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This piece was originally published by Small Wars Journal. Any errors and opinions are not those of the Department of Defense and are attributable solely to the author. Perhaps nowhere in the world has a country and the international community faced an illicit drug economy as deeply entrenched as in Afghanistan. In , opium poppy was cultivated on some , hectares in Afghanistan, one of the highest levels of cultivation in the country. But neither opium poppy cultivation nor heroin production was only a post phenomenon in Afghanistan; each was robust and steadily expanding during the Taliban era. In the post-Taliban era decreases in poppy cultivation and opiate production 3 that periodically took place over the previous two decades have largely been the result of the saturation of global and local drug markets, poppy crop disease, inauspicious weather such as drought, or temporary coercive measures in certain parts of Afghanistan that could not be sustained economically or politically, and rapidly broke down. Several structural factors determined the shape of the Afghan poppy economy during this period: insecurity, political power arrangements, and a lack of ready economic alternatives. After toppling the Ashraf Ghani government in August of this year, the Taliban has announced its intention 4 to rid Afghanistan of drugs. Taliban interlocutors stated that same objective in conversations with me in winter Yet implementing and maintaining any kind of poppy ban will be wickedly difficult for the Taliban. The Taliban regime could ram through temporary poppy bans, but it will struggle to maintain the bans even more than it had to three decades ago. In fact, any effort to maintain them could critically internally destabilize the Taliban. But unlike in the s, it is a new drug world out there—replete with synthetic opioids. In the s, the Taliban did not originally exploit the drug economy out of a need for financial profits, nor did it need the drug profits to expand its military capabilities and intensify the conflict. When the movement first emerged in Kandahar in and started expanding in southern Afghanistan, its financial resources and operational capacities, such as weapons, came from other sources—namely, external sponsors, such as Pakistan and Saudi Arabia, and from the successful exploitation of the illicit traffic with legal goods with undeclared legal goods under the Afghan Transit Trade Agreement ATTA. It was the need to consolidate its political power once its military expansion had taken place that drove the Taliban to embrace the drug economy. By October the Taliban fielded at least 25, men and was armed with tanks, armored vehicles, helicopters, and fighter aircraft. Under the Afghan Transit Trade Agreement, negotiated in the s, landlocked Afghanistan secured a deal from Islamabad that allowed goods to pass from the port of Karachi through Pakistan and over the border to Afghanistan duty-free. Yet, the subsequent U-turn scheme that emerged benefited the smugglers above all and worked like this: a buyer in Afghanistan issued a letter of credit to import some goods, say refrigerators, through the port of Karachi. The appliances were then driven through Pakistan into Afghanistan duty-free. The trucks unloaded their cargo on the Afghan side and returned to Pakistan empty. Meanwhile, the tax-free goods were carried back to Pakistan illegally, for example, by camels and donkeys. The goods, which sold for far less than the goods imported into Afghanistan legally, were then distributed via a trucking industry to a large extent controlled by Afghan refugees in Pakistan. The growing chaos of the early s and the increasingly higher and higher tolls and taxes charged by the local warlords severely threatened the interests of the transport mafia. On any route a transport could have been stopped as many as twenty times and forced to pay tolls, and occasionally the local warlords even robbed the transported goods. Although, purported to be long incensed with the excesses of the predatory warlords on the highways and by their arbitrary taxation and extortion, the Taliban provided protection to the smuggling enterprise. The Taliban set up a one-toll system for trucks entering Afghanistan at Spin Boldak, patrolled the highway against other warlords, and, crucially, declared that the Taliban would not allow goods bound for Afghanistan to be carried out by Pakistani trucks, thus satisfying a key demand of the Afghan transport mafia. Compared to the greedy and unpredictable local powerbrokers who had controlled and taxed the trafficking routes prior to the Taliban, the Taliban significantly lowered many transaction costs for the traffickers, preventing constant power shifts and bringing stability to the industry and helping to streamline it. When in late and early the Taliban moved out of Kandahar west to the Helmand Valley, the main poppy growing region in Afghanistan at the time, it banned the drug trade. The emergence of the Taliban on the political and military scene in the poppy growing regions halved the acreage allocated for poppy for the following growing season, a trend that farmers attributed to the fear of reprisals from the Taliban. But wheat prices were also booming that year and there was a significant carry-over of raw opium from the bumper opium harvest in By , the Taliban adopted a laissez-faire approach to drug