and withdrawal symptoms [9,[12][13][14]. However, the conflicting nature of the research findings remains a controversial issue. Although there was evidence against the effectiveness of acupuncture in drug addiction treatment [7,35,36], recent studies have shown an effect for AA [23,24,26,68,73] and transcutaneous electric acupoint stimulation [66] per se or as adjunct treatments. Issues of safety and placebo effects suggest the need for further research [26,35,36,66]. See Table 7 for study details.

Conclusion
AA and NADA protocols failed to show a strong therapeutic effect for cocaine, nicotine, and alcohol addiction treatment. However, some studies discussed here Acupoints in NADA protocol are located at (sympathetic: in the deltoid fossa at the junction of the infra-antihelix crus and the medial order of the helix, lung: in the center of the cavum concha, liver: located in the posterior to upper portion of the helix crus, kidney: in the cleft between the upper plateau, and the helix) indicate that acupuncture at Shenmen (HT7), Zusanli (ST36), and Sanyinjiao (SP6) acupoints can affect druginduced physiological activities.