cultivation, that progressively evolved into taxing the farmers as well as providing security for and taxing the traffickers. The consumption of opiates is forbidden, as is the manufacture of heroin, but the production and trading in opium is not forbidden. Thus, poppy cultivation continued increasing throughout the s. In , the total production of opium in Afghanistan consisted of metric tons. By , it had climbed to 1, metric tons in , by to 3, metric tons in and 4, in Not only was this livelihood fairly lucrative, it was frequently the only source of livelihood available to the population in an otherwise devastated economy. All economic activity, short of subsistence production and the microeconomic spillover from illicit activities came to a halt. Moreover, as in the case of illicit smuggling of legal goods, the illicit narcotics economy also allowed other forms of microeconomic activity to develop in areas where there was previously only limited agricultural production. Services, such as rest stops, teashops, and fuel stations sprung up in connection with the smuggling of narcotics. But unlike the smuggling of legal goods under ATTA, the illicit narcotics economy, being highly labor intensive, also provided a reliable, and frequently sole source of livelihood to the vast segments of the rural population. The Taliban have brought us security so we can grow our poppy in peace. I need to grow poppy crop to support my 14 family members. We cannot push the people to grow wheat as there would be an uprising against the Taliban if we forced them to stop poppy cultivation. So we grow opium and get our wheat from Pakistan. Yet in late , the Taliban did issue a ban on poppy cultivation that resulted in the largest reduction of opium poppy cultivation in a country in any single year. Cultivation fell from an estimated 82, hectares in to less than 8, in Unable to repay their debts, others were driven to borrow even further or abscond into Pakistan. While banning opium cultivation in , the Taliban did not ban or otherwise interfere with the sale and trafficking of opium and poppy during that period. In choosing to curb the production, the Taliban risked its domestic political capital, based crucially on its sponsorship of the poppy economy, in the hope of obtaining international legitimacy. Through the ban, the Taliban might have also sought to boost the price of opium and consolidate its control over the heroin trade. As cultivation exploded during the s, the farmgate prices for opium plummeted. Vanda Felbab-Brown Bruce Riedel. Moreover, the ban was not sustainable. By the summer of , with the ban still in place, some farmers started seeding poppy once again. In fact, in , after the United States toppled the Taliban regime and Hamid Karzai became the new president, farmers in southern Afghanistan complained that Karzai had promised to let them grow poppy in exchange for their help in toppling the Taliban regime, and that they now felt betrayed. In short, the popular myth that if the Taliban remained in power the drug economy would not have emerged and expanded in Afghanistan is incorrect. The political costs of destroying the sole source of livelihood for large segments of the population were too great even for the Taliban to ignore, and it became a willing sponsor of the drug economy. Poppy is deeply entwined in the socio-economic fabric of the country, and hence, inescapably, in its political arrangements and power relations. The Taliban has been profiting from the drug trade, as were various criminal gangs sometimes connected to the government , the Afghan police, various militias, tribal elites, and many ex-warlords-cum-government officials at various levels of the Afghan government. Sometimes the involved individuals and groups, including of those nominally on the opposite sides of the violent conflict, strongly overlap, and multiple intersections and connections exist among them. During the past 20 years, police units, often highly abusive and criminalized, taxed the drug economy. Local commanders and powerbrokers equally taxed it as well as owned or sponsored poppy fields. They also rented land to poppy farmers and provided microcredit for cultivation. Border officials, such as at Kabul airport or at the Spin Boldak or Zaranj crossings, let trafficking pass for a cut of drug profits. With its widespread territorial influence and reach throughout the country, the Taliban has taxed cultivation, processing, and smuggling of drugs; and units and members of the Taliban have been deeply involved in all these elements. In various years, the Taliban allowed its fighters to disengage from fighting in order to collect the drug harvest. The Taliban also collects taxes from independent drug traders and various criminal groups, while suppressing others. Over the past twenty years, the Taliban has been able to obtain tens to hundreds of millions of dollars from the Afghan poppy economy per year. In contrast, the attitude of the Islamic State in Khorasan toward the drug economy has been varied. Its western branch in Herat, now largely moribund, was deeply implicated in the drug trade. Its eastern branch in Nangarhar, surprisingly, sought to suppress opium poppy cultivation there, despite the highly negative economic impact on local populations. Unfortunately, many of the counternarcotics policies adopted during most of the s not only failed to reduce the size and scope of the illicit economy in Afghanistan, but also had serious counterproductive effects on the other objectives of peace, state-building, and economic reconstruction. The initial objective of the US intervention in was to degrade al Qaeda capabilities and institute a regime change in Afghanistan. Dealing with the illicit economy was not considered to be integral with the military objectives. Thus until , US counternarcotics policy in Afghanistan was essentially laissez-faire. The US military understood that it would not be able to obtain intelligence on the Taliban and al Qaeda if it tried to eradicate poppy. Meanwhile, it relied on key warlords who were often deeply involved in the drug economy since the s, not simply to provide intelligence on the Taliban, but also to carry out direct military operations against the Taliban and al Qaeda. By , increased interdiction was undertaken instead. Its goal was to target large traffickers and processing laboratories. Immediately, however, the effort was manipulated by local Afghan strongmen to eliminate drug competition and ethnic, tribal, and other political rivals. Instead of targeting top echelons of the drug economy, many of whom had considerable political clout, interdiction operations were largely conducted against small vulnerable traders who could neither sufficiently bribe nor adequately intimidate the interdiction teams and their supervisors within the Afghan government. The result was a significant vertical integration of the drug industry in Afghanistan. The other—again undesirable—effect of how interdiction was carried out was that it allowed the Taliban to integrate itself back into the Afghan drug trade. Having recouped in Pakistan, the Taliban was once again needed to provide protection to traffickers targeted by interdiction. Alarmed by the spread of opium poppy cultivation, some public officials in the United States in and also started calling for a strong poppy eradication campaign, including aerial spraying. Immediately, the scheme generated violent strikes and social protests against it. Another wave of eradication took place in when reduction in poppy cultivation was achieved. Most of the reduction was due to cultivation suppression in Nangarhar province where, through promises of alternative development and threats of imprisonment, production was slashed by 90 percent. However, alternative livelihoods never materialized for many. The Cash-for-Work programs reached only a small percentage of the population, mainly those living close to cities. The overall pauperization of the population there was devastating. In Pakistan, the refugees frequently have ended up in the radical Deobandi madrasas and have begun refilling the ranks of the Taliban. Apart from incorporating the displaced farmers into their ranks, the Taliban also began to protect the opium fields of the farmers, in addition to protecting the drug traffic. In fact, the antagonized poppy farmers came to constitute a strong and key base of support for the Taliban, denying intelligence to ISAF and providing it to the Taliban. In a courageous break with a previous counterproductive policy, the US administration of President Barack Obama wisely decided in to scale back poppy eradication in Afghanistan, but it struggled to implement its new strategy effectively. Rural development policies similarly failed to address the structural drivers of poppy cultivation and many were not sustainable. Indeed, no supply side suppression measures—whether eradication, interdiction, or alternative livelihoods—have ever been effective and lasting anywhere in the world in the context of an on-going war. Peace and security and extensive government presence are inescapable preconditions for successful supply reduction measures. Under conditions of intense and growing insecurity, demand reduction measures in Afghanistan, such as treatment and prevention, have for years been the most promising and highly beneficial venue for drug policy interventions. Yet they were never adequately funded or prioritized either by international donors or the Afghan government. Delivering on its stated promise to rid Afghanistan of poppy will be extremely difficult for the Taliban. The Taliban cannot simply double its poppy economy—the global market being already saturated with opioids, including synthetic ones. Maintaining any such ban would require extensive and lasting repression. Beyond immiserating already desperately poor people hit by COVID, drought, and large economic contractions in a country where 90 percent of people live in poverty and at least 12 million in condition of malnutrition, such a ban would also eliminate income and employment for its middle-layer commanders and rank-and-file fighters. But the challenge of maintaining cohesiveness across its many different groups and factions having varied ideological intensity and materials interests is very different in war than it is now that the Taliban is in power. The various factions have highly disparate views about how the new regime should rule across just about all dimensions of governance: from inclusiveness, to dealing with foreign fighters, to the economy, to external relations. Many of the middle-level battlefield commanders—younger, more plugged into global jihadi networks, and without the same personal experience of the Taliban mismanaging its s rule—are more hardline than some older top Taliban leaders and shadow governors. To survive as a regime, the Taliban will not only need to bridge and manage their different views on ruling but it will also have to assure that key commanders and their rank-and-file soldiers retain enough income not to be tempted to defect. A poppy ban would significantly constrain the pool of resources to keep the various Taliban elements happy. It yet remains to be seen whether the Taliban top or local leadership will get greedy and renege on those promises, seeking instead to displace non-Taliban political and criminal structures from the drug trade and other local economies. A Taliban move to exclude others from local rents would be a replay of the behavior of anti-Taliban warlords after , but it would once again generate new sources of frictions amidst a tanking Afghan economy and potential bases of armed opposition. Even without a ban, the Taliban will struggle to find jobs for the many now unemployed soldiers of the Afghan security forces whom the United States paid. Even if half of the nominal force were ghost soldiers or are dead, and say only , soldiers actually fought, they are now a loose force without income for themselves and their families. They melted before the Taliban, but in time may resort to banditry or be tempted to join old or new militias, even if only to get economic rents. Those interests trump for those countries any economic opportunities Afghanistan offers. And with the exception of China and the Gulf countries, their aid pockets are shallow. What those complexities likely means is that the Taliban will likely repeat some of the script of its s policy playbook. Until then, the Taliban will likely argue it cannot starve the Afghan people by implementing a ban. And if and when the Taliban decides to risk the political—and potentially armed—backlash to enforcing a ban, it will struggle to sustain it. Even if the Taliban were able to maintain adequate security, and international donors did agree to deliver alternative livelihoods aid, it would take decades of extremely auspicious policies and circumstances for rural development to effectively compensate for poppy suppression. Moreover, unlike in Myanmar where the various ethno-nationalist groups compensated income losses due to poppy eradication by expanding methamphetamine 55 production, the Taliban cannot easily do so. The existing meth production 56 in Afghanistan is nowhere as established as the one in Myanmar which dominates East Asia and Australian markets, while Europe is supplied from United States out of robust production in Mexico. The only places where a market for Afghan meth could expand significantly are Africa and the Middle East where meth consumption is still relatively small. But a lot of other drugs, such as tramadol and captagon, dominate in those areas. Moreover, if meth use did start taking off there Chinese and Myanmar-based meth producers could also seek to expand their operations there and thus compete with either meth—or heroin—produced in Afghanistan. And the 21 st drug century is fundamentally different from the s: it abounds with cheap and potent synthetic opioids. Thus, even after it rescinded a ban, it may not be able to recover its financial losses or restore employment to oppressed and impoverished Afghans, restive militias and powerbrokers, and its own disaffected factions. Vanda Felbab-Brown, Scott R. Anderson, Doyle Hodges. Foreign Policy. Initiative on Nonstate Armed Actors. Pipe dreams: The Taliban and drugs from the s into its new regime. Sections Sections. Sign Up. Commentary Pipe dreams: The Taliban and drugs from the s into its new regime. Vanda Felbab-Brown. Related Books Aspiration and Ambivalence. Anderson, Doyle Hodges September 3, Will the Taliban regime survive? Afghanistan Will the Taliban regime survive? Vanda Felbab-Brown August 31, Why the Taliban won, and what Washington can do about it now. New Haven: Yale University Press: , p. Balfour at note 6. Michael Griffin, Reaping the Whirlwind. London: Pluto Press: , p. Ibid, p. Geopolitical Drug Dispatch, No. Rashid, Taliban at Note 7, p. Quoted in Griffin at Note 10, p. December ; and Barnett R. The peasants growing poppy make only very small profits from the drug industry, compared to the traffickers and those who profit from the drug industry higher up the chain. A case study of the opium economy in North East Afghanistan. Quoted in Rashid, Taliban at Note 7, p. May Kenneth J. January , p. Caryl at Note 25, p. Indira R. Experience in Afghanistan. Weighs Role in Heroin War in Afghanistan. See John F. See Pain, Op. Opium Trading Systems at Note See David Mansfield, Pariah or Poverty? For details, see, Op. Felbab-Brown, Shooting Up at Note 2, pp. Cambridge: Cambridge University Press, London School of Economics and Political Science. Taliban vow to ban heroin, but can they survive without it? Vanda Felbab-Brown, Jonathan P. More On. The rising threat of synthetic opioids in Europe. US-Mexico relations and the fight against fentanyl trafficking.

Pipe dreams: The Taliban and drugs from the 1990s into its new regime

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Official websites use. Share sensitive information only on official, secure websites. E-mail: tmclee hku. E-mail: hrmaskf hku. Heroin abuse and natural aging exert common influences on immunological cell functioning. This observation led to a recent and untested idea that aging may be accelerated in abusers of heroin. We examined this claim by testing whether heroin use is associated with premature aging at both cellular and brain system levels. These measures included peripheral blood telomerase activity, which reflects cellular aging, and both structural and functional measures of brain magnetic resonance imaging. We found that heroin users were characterized by significantly low telomerase activity 0. To our knowledge, this study is the first to attempt a direct integration of peripheral molecular, brain system and behavioral measures in the context of substance abuse. The present finding that heroin abuse is associated with accelerated aging at both cellular and brain system levels is novel and forms a unique contribution to our knowledge in how the biological processes of drug abusers may be disrupted. Keywords: addiction, aging, heroin, MRI, prefrontal cortex, resting state, telomerase. Heroin abuse is crippling to both society and individual abusers. One of the many adverse effects of heroin on individuals' biopsychosocial functioning is in immunological cell functioning. To compensate for this telomere shortening, the enzyme telomerase is recruited to elongate telomeres in order to prevent cell senescence and apoptosis. Whether substance abuse, specifically heroin abuse, impacts telomerase activity remains an unexplored question. Another outstanding question that remains to be explored is whether heroin abuse accelerates aging at the brain system level. It is well documented that the prefrontal cortex PFC and medial temporal lobe MTL are the two brain areas most implicated in the aging process. Abnormality in the brains of heroin abusers likely mediates deficits in various cognitive domains such as decision making, 35 impulse control 36 , 37 and memory. However, it remains untested whether and to what extent aging and heroin abuse interact to impact similar brain systems. To this end, the present study sought to investigate the impact that heroin abuse may have on telomerase activity and MRI brain measures, which included both structural volumetric and functional resting-state connectivity indices. Specifically, we examined group differences heroin users vs healthy controls in telomerase activity and tested for group-by-telomerase activity interactions in both structural and functional measures of the brain. It was hypothesized that: 1 heroin users would show a deficiency in telomerase activity as measured from peripheral blood; 2 there are interactions between telomerase activity and heroin abuse at the brain system level; and 3 such interactions would occur in brain areas implicated in aging, namely the PFC and the MTL. Participants included in this study were 33 abstinent heroin users and 30 healthy controls without a history of substance abuse. All were males and right-handed. Heroin users were recruited from two male drug rehabilitation centers. In order to avoid medication effects, only heroin users who were not receiving replacement treatment, such as methadone maintenance therapy, were included in this study. All drug users in this study were diagnosed with heroin abuse or dependence based on structured clinical interviews. The healthy controls were recruited through advertisement in the local communities. Exclusion criteria for both the heroin users and the controls were history of neurological disorder, psychiatric disorder other than substance-related disorder, contraindication for MRI scanning and history of substance use for the control group. All participants completed the Raven's Progressive Matrices 40 to ensure matching between the heroin users and the healthy controls on intelligence. Peripheral blood was collected in EDTA containing tubes. Telomerase activity was measured according to the telomeric repeat amplification protocol, in line with some previous studies. The centrifuged lysates were added into the reaction buffer to allow the addition of telomeric repeats TTAGGG to the biotin-labeled primers by the telomerase in the samples. Then the elongated products were amplified by PCR. After PCR, an aliquot of the PCR product was denatured and hybridized to a digoxigenin-labeled, telomeric repeat-specific detection probe. The resulting product was immobilized to a streptavidin-coated microplate. The detection probe and the hybridization conditions have been optimized for obtaining the highest specificity and sensitivity. The immobilized PCR product was then detected with an antibody against digoxigenin anti-digoxigenin-POD that is conjugated to peroxidase. Finally, the probe was visualized by virtue of peroxidase metabolizing tetramethylbenzidine to form a colored reaction product. Specifically, each image was reoriented to match that of the template by manually locating the anterior commissure as the point of origin. The East Asian template was used for affine registration. Thorough cleanup was used to optimize the removal of non-brain tissues. The images were segmented into three tissue types: gray matter GM , white matter WM and cerebrospinal fluid. High-dimensional DARTEL 45 was used for spatial normalization, as it is an optimal approach for whole-brain alignment and particularly sensitive for examining small brain structures, including deep brain nuclei. Normalized, unsegmented images were visually inspected for gross artifacts resulting from normalization. In addition, to identify potential outliers, covariance for both normalized GM and WM segments were checked for sample homogeneity. Finally, both the GM and WM segments were smoothed with an 8-mm full-width half-maximum Gaussian kernel. Analysis of GM and WM segments were carried out independently. To characterize group differences in the association between brain structure and telomerase activity, whole-brain interaction analyses were carried out. The factor of group was tested for its interaction with telomerase activity. This aimed to establish the direction of each significant interaction effect. The statistical analyses were carried out with years of education and HADS scores as covariates. The resulting analyses, therefore, revealed effects between groups that were matched in sex, age, body mass index and estimated intelligence quotient, and adjusted for education and affective status. For each participant, the first 10 volumes were discarded to avoid interference stemming from instable signals and inability of participants to adapt during the initial stage of scanning. The preserved images were first corrected for the acquisition time difference among multiple slices within an image and spatially realigned to the first volume in the whole session for participant's head motion. Normalized images were spatially smoothed with a 6-mm full-width half-maximum Gaussian kernel. Then, using the REST toolkit, images were band-pass filtered at 0. Nuisance variables included six head motion parameters and mean signals of the whole brain that is, global trend , WM and cerebrospinal fluid. For each subject, the neural activity of the seed region was computed as the mean time series of all voxels within the region-of-interest mask. Functional connectivity between the mean time series in the seed region and all the voxels in the brain was then calculated by Pearson correlations. The correlation R values were transformed into Fisher's Z scores in each voxel of the brain. The seed-based correlation method was employed to examine the functional connectivity during rest. The seed region was chosen based on the significant group-by-telomerase activity interaction on the GM volume in the previous structural MRI analysis that is, the right dorsolateral prefrontal cortex DLPFC. The Z-images representing the standardized functional connectivity were entered into the same second-level whole-brain interaction analyses to characterize group differences in the association between functional connectivity with DLPFC and telomerase activity. For each significant brain cluster, the average Z values were derived and included in further correlation analyses to establish the directions of these interactions. To establish the behavioral relevance for each of the above significant functional brain cluster, the average Z values for the heroin users were correlated Pearson correlation with their performance on six behavioral tasks that are well established to measure the following cognitive domains: executive functioning, attentional control, sustained attention, working memory, learning and memory, and visuospatial processing. This task required participants to derive the implicit rules, based on feedback from previous trials, in order to correctly sort cards according to the color, shape or number of stimuli on each card. Dependent measures were the number of correct trials, percentage of perseverative response, percentage of perseverative error and percentage of nonperseverative error. Attentional control was measured using a computerized task based on the classic Eriksen and Eriksen flankers task. There were 60 trials for each of the congruent distracters compatible with central target and incongruent distracters incompatible with central target condition. Dependent measures were rate of accuracy and reaction time for each condition. Sustained attention was measured using the computerized Conners' Continuous Performance Test II, which consisted of trials in which participants were required to remain continuous vigilance in order to correctly press a button in response to targets alphabetical letters , with the exception of non-targets, which were relatively rare. Working memory was measured using a computerized, 2-back version of the n -back test. There were trials in total. Dependent measures were overall accuracy and reaction time. Learning and memory was measured using a computerized, visuospatial version of the paired-associate learning test PAL. If the location of each figure was not recalled correctly, the participant was instructed to try again until the participant achieved perfect recall or until the maximum of 10 trials was reached. There were five sets of blocks: one with three figures, two with five figures and two with eight figures. Dependent measures for the PAL were total number of trials attempted a higher number reflects poorer performance and overall accuracy. There was 30 items on this test. The dependent measure was the total number of correct responses. First, in terms of the association between GM and telomerase activity, a cluster within the right middle frontal gyrus, part of the DLPFC, was more positively associated with telomerase activity for the heroin users, relative to the healthy controls Figure 1a. Corroboratively, a cluster of WM in a nearby brain region of right DLPFC also revealed a significant interaction between group and telomerase activity Figure 1a. Years of education and Hospital Anxiety and Depression Scale scores were included as covariates of no interest. Coordinates are in Montreal Neurological Institute space. Volumetric analyses revealing brain regions with significant interaction between group and telomerase activity, and the corresponding scatter plots that depict correlations within each group. The left side of the brain is shown on the left. The template brain image is the bias-corrected average image from all participants. Coordinates are in MNI space. Having identified the right DLPFC as the location where its structural integrity was compromised by heroin abuse and low telomerase activity, we next sought to characterize the functional connectivity of this region during resting state. An interaction analysis was used to test for brain regions where the association between telomerase activity and functional connectivity with the right DLPFC significantly differed between the heroin users and the healthy controls Table 3. The seed region was chosen as the right dorsolateral prefrontal cortex gray matter cluster identified from the structural brain analyses. In the contrast that revealed brain regions where the slope between telomerase activity and functional connectivity with DLPFC was significantly more positive for the control group compared with the heroin group, four brain regions were identified Figure 2. Specifically, for heroin users there was a negative coupling between DLPFC and OFC and this coupling decreased in proportion to decrease in telomerase activity. For heroin users, the DLPFC-OP coupling shifted from negative to positive coupling as telomerase activity decreased, whereas the coupling was positive and stable for the healthy controls. Connectivity analyses with the right dorsolateral prefrontal cortex DLPFC as the seed region revealing brain regions with significant interaction between group and telomerase activity, and the corresponding scatter plots that depict correlations within each group. Individual points are not presented for reason of clarity. In the reverse contrast that revealed brain regions where the association between telomerase activity and functional connectivity with DLPFC was more positive for the heroin users compared with the controls, a cluster in the right superior temporal gyrus STG was identified Figure 2. In order to explore whether the observed interaction effects between group and telomerase activity were driven by the heroin users being heavier consumers of cigarettes and alcohol, we correlated the number of cigarette and the amount of alcohol consumed each day with the volume amount or connectivity strength of clusters identified from the above interaction analyses. This suggests that the group difference in the association between telomerase activity and brain structure or functional connectivity could not have been driven by the group difference in cigarette and alcohol use. Supplementary Table 1 presents summary statistics for each of the six behavioral tasks, which measured the following cognitive domains: executive functioning WCST , attentional control flankers task , sustained attention Continuous Performance Test , working memory n -back task , learning and memory PAL and visuospatial processing Judgment of Line Orientation test. We correlated the heroin users' behavioral performance with functional brain index in order to establish the behavioral relevance for each significant brain region Table 4. This study aimed to investigate the relationship between heroin use and aging, specifically we examined whether heroin abuse is associated with a deficiency in telomerase activity, and whether such deficiency would interact with heroin use to impact brain systems and functions implicated in aging. Four main results emerged: 1 long-term heroin users had significantly lower telomerase activity, which is an index of cellular aging; 2 low telomerase activity in the heroin users was associated with compromised structural integrity of the right DLPFC; 3 low telomerase activity in the heroin users was associated with an altered pattern of functional connectivity between the right DLPFC and brain regions implicated in heroin abuse and aging; and 4 functional brain regions found to interact with heroin abuse and aging correlated with behavioral performance that are consistent with each of the brain regions' cognitive domain, namely executive functioning, memory and attentional control. The observation that long-term heroin abuse is associated with significantly lower telomerase activity suggests that cellular aging may be accelerated in heroin users, consistent with a previously established hypothesis. Specifically, acute and chronic stress could elevate and alleviate telomerase activity, respectively. It is possible that decreased telomerase activity reflects both pathological reduced cell protection and beneficial reduced need to protect processes. Owing to heroin's deleterious impact on immunologically related biomarkers, 2 it is reasonable to assume that the current observation of lowered telomerase activity in heroin users fits into the pathological model in which heroin abuse exacerbates cellular aging. If lower telomerase activity in heroin users indeed reflects accelerated aging, then heroin abuse and telomerase activity should interact to impact brain systems related to both heroin abuse and aging. Our observation that the heroin users' low telomerase activity was associated with greater DLPFC atrophy was therefore consistent with this prediction. The PFC is a key brain area implicated in the neuropathology of drug addiction. In particular, DLPFC is the likely region that mediates the link between substance abuse and impaired higher-cognitive processes. Resting state functional connectivity is a measure of the intrinsic, spontaneous functional organization of brain systems 58 and is reflective of neuronal metabolic processes. Specifically, it was found that heroin abusers were characterized by deficits in impulse control, 62 , 63 which forms a vital component of executive functioning. This suggests that a greater acceleration of the cellular aging process in the heroin users was associated with more severe atrophy in the DLPFC-OFC functional connectivity. This interpretation is consistent with both the prefrontal theories of drug addiction 55 and the aging literature, which has demonstrated that aging can have a detrimental impact on OFC functions, including reward-based decision-making 66 and learning reversal. The DLPFC-EC coupling correlated with performance on executive functioning, suggesting that the connection between these regions form part of the executive functioning network. There seems to be an intricate relationship between memory and addiction processes at both cellular and brain system levels. Despite prominent atrophy to the hippocampus as a function of increasing age, the EC is relatively resistant to damage from healthy aging. It has been shown that the extent of EC atrophy is predictive of future progression from the healthy to disease state. Two of these brain regions, the OP and the ACC, are part of the several regions implicated in attention and cognitive control processes. The attentional control system in heroin abusers and addiction in general is known to characterize a bias such that an abnormally large attentional focus is put on drug-related stimuli. An explanation for this observation is that the DLPFC-STG coupling denotes a function that was not part of our primary interest for instance, auditory processing, which is a known key function of the STG. The present study consists of several limitations that must be taken into consideration. First, the correlative nature of this study prevents an inference on cause and effect. Although the present findings suggest that heroin abuse may accelerate biological aging, prospective studies are needed to establish the causative mechanisms that mediate heroin abuse and biological aging. Second, telomerase activity was measured via peripheral blood rather than directly from the brain where system level measures were derived and examined with telomerase. Despite the existence of telomerase in neural progenitor cells of the brain, 79 to measure it in vivo is not yet feasible. For this reason, we used peripheral telomerase activity as a solution for measuring cellular aging. Moreover, future studies should adopt a multi-aging molecular biomarker approach to further elucidate the relationship between heroin abuse and aging. Third, only male participants were recruited as female abusers of heroin are less prevalent to their male counterparts. Finally, it is important to test whether the present findings are specific to heroin use or a general pattern observable in people who abuse other substances. Previously documented effects of heroin on age-related immunological biomarkers led us to investigate heroin addiction in the present study. However, a recent study provides important evidence that cocaine abuse could also accelerate aging at the brain system level. Based on a novel integration of peripheral molecular and brain system measures, the present study presents evidence that the long-term heroin abuse is associated with an acceleration of both cellular and brain system aging. Specifically, heroin users were characterized by significantly lower telomerase activity, which interacted with heroin use to impact age-related brain systems and functions. These findings constitutes a significant contribution to our understanding of how heroin abuse influences the brain and body, and lays an important foundation for studies that seek to further characterize the mechanisms that mediate substance abuse and biological aging. Understanding such mechanisms raises the possibility of reversing the detrimental effects of drug addiction, and ultimately enriches past abusers with a greater potential to endeavor in life. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This section collects any data citations, data availability statements, or supplementary materials included in this article. As a library, NLM provides access to scientific literature. Transl Psychiatry. Find articles by G L F Cheng. Find articles by H Zeng. Find articles by M-K Leung. Find articles by H-J Zhang. Find articles by B W M Lau. Find articles by Y-P Liu. Find articles by G-X Liu. Find articles by P C Sham. Find articles by C C H Chan. Find articles by K-F So. Find articles by T M C Lee. Mean s. T P -value Age years Open in a new tab. Abbreviations: B, bilateral; L, left; R, right. Click here for additional data file. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel. Years of education a. Estimated intelligence RPM b. Cigarette per day c. Drink per day c. Duration of previous heroin use months. Association between telomerase activity and GM. Association between telomerase activity and WM. Superior occipitoparietal cortex. Number of correct trials.

